自噬相关基因Beclin 1在子宫腺肌病中的作用及缺氧对Beclin 1影响的研究
|
摘要
子宫腺肌病是正常位置的子宫内膜腺体和间质向肌壁内良性侵入的一种妇科疾病,伴随周围肌层的代偿性肥大和增生。发病率不断上升,多发生于40-50岁的经产妇女,其典型症状为盆腔疼痛和异常子宫出血。目前多数研究者认为子宫腺肌病是子宫内膜基底层向肌层内陷生长、迁移播散的结果。保守治疗包括子宫动脉栓塞、激素治疗(孕激素、持续口服避孕药、抗雌激素制剂和GnRHa)和超声聚焦等,但效果有限。子宫切除术是严重子宫腺肌病患者的选择和最终明确诊断的方法。子宫腺肌病的病因、发病机制和更好的保守治疗手段目前仍不明了,需进一步探究。
自噬以自噬体和自噬溶酶体的聚集为特征,被认为是一种区别于凋亡的Ⅱ型程序性细胞死亡。Beclin 1是酵母自噬相关基因的哺乳细胞同源基因,Beclin 1基因定位于染色体17q21,是自噬的直接执行者。在75%的卵巢癌,50%的乳腺癌和40%的前列腺癌中等位基因缺失,已被确定为一个新的候选抑癌基因。Beclin 1蛋白是自噬与凋亡重要的汇合点。Beclin 1具有BH3结构域,中央卷曲螺旋结构域(CCD)和进化上保守的结构域(ECD)。Bcl-2与Beclin 1的BH3结构域相互作用。
缺氧诱导因子-1α(HIF-1α)是细胞应激缺氧时所产生的转录激活因子。研究显示HIF-1α在很多正常组织中不表达,而在人类肿瘤中高表达。HIF-1α激活代谢和致病途径,与肿瘤的血管生成、生长、侵袭和转移有关。HIF-1α在恶性肿瘤进展中的功能可分为以下几种：(1)促进肿瘤细胞离散；(2)促进自分泌移动因子及各种生长因子的表达；(3)提高基质金属蛋白酶家族的表达,促进肿瘤细胞对细胞外间质的降解而发生侵袭；(4)促进新生血管生成。可见缺氧贯穿于肿瘤整个生长过程,赋予肿瘤细胞不断生长、恶性演进和转移的潜能,HIF-1α与肿瘤的发生、发展密切相关。
研究显示自噬与缺氧相关。缺氧能诱导拥有完整凋亡机制的肿瘤细胞发生自噬性细胞死亡。在小鼠胚胎成纤维细胞中,HIF-1诱导BNIP3表达,其中BNIP3能激发线粒体发生选择性的自噬,这个过程需要HIF-1依赖的BNIP3的表达和Beclin 1的固有表达,延长细胞缺氧的时间后,线粒体自噬是阻止活性氧过多产生和细胞死亡增加的适应性代谢反应。细胞缺氧培养24小时后BNIP3和BNIP3L表达上调,而流式细胞技术检测不到凋亡,由此显示BNIP3和BNIP3L能促进细胞自噬而不是凋亡。有研究显示Beclin 1和HIF-1a是重要的预后因子。
目前尚未见Beclin 1与子宫腺肌病发生发展关系的报道及Beclin 1与HIF-1a在子宫腺肌病相关性的报道。为明确Beclin 1在子宫腺肌病发生发展中的作用及缺氧对其的影响,本文利用免疫组化、RT-PCR.蛋白免疫印迹和细胞培养等技术从以下几个方面进行研究：1. Beclin 1在子宫腺肌病在位内膜中的表达及其临床意义；2. Beclin 1和HIF-1α在子宫腺肌病在位内膜、病灶中的表达、临床意义及相关性研究；3. Beclin 1在子宫腺肌病在位内膜间质细胞中的表达及缺氧对其的影响。
第一部分Beclin 1在子宫腺肌病在位内膜中的表达及其临床意义
目的：探讨自噬相关基因Beclin 1在子宫腺肌病在位内膜中的表达及其与临床特征的相关性。
方法：采用RT-PCR和蛋白免疫印迹技术检测30例子宫腺肌病在位内膜组织中Beclin 1 mRNA及蛋白的表达,并以32例正常子宫内膜组织作为对照。
结果：1.通过灰度分析,子宫腺肌病组Beclin 1 mRNA相对表达量为(0.71±0.10),明显低于对照组(0.93±0.10)(P<0.001)。子宫腺肌病组Beclin 1蛋白相对表达量为(0.82±0.22),明显低于对照组(1.22±0.36)(P<0.001)。2.内膜Beclin 1蛋白表达水平与血清中CA125水平呈负相关(n=62,r2=0.094,P=0.015),与盆腔疼痛亦呈负相关(n=62,r2=0.293,P=0.000)。
第二部分Beclin 1和HIF-1α在子宫腺肌病在位内膜、病灶中的表达、临床意义及相关性研究
目的：探讨Beclin 1和HIF-1α在子宫腺肌病在位内膜、病灶中的表达、临床意义及其相关性。
方法：采用免疫组化方法检测53例子宫腺肌病在位内膜组织中Beclin 1和HIF-1α的表达,并以57例正常子宫内膜组织作为对照,同时检测30例病灶中Beclin1和HIF-1α的表达。
结果：1. Beclin 1蛋白在子宫内膜组织标本中腺细胞和间质细胞中均有表达,其表达主要见于细胞浆内。HIF-1α蛋白在子宫内膜组织标本中腺细胞和间质细胞中均有表达,其表达细胞浆、细胞核均有表达,在腺肌病病灶中以腺上皮表达为主,其表达主要见于细胞浆内。2.在位腺肌病组Beclin 1表达(3.62±2.69)显著低于对照组Beclin 1表达(10.32±4.12)(P<0.01)。腺肌病病灶组Beclin 1表达(0.27±0.52)显著低于在位腺肌病组及对照组(P<0.01)。在位腺肌病组HIF-1α表达(8.70±2.13)显著高于对照组HIF-1α表达(4.49±2.55)(P<0.01)。腺肌病病灶组HIF-1α表达(7.97±2.54)显著高于对照组(P<0.01),与在位腺肌病组之间无显著性差异。腺肌病组Beclin 1表达增殖期与分泌期之间无显著性差异,对照组Beclin 1表达增殖期与分泌期之间无显著性差异。增殖期Beclin 1表达腺肌病组与对照组间有显著性差异(P<0.01)。分泌期Beclin 1表达腺肌病组与对照组间有显著性差异(P<0.01)。腺肌病组HIF-1α表达增殖期与分泌期之间无显著性差异,对照组HIF-1α表达增殖期与分泌期之间有显著性差异(P<0.01)。增殖期HIF-1α表达腺肌病组显著高于对照组(P<0,01)。分泌期HIF-1α表达腺肌病组与对照组间无显著性差异。腺肌病病灶组Beclin 1表达显著低于腺肌病增殖期组、腺肌病分泌期组、对照增殖期组及对照分泌期组(P<0.01)。腺肌病病灶组Beclin 1表达显著低于HIF-1α表达(P<0.01)。腺肌病病灶组HIF-1α表达显著高于对照增殖期组(P<0.01),与腺肌病增殖期组、腺肌病分泌期组及对照分泌期组之间均无显著性差异。3.Beclin 1表达水平与血清CA125水平呈负相关(n=140,r2=0.232,P=0.000),与盆腔疼痛(VAS评分)亦呈负相关(n=140,r2=0.508,P=0.000)。4.HIF-1α表达水平与血清CA125水平呈正相关(n=140,r2=0.268,P=0.000)。HIF-1α表达水平与盆腔疼痛(VAS评分)亦呈正相关(n=140,r2=0.574,P=0.000)。5.Beclin 1表达水平与HIF-1α表达水平呈负相关(n=140,r2=0.201,P=0.000)。
第三部分Beclin 1在子宫腺肌病在位内膜间质细胞中的表达及缺氧对其的影响
目的：探讨Beclin 1在子宫腺肌病子宫内膜间质细胞的表达及缺氧对其的影响,并对缺氧培养24小时后Beclin 1表达水平与其增殖、迁移能力进行相关性分析。
方法：对子宫内膜间质细胞进行原代培养并进行缺氧24小时处理,通过RT-PCR、蛋白免疫印迹技术、MTT及细胞迁移实验观察其增殖、迁移能力变化以及Beclin 1表达变化。
结果：1.通过灰度分析,子宫腺肌病组Beclin 1 mRNA相对表达量为(0.72±0.19),明显低于对照组(1.17±0.44)(P<0.05)。子宫腺肌病组Beclin 1蛋白相对表达量为(0.20±0.03),明显低于对照组(0.71±0.12)(P<0.01)。2.MTT比色法发现,腺肌病常氧培养组OD值为(0.33±0.03),明显高于对照常氧培养组(0.24±0.04)(P<0.01),腺肌病缺氧培养组OD值为(0.46±0.03),明显高于腺肌病常氧培养组(0.33±0.03)(P<0.01),对照缺氧培养组OD值为(0.20±0.02),明显低于对照常氧培养组(0.24±0.04)(P<0.05)。3.细胞迁移实验发现,腺肌病常氧培养组细胞迁移距离为(0.31±0.02mm),明显高于对照常氧培养组(0.28±0.02mm)(P<0.01),腺肌病缺氧培养组细胞迁移距离为(0.37±0.02mm),明显高于腺肌病常氧培养组(0.31±0.02mm)(P<0.01),对照缺氧培养组细胞迁移距离为(0.14±0.02mm),明显低于对照常氧培养组(0.28±0.02mm)(P<0.01)。4.腺肌病缺氧组Beclin 1蛋白相对表达量为(0.30±0.01),明显低于腺肌病常氧组(0.49±0.01)(P<0.01)。腺肌病缺氧组Beclin 1蛋白相对表达量为(0.30±0.01),明显低于对照缺氧组(0.65±0.02)(P<0.01)。对照缺氧组Beclin 1蛋白相对表达量为(0.65±0.02)与对照常氧组(0.70±0.03)之间无统计学差异(P>0.05)。腺肌病常氧组Beclin 1蛋白相对表达量为(0.49±0.01),明显低于对照常氧组(0.70±0.03)(P<0.01)。5.通过Pearson相关分析发现,腺肌病在位内膜间质细胞缺氧培养24小时后Beclin 1蛋白表达水平与MTT所测的OD值,迁移距离呈明显的负相关关系(r2=0.564,0.469；P=0.004,0.042)。
结论
1. Beclin 1蛋白定位于子宫内膜腺细胞和间质细胞。子宫腺肌病在位内膜和病灶Beclin 1表达均下调,Beclin 1蛋白表达与血清CA125水平和盆腔疼痛呈负相关。Beclin 1可能在子宫腺肌病的发病和进展中发挥作用。
2.HIF-1α蛋白定位于子宫内膜腺细胞和间质细胞,病灶以腺上皮表达为主。子宫腺肌病在位内膜和病灶HIF-1α表达均上调,HIF-1α表达水平与血清CA125水平及盆腔疼痛呈正相关。HIF-1α可能在子宫腺肌病的发病和进展中发挥作用。
3. Beclin 1表达水平与HIF-1α表达水平呈负相关。HIF-1α表达越高、Beclin 1表达越低,可能预示着子宫腺肌病病情越严重。
4.腺肌病在位内膜间质细胞增殖和迁移能力明显高于正常对照组。腺肌病在位内膜间质细胞缺氧培养24小时后增殖和迁移能力明显高于腺肌病常氧培养组。对照组在位内膜间质细胞缺氧培养24小时后增殖和迁移能力明显低于对照常氧培养组。缺氧使腺肌症在位内膜间质细胞拥有更强的增殖和迁移能力。5.腺肌病在位内膜间质细胞缺氧培养24小时后Beclin 1蛋白表达明显低于腺肌病常氧培养组。对照缺氧组Beclin 1蛋白表达与对照常氧组之间无统计学差异。6.腺肌病在位内膜间质细胞缺氧培养24小时后Beclin 1蛋白表达水平与MTT所测的OD值,迁移距离呈明显的负相关关系,缺氧诱导Beclin1变化可能在子宫腺肌病致病过程中发挥着作用。
Adenomyosis is a nontumorous condition characterized by the presence of ectopic endometrium in the myometrium with hyperplasia of adjacent smooth muscle. This probably occurs by invagination of the basalis endometrium into the myometrium. The process of invagination and intramyometrial dissemination may be facilitated by the non-cyclic, anti-apoptotic activity of the basalis associated with relative hyper-oestrogenic states. Most cases of adenomyosis are discovered in multiparous women during the transitional years (40-50 years). It can result in debilitating pelvic pain (both cyclical and non-cyclical) and abnormal uterine bleeding. Magnetic resonance imaging establishes the diagnosis in cases of equivocal or nondiagnostic ultrasounds. Definite diagnosis and treatment of adenomyosis are obtained by hysterectomy. Vessel embolization, hormonal treatments (progestagens, continuous oral contraceptive pills, anti-estrogens and gonadotrophin-releasing hormone (GnRH) analogues) and high-intensity focused ultrasound can be tried in infertile women, however, the effect of these treatments is limited. Surgical extirpation has been the best therapeutic option for symptom relief so far. The etiology, pathogenesis and the better conservative treatment are still unknown to date.
Autophagy, characterized by autophagic vacuoles accumulating, is considered as programmed cell death typeⅡwhich is known as autophagic cell death. Autophagy is involved not only in the balance between protein synthesis and degradation but also in the balance between cell survival and cell death. Beclin 1, a haploinsufficient tumor suppressor gene on chromosome 17q21 and a mammalian homolog of yeast Atg6/Vps30, is monoallelically deleted in up to 75% of ovarian cancers,50% of breast cancers and 40% of prostate cancers. Reduction of Beclin 1 is also observed in other cancers including human brain tumors and cervical carcinoma. Overexpression of Beclin 1 not only promotes nutrient deprivation-induced autophagy but also inhibits clonigenicity and tumorigenesis in human breast carcinoma cells. Structural studies display that Beclin 1 has a BH3-only domain, a central coiled-coil domain (CCD), and an evolutionarily conserved domain (ECD). The ECD of Beclin 1 is required for Vps34 binding, autophagy and tumor suppression. The BH3-only domain can interact with Bcl-2 and Bcl-XL. The Beclin 1 protein is an important convergence point of autophagy and apoptosis; it interacts with the anti-apoptotic and anti-autophagic Bcl-2 protein.
Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-la subunit. HIF-1a is a transcriptional factor that regulates genes involved in response to hypoxia and promotes neoangiogenesis, which are considered essential for tumor growth and progression. Under normoxic conditions it is constitutively produced and degraded by the ubiquitin-proteasome system. But under hypoxic conditions it becomes stabilized.
Hypoxia is associated with autophagy. Mitochondrial autophagy is induced by hypoxia, this process requires the HIF-1-dependent expression of BNIP3 and the constitutive expression of Beclin-1. In cells subjected to prolonged hypoxia, mitochondrial autophagy is an adaptive metabolic response which is necessary to prevent increased levels of reactive oxygen species and cell death.
Researchers have launched a new area of febrile investigations on the autophagy-related gene Beclin 1. However, no study has previously shown the contribution of Beclin 1 to adenomyosis and the correlation between Beclin 1 and HIF-1a. This study investigated the expression of Beclin 1 in human adenomyosis, its association with clinical characteristics and its regulation in endometrial stromal cells by hypoxia. Cell cultures, immunohistochemical technique, RT-PCR, and western blotting were used in this study. The study was divided into three parts:1. Decreased expression of Beclin 1 in eutopic endometrium of women with adenomyosis and its association with clinical characteristics.2. Beclin 1, HIF-1αexpression in eutopic endometrium and adenomyotic foci of women with adenomyosis and the correlation between Beclin 1 and HIF-1α.3. Beclin 1 expression in endometrial stromal cells from adenomyois and its regulation by hypoxia.
Part one Decreased expression of Beclin 1 in eutopic endometrium of women with adenomyosis and its association with clinical characteristics.
Objective:To investigate whether Beclin 1 expression is altered in eutopic endometrium of women with adenomyosis.
Methods:We collected tissue samples from the eutopic endometria of 30 women with adenomyosis and 32 healthy women undergoing surgery for benign indications. Beclin 1 expression of eutopic endometrial tissues was assessed by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis.
Results:Beclin 1 mRNA expression level in tissue samples of women with adenomyosis (0.71±0.10) was significantly lower than that of control (0.93±0.10) (P<0.001). The average level of Beclin 1 protein expression of women with adenomyosis in tissue samples (0.82±0.22) was also significantly lower than that of control (1.22±0.36) (P<0.001). Beclin 1 protein expression in eutopic endometrial tissues was negatively correlated with serum CA125 (r=-0.307, P=0.015), and pelvic pain (r=-0.542, P=0.000).
Part two Beclin 1, HIF-la expression in eutopic endometrium and adenomyotic foci of women with adenomyosis and the correlation between Beclin 1 and HIF-1α.
Objective:To investigate whether Beclin 1 and HIF-la were expressed in eutopic endometrium and adenomyotic foci of women with adenomyosis and the correlation between Beclin 1 and HIF-1α.
Methods: Beclin 1 and HIF-1αexpression were assessed by immunohistochemistry.
Results:1. Beclin 1 immunoreactive staining was present in the cytoplasm of glandular epithelial and stromal cells. HIF-1αimmunoreactive staining was present in the cytoplasm and nucleus of glandular epithelial and stromal cells in eutopic endometrium, mainly in the cytoplasm of glandular epithelial cells in adenomyotic foci. 2. Beclin 1 expression in eutopic endometrium of adenomyosis (3.62±2.69) was significantly lower than that in control (10.32±4.12)(P<0.01). Beclin 1 expression in adenomyotic foci (0.27±0.52) was significantly lower than that in eutopic endometrium of adenomyosis or in control (P<0.01). HIF-1αexpression in eutopic endometrium of adenomyosis (8.70±2.13) was significantly higher than that in control (4.49±2.55)(P<0.01). HIF-1αexpression in adenomyotic foci(7.97±2.54)was significantly higher than that in control(P<0.01), and not different from that in eutopic endometrium of adenomyosis. There were no differences of Beclin 1 expression between proliferative period and secretory period in adenomyosis or control. Beclin 1 expression of proliferative period or secretory period in adenomyosis was significantly lower than that in control(P<0.01). There were no differences of HIF-1αbetween proliferative period and secretory period in adenomyosis. There were differences of HIF-1αexpression between proliferative period and secretory period in control (P<0.01). HIF-1αexpression of proliferative period in adenomyosis was significantly higher than that in control(P<0.01). There were no differences of HIF-1αbetween adenomyosis and control in secretory period. Beclin 1 expression in adenomyotic foci was significantly lower than HIF-1αexpression(P<0.01).3. Beclin 1 expression was negatively correlated with serum CA125 (n=140, r2=0.232, P=0.000), and pelvic pain (n=140, r2=0.508, P=0.000). HIF-1αexpression was positively correlated with serum CA125 (n=140, r2 =0.268, P=0.000), and pelvic pain (n=140, r2=0.574, P=0.000). Beclin 1 expression was negatively correlated with HIF-1αexpression (n=140, r2=0.201, P=0.000).
Part three Beclin 1 expression in endometrial stromal cells from adenomyois and its regulation by hypoxia
Objective:To investigate whether Beclin 1 expression is altered in endometrial stromal cells from adenomyosis and its regulation by hypoxia.
Methods:Beclin 1 expression was assessed by RT-PCR and western blot analysis. The capability of proliferation and metastasis of endometrial stromal cells were assessed by MTT and migration assay.
Results:1. Beclin 1 mRNA expression level in cultured stromal cells of women with adenomyosis (0.72±0.19) was significantly lower than that of without (1.17±0.44) (P<0.05). Beclin 1 protein expression of women with adenomyosis in cultured stromal cells (0.20±0.03) was significantly lower compared with that of control (0.71±0.12)(P<0.01).2. The growth rate by MTT assay and the migrated distance of endometrial stromal cells in adenomyosis (0.33±0.03,0.31±0.02mm, respectively) were significantly higher than those in the control group (0.24±0.04,0.28±0.02mm, respectively) (P<0.01). The growth rate by MTT assay and the migrated distance of endometrial stromal cells after 24h hypoxia in adenomyosis (0.46±0.03,0.37±0.02mm, respectively) were significantly higher than those under normoxia in adenomyosis (0.33±0.03,0.31±0.02mm, respectively) (P<0.01). The growth rate by MTT assay and the migrated distance of endometrial stromal cells after 24h hypoxia in control (0.20±0.02,0.14±0.02mm, respectively) were significantly lower than those under normoxia in control (0.24±0.04,0.28±0.02mm, respectively) (P<0.05).3. Beclin 1 protein expression of endometrial stromal cells after 24h hypoxia in adenomyosis (0.30±0.01) was significantly lower than that in adenomyosis under normoxia (0.49±0.01) (P<0.01)。Beclin 1 protein expression of endometrial stromal cells after 24h hypoxia in adenomyosis (0.30±0.01) was significantly lower than that in control under hypoxia (0.65±0.02) (P<0.01)。Beclin 1 protein expression of endometrial stromal cells from in adenomyosis (0.49±0.01) was significantly lower than that in control (0.70±0.03) (P<0.01)。There was no difference between the control group under hypoxia (0.65±0.02) and the control group under normoxia (0.70±0.03).4. In endometrial stromal cells after 24h hypoxia from adenomyosis, Beclin 1 protein level was negatively related with the cell proliferation and migration(r2=0.564,0.469;P=0.004,0.042).
Conclusion:
1. Beclin 1 immunoreactive staining was present in the cytoplasm of glandular epithelial and stromal cells. Expression of Beclin 1 was decreased in eutopic endometrium and adenomyotic foci of women with adenomyosis, and the Beclin 1 expression was negatively correlated with the serum CA125 and pelvic pain, which might be related to the pathogenesis and progress of adenomyosis.
2. HIF-1αimmunoreactive staining was present in the cytoplasm and nucleus of glandular epithelial and stromal cells in eutopic endometrium, mainly in the cytoplasm of glandular epithelial cells in adenomyotic foci. Expression of HIF-1αwas increased in eutopic endometrium and adenomyotic foci of women with adenomyosis. Its expression level was positively correlated with the serum CA125 and pelvic pain, which might be related to the pathogenesis and progress of adenomyosis.
3. Beclin 1 expression was negatively correlated with HIF-1αexpression. If the expression of HIF-1αis higher and the expression of Beclin 1 is lower, the adenomyosis is more severe.
4. The growth rate and the migrated distance of endometrial stromal cells in adenomyosis were significantly higher than those in control. The growth rate and the migrated distance of endometrial stromal cells after 24h hypoxia in adenomyosis were significantly higher than those under normoxia in adenomyosis. The endometrial stromal cells of adenomyosis had the greater capacity of proliferation and migration induced by hypoxia.
5. Beclin 1 protein expression of endometrial stromal cells under hypoxia in adenomyosis was significantly lower than that under normoxia in adenomyosis。Beclin 1 protein expression of endometrial stromal cells under hypoxia in adenomyosis was significantly lower than that under hypoxia in control.
6. In endometrial stromal cells after 24h hypoxia from adenomyosis, Beclin 1 protein level was negatively related with the cell proliferation and migration, hypoxia-induced change of Beclin 1 might be related to the pathogenesis and progress of adenomyosis.
自噬以自噬体和自噬溶酶体的聚集为特征,被认为是一种区别于凋亡的Ⅱ型程序性细胞死亡。Beclin 1是酵母自噬相关基因的哺乳细胞同源基因,Beclin 1基因定位于染色体17q21,是自噬的直接执行者。在75%的卵巢癌,50%的乳腺癌和40%的前列腺癌中等位基因缺失,已被确定为一个新的候选抑癌基因。Beclin 1蛋白是自噬与凋亡重要的汇合点。Beclin 1具有BH3结构域,中央卷曲螺旋结构域(CCD)和进化上保守的结构域(ECD)。Bcl-2与Beclin 1的BH3结构域相互作用。
缺氧诱导因子-1α(HIF-1α)是细胞应激缺氧时所产生的转录激活因子。研究显示HIF-1α在很多正常组织中不表达,而在人类肿瘤中高表达。HIF-1α激活代谢和致病途径,与肿瘤的血管生成、生长、侵袭和转移有关。HIF-1α在恶性肿瘤进展中的功能可分为以下几种：(1)促进肿瘤细胞离散；(2)促进自分泌移动因子及各种生长因子的表达；(3)提高基质金属蛋白酶家族的表达,促进肿瘤细胞对细胞外间质的降解而发生侵袭；(4)促进新生血管生成。可见缺氧贯穿于肿瘤整个生长过程,赋予肿瘤细胞不断生长、恶性演进和转移的潜能,HIF-1α与肿瘤的发生、发展密切相关。
研究显示自噬与缺氧相关。缺氧能诱导拥有完整凋亡机制的肿瘤细胞发生自噬性细胞死亡。在小鼠胚胎成纤维细胞中,HIF-1诱导BNIP3表达,其中BNIP3能激发线粒体发生选择性的自噬,这个过程需要HIF-1依赖的BNIP3的表达和Beclin 1的固有表达,延长细胞缺氧的时间后,线粒体自噬是阻止活性氧过多产生和细胞死亡增加的适应性代谢反应。细胞缺氧培养24小时后BNIP3和BNIP3L表达上调,而流式细胞技术检测不到凋亡,由此显示BNIP3和BNIP3L能促进细胞自噬而不是凋亡。有研究显示Beclin 1和HIF-1a是重要的预后因子。
目前尚未见Beclin 1与子宫腺肌病发生发展关系的报道及Beclin 1与HIF-1a在子宫腺肌病相关性的报道。为明确Beclin 1在子宫腺肌病发生发展中的作用及缺氧对其的影响,本文利用免疫组化、RT-PCR.蛋白免疫印迹和细胞培养等技术从以下几个方面进行研究：1. Beclin 1在子宫腺肌病在位内膜中的表达及其临床意义；2. Beclin 1和HIF-1α在子宫腺肌病在位内膜、病灶中的表达、临床意义及相关性研究；3. Beclin 1在子宫腺肌病在位内膜间质细胞中的表达及缺氧对其的影响。
第一部分Beclin 1在子宫腺肌病在位内膜中的表达及其临床意义
目的：探讨自噬相关基因Beclin 1在子宫腺肌病在位内膜中的表达及其与临床特征的相关性。
方法：采用RT-PCR和蛋白免疫印迹技术检测30例子宫腺肌病在位内膜组织中Beclin 1 mRNA及蛋白的表达,并以32例正常子宫内膜组织作为对照。
结果：1.通过灰度分析,子宫腺肌病组Beclin 1 mRNA相对表达量为(0.71±0.10),明显低于对照组(0.93±0.10)(P<0.001)。子宫腺肌病组Beclin 1蛋白相对表达量为(0.82±0.22),明显低于对照组(1.22±0.36)(P<0.001)。2.内膜Beclin 1蛋白表达水平与血清中CA125水平呈负相关(n=62,r2=0.094,P=0.015),与盆腔疼痛亦呈负相关(n=62,r2=0.293,P=0.000)。
第二部分Beclin 1和HIF-1α在子宫腺肌病在位内膜、病灶中的表达、临床意义及相关性研究
目的：探讨Beclin 1和HIF-1α在子宫腺肌病在位内膜、病灶中的表达、临床意义及其相关性。
方法：采用免疫组化方法检测53例子宫腺肌病在位内膜组织中Beclin 1和HIF-1α的表达,并以57例正常子宫内膜组织作为对照,同时检测30例病灶中Beclin1和HIF-1α的表达。
结果：1. Beclin 1蛋白在子宫内膜组织标本中腺细胞和间质细胞中均有表达,其表达主要见于细胞浆内。HIF-1α蛋白在子宫内膜组织标本中腺细胞和间质细胞中均有表达,其表达细胞浆、细胞核均有表达,在腺肌病病灶中以腺上皮表达为主,其表达主要见于细胞浆内。2.在位腺肌病组Beclin 1表达(3.62±2.69)显著低于对照组Beclin 1表达(10.32±4.12)(P<0.01)。腺肌病病灶组Beclin 1表达(0.27±0.52)显著低于在位腺肌病组及对照组(P<0.01)。在位腺肌病组HIF-1α表达(8.70±2.13)显著高于对照组HIF-1α表达(4.49±2.55)(P<0.01)。腺肌病病灶组HIF-1α表达(7.97±2.54)显著高于对照组(P<0.01),与在位腺肌病组之间无显著性差异。腺肌病组Beclin 1表达增殖期与分泌期之间无显著性差异,对照组Beclin 1表达增殖期与分泌期之间无显著性差异。增殖期Beclin 1表达腺肌病组与对照组间有显著性差异(P<0.01)。分泌期Beclin 1表达腺肌病组与对照组间有显著性差异(P<0.01)。腺肌病组HIF-1α表达增殖期与分泌期之间无显著性差异,对照组HIF-1α表达增殖期与分泌期之间有显著性差异(P<0.01)。增殖期HIF-1α表达腺肌病组显著高于对照组(P<0,01)。分泌期HIF-1α表达腺肌病组与对照组间无显著性差异。腺肌病病灶组Beclin 1表达显著低于腺肌病增殖期组、腺肌病分泌期组、对照增殖期组及对照分泌期组(P<0.01)。腺肌病病灶组Beclin 1表达显著低于HIF-1α表达(P<0.01)。腺肌病病灶组HIF-1α表达显著高于对照增殖期组(P<0.01),与腺肌病增殖期组、腺肌病分泌期组及对照分泌期组之间均无显著性差异。3.Beclin 1表达水平与血清CA125水平呈负相关(n=140,r2=0.232,P=0.000),与盆腔疼痛(VAS评分)亦呈负相关(n=140,r2=0.508,P=0.000)。4.HIF-1α表达水平与血清CA125水平呈正相关(n=140,r2=0.268,P=0.000)。HIF-1α表达水平与盆腔疼痛(VAS评分)亦呈正相关(n=140,r2=0.574,P=0.000)。5.Beclin 1表达水平与HIF-1α表达水平呈负相关(n=140,r2=0.201,P=0.000)。
第三部分Beclin 1在子宫腺肌病在位内膜间质细胞中的表达及缺氧对其的影响
目的：探讨Beclin 1在子宫腺肌病子宫内膜间质细胞的表达及缺氧对其的影响,并对缺氧培养24小时后Beclin 1表达水平与其增殖、迁移能力进行相关性分析。
方法：对子宫内膜间质细胞进行原代培养并进行缺氧24小时处理,通过RT-PCR、蛋白免疫印迹技术、MTT及细胞迁移实验观察其增殖、迁移能力变化以及Beclin 1表达变化。
结果：1.通过灰度分析,子宫腺肌病组Beclin 1 mRNA相对表达量为(0.72±0.19),明显低于对照组(1.17±0.44)(P<0.05)。子宫腺肌病组Beclin 1蛋白相对表达量为(0.20±0.03),明显低于对照组(0.71±0.12)(P<0.01)。2.MTT比色法发现,腺肌病常氧培养组OD值为(0.33±0.03),明显高于对照常氧培养组(0.24±0.04)(P<0.01),腺肌病缺氧培养组OD值为(0.46±0.03),明显高于腺肌病常氧培养组(0.33±0.03)(P<0.01),对照缺氧培养组OD值为(0.20±0.02),明显低于对照常氧培养组(0.24±0.04)(P<0.05)。3.细胞迁移实验发现,腺肌病常氧培养组细胞迁移距离为(0.31±0.02mm),明显高于对照常氧培养组(0.28±0.02mm)(P<0.01),腺肌病缺氧培养组细胞迁移距离为(0.37±0.02mm),明显高于腺肌病常氧培养组(0.31±0.02mm)(P<0.01),对照缺氧培养组细胞迁移距离为(0.14±0.02mm),明显低于对照常氧培养组(0.28±0.02mm)(P<0.01)。4.腺肌病缺氧组Beclin 1蛋白相对表达量为(0.30±0.01),明显低于腺肌病常氧组(0.49±0.01)(P<0.01)。腺肌病缺氧组Beclin 1蛋白相对表达量为(0.30±0.01),明显低于对照缺氧组(0.65±0.02)(P<0.01)。对照缺氧组Beclin 1蛋白相对表达量为(0.65±0.02)与对照常氧组(0.70±0.03)之间无统计学差异(P>0.05)。腺肌病常氧组Beclin 1蛋白相对表达量为(0.49±0.01),明显低于对照常氧组(0.70±0.03)(P<0.01)。5.通过Pearson相关分析发现,腺肌病在位内膜间质细胞缺氧培养24小时后Beclin 1蛋白表达水平与MTT所测的OD值,迁移距离呈明显的负相关关系(r2=0.564,0.469；P=0.004,0.042)。
结论
1. Beclin 1蛋白定位于子宫内膜腺细胞和间质细胞。子宫腺肌病在位内膜和病灶Beclin 1表达均下调,Beclin 1蛋白表达与血清CA125水平和盆腔疼痛呈负相关。Beclin 1可能在子宫腺肌病的发病和进展中发挥作用。
2.HIF-1α蛋白定位于子宫内膜腺细胞和间质细胞,病灶以腺上皮表达为主。子宫腺肌病在位内膜和病灶HIF-1α表达均上调,HIF-1α表达水平与血清CA125水平及盆腔疼痛呈正相关。HIF-1α可能在子宫腺肌病的发病和进展中发挥作用。
3. Beclin 1表达水平与HIF-1α表达水平呈负相关。HIF-1α表达越高、Beclin 1表达越低,可能预示着子宫腺肌病病情越严重。
4.腺肌病在位内膜间质细胞增殖和迁移能力明显高于正常对照组。腺肌病在位内膜间质细胞缺氧培养24小时后增殖和迁移能力明显高于腺肌病常氧培养组。对照组在位内膜间质细胞缺氧培养24小时后增殖和迁移能力明显低于对照常氧培养组。缺氧使腺肌症在位内膜间质细胞拥有更强的增殖和迁移能力。5.腺肌病在位内膜间质细胞缺氧培养24小时后Beclin 1蛋白表达明显低于腺肌病常氧培养组。对照缺氧组Beclin 1蛋白表达与对照常氧组之间无统计学差异。6.腺肌病在位内膜间质细胞缺氧培养24小时后Beclin 1蛋白表达水平与MTT所测的OD值,迁移距离呈明显的负相关关系,缺氧诱导Beclin1变化可能在子宫腺肌病致病过程中发挥着作用。
Adenomyosis is a nontumorous condition characterized by the presence of ectopic endometrium in the myometrium with hyperplasia of adjacent smooth muscle. This probably occurs by invagination of the basalis endometrium into the myometrium. The process of invagination and intramyometrial dissemination may be facilitated by the non-cyclic, anti-apoptotic activity of the basalis associated with relative hyper-oestrogenic states. Most cases of adenomyosis are discovered in multiparous women during the transitional years (40-50 years). It can result in debilitating pelvic pain (both cyclical and non-cyclical) and abnormal uterine bleeding. Magnetic resonance imaging establishes the diagnosis in cases of equivocal or nondiagnostic ultrasounds. Definite diagnosis and treatment of adenomyosis are obtained by hysterectomy. Vessel embolization, hormonal treatments (progestagens, continuous oral contraceptive pills, anti-estrogens and gonadotrophin-releasing hormone (GnRH) analogues) and high-intensity focused ultrasound can be tried in infertile women, however, the effect of these treatments is limited. Surgical extirpation has been the best therapeutic option for symptom relief so far. The etiology, pathogenesis and the better conservative treatment are still unknown to date.
Autophagy, characterized by autophagic vacuoles accumulating, is considered as programmed cell death typeⅡwhich is known as autophagic cell death. Autophagy is involved not only in the balance between protein synthesis and degradation but also in the balance between cell survival and cell death. Beclin 1, a haploinsufficient tumor suppressor gene on chromosome 17q21 and a mammalian homolog of yeast Atg6/Vps30, is monoallelically deleted in up to 75% of ovarian cancers,50% of breast cancers and 40% of prostate cancers. Reduction of Beclin 1 is also observed in other cancers including human brain tumors and cervical carcinoma. Overexpression of Beclin 1 not only promotes nutrient deprivation-induced autophagy but also inhibits clonigenicity and tumorigenesis in human breast carcinoma cells. Structural studies display that Beclin 1 has a BH3-only domain, a central coiled-coil domain (CCD), and an evolutionarily conserved domain (ECD). The ECD of Beclin 1 is required for Vps34 binding, autophagy and tumor suppression. The BH3-only domain can interact with Bcl-2 and Bcl-XL. The Beclin 1 protein is an important convergence point of autophagy and apoptosis; it interacts with the anti-apoptotic and anti-autophagic Bcl-2 protein.
Hypoxia-inducible factor 1 (HIF-1) activates transcription of genes encoding glucose transporters, glycolytic enzymes, and vascular endothelial growth factor. HIF-1 transcriptional activity is determined by regulated expression of the HIF-la subunit. HIF-1a is a transcriptional factor that regulates genes involved in response to hypoxia and promotes neoangiogenesis, which are considered essential for tumor growth and progression. Under normoxic conditions it is constitutively produced and degraded by the ubiquitin-proteasome system. But under hypoxic conditions it becomes stabilized.
Hypoxia is associated with autophagy. Mitochondrial autophagy is induced by hypoxia, this process requires the HIF-1-dependent expression of BNIP3 and the constitutive expression of Beclin-1. In cells subjected to prolonged hypoxia, mitochondrial autophagy is an adaptive metabolic response which is necessary to prevent increased levels of reactive oxygen species and cell death.
Researchers have launched a new area of febrile investigations on the autophagy-related gene Beclin 1. However, no study has previously shown the contribution of Beclin 1 to adenomyosis and the correlation between Beclin 1 and HIF-1a. This study investigated the expression of Beclin 1 in human adenomyosis, its association with clinical characteristics and its regulation in endometrial stromal cells by hypoxia. Cell cultures, immunohistochemical technique, RT-PCR, and western blotting were used in this study. The study was divided into three parts:1. Decreased expression of Beclin 1 in eutopic endometrium of women with adenomyosis and its association with clinical characteristics.2. Beclin 1, HIF-1αexpression in eutopic endometrium and adenomyotic foci of women with adenomyosis and the correlation between Beclin 1 and HIF-1α.3. Beclin 1 expression in endometrial stromal cells from adenomyois and its regulation by hypoxia.
Part one Decreased expression of Beclin 1 in eutopic endometrium of women with adenomyosis and its association with clinical characteristics.
Objective:To investigate whether Beclin 1 expression is altered in eutopic endometrium of women with adenomyosis.
Methods:We collected tissue samples from the eutopic endometria of 30 women with adenomyosis and 32 healthy women undergoing surgery for benign indications. Beclin 1 expression of eutopic endometrial tissues was assessed by reverse transcription polymerase chain reaction (RT-PCR) and western blot analysis.
Results:Beclin 1 mRNA expression level in tissue samples of women with adenomyosis (0.71±0.10) was significantly lower than that of control (0.93±0.10) (P<0.001). The average level of Beclin 1 protein expression of women with adenomyosis in tissue samples (0.82±0.22) was also significantly lower than that of control (1.22±0.36) (P<0.001). Beclin 1 protein expression in eutopic endometrial tissues was negatively correlated with serum CA125 (r=-0.307, P=0.015), and pelvic pain (r=-0.542, P=0.000).
Part two Beclin 1, HIF-la expression in eutopic endometrium and adenomyotic foci of women with adenomyosis and the correlation between Beclin 1 and HIF-1α.
Objective:To investigate whether Beclin 1 and HIF-la were expressed in eutopic endometrium and adenomyotic foci of women with adenomyosis and the correlation between Beclin 1 and HIF-1α.
Methods: Beclin 1 and HIF-1αexpression were assessed by immunohistochemistry.
Results:1. Beclin 1 immunoreactive staining was present in the cytoplasm of glandular epithelial and stromal cells. HIF-1αimmunoreactive staining was present in the cytoplasm and nucleus of glandular epithelial and stromal cells in eutopic endometrium, mainly in the cytoplasm of glandular epithelial cells in adenomyotic foci. 2. Beclin 1 expression in eutopic endometrium of adenomyosis (3.62±2.69) was significantly lower than that in control (10.32±4.12)(P<0.01). Beclin 1 expression in adenomyotic foci (0.27±0.52) was significantly lower than that in eutopic endometrium of adenomyosis or in control (P<0.01). HIF-1αexpression in eutopic endometrium of adenomyosis (8.70±2.13) was significantly higher than that in control (4.49±2.55)(P<0.01). HIF-1αexpression in adenomyotic foci(7.97±2.54)was significantly higher than that in control(P<0.01), and not different from that in eutopic endometrium of adenomyosis. There were no differences of Beclin 1 expression between proliferative period and secretory period in adenomyosis or control. Beclin 1 expression of proliferative period or secretory period in adenomyosis was significantly lower than that in control(P<0.01). There were no differences of HIF-1αbetween proliferative period and secretory period in adenomyosis. There were differences of HIF-1αexpression between proliferative period and secretory period in control (P<0.01). HIF-1αexpression of proliferative period in adenomyosis was significantly higher than that in control(P<0.01). There were no differences of HIF-1αbetween adenomyosis and control in secretory period. Beclin 1 expression in adenomyotic foci was significantly lower than HIF-1αexpression(P<0.01).3. Beclin 1 expression was negatively correlated with serum CA125 (n=140, r2=0.232, P=0.000), and pelvic pain (n=140, r2=0.508, P=0.000). HIF-1αexpression was positively correlated with serum CA125 (n=140, r2 =0.268, P=0.000), and pelvic pain (n=140, r2=0.574, P=0.000). Beclin 1 expression was negatively correlated with HIF-1αexpression (n=140, r2=0.201, P=0.000).
Part three Beclin 1 expression in endometrial stromal cells from adenomyois and its regulation by hypoxia
Objective:To investigate whether Beclin 1 expression is altered in endometrial stromal cells from adenomyosis and its regulation by hypoxia.
Methods:Beclin 1 expression was assessed by RT-PCR and western blot analysis. The capability of proliferation and metastasis of endometrial stromal cells were assessed by MTT and migration assay.
Results:1. Beclin 1 mRNA expression level in cultured stromal cells of women with adenomyosis (0.72±0.19) was significantly lower than that of without (1.17±0.44) (P<0.05). Beclin 1 protein expression of women with adenomyosis in cultured stromal cells (0.20±0.03) was significantly lower compared with that of control (0.71±0.12)(P<0.01).2. The growth rate by MTT assay and the migrated distance of endometrial stromal cells in adenomyosis (0.33±0.03,0.31±0.02mm, respectively) were significantly higher than those in the control group (0.24±0.04,0.28±0.02mm, respectively) (P<0.01). The growth rate by MTT assay and the migrated distance of endometrial stromal cells after 24h hypoxia in adenomyosis (0.46±0.03,0.37±0.02mm, respectively) were significantly higher than those under normoxia in adenomyosis (0.33±0.03,0.31±0.02mm, respectively) (P<0.01). The growth rate by MTT assay and the migrated distance of endometrial stromal cells after 24h hypoxia in control (0.20±0.02,0.14±0.02mm, respectively) were significantly lower than those under normoxia in control (0.24±0.04,0.28±0.02mm, respectively) (P<0.05).3. Beclin 1 protein expression of endometrial stromal cells after 24h hypoxia in adenomyosis (0.30±0.01) was significantly lower than that in adenomyosis under normoxia (0.49±0.01) (P<0.01)。Beclin 1 protein expression of endometrial stromal cells after 24h hypoxia in adenomyosis (0.30±0.01) was significantly lower than that in control under hypoxia (0.65±0.02) (P<0.01)。Beclin 1 protein expression of endometrial stromal cells from in adenomyosis (0.49±0.01) was significantly lower than that in control (0.70±0.03) (P<0.01)。There was no difference between the control group under hypoxia (0.65±0.02) and the control group under normoxia (0.70±0.03).4. In endometrial stromal cells after 24h hypoxia from adenomyosis, Beclin 1 protein level was negatively related with the cell proliferation and migration(r2=0.564,0.469;P=0.004,0.042).
Conclusion:
1. Beclin 1 immunoreactive staining was present in the cytoplasm of glandular epithelial and stromal cells. Expression of Beclin 1 was decreased in eutopic endometrium and adenomyotic foci of women with adenomyosis, and the Beclin 1 expression was negatively correlated with the serum CA125 and pelvic pain, which might be related to the pathogenesis and progress of adenomyosis.
2. HIF-1αimmunoreactive staining was present in the cytoplasm and nucleus of glandular epithelial and stromal cells in eutopic endometrium, mainly in the cytoplasm of glandular epithelial cells in adenomyotic foci. Expression of HIF-1αwas increased in eutopic endometrium and adenomyotic foci of women with adenomyosis. Its expression level was positively correlated with the serum CA125 and pelvic pain, which might be related to the pathogenesis and progress of adenomyosis.
3. Beclin 1 expression was negatively correlated with HIF-1αexpression. If the expression of HIF-1αis higher and the expression of Beclin 1 is lower, the adenomyosis is more severe.
4. The growth rate and the migrated distance of endometrial stromal cells in adenomyosis were significantly higher than those in control. The growth rate and the migrated distance of endometrial stromal cells after 24h hypoxia in adenomyosis were significantly higher than those under normoxia in adenomyosis. The endometrial stromal cells of adenomyosis had the greater capacity of proliferation and migration induced by hypoxia.
5. Beclin 1 protein expression of endometrial stromal cells under hypoxia in adenomyosis was significantly lower than that under normoxia in adenomyosis。Beclin 1 protein expression of endometrial stromal cells under hypoxia in adenomyosis was significantly lower than that under hypoxia in control.
6. In endometrial stromal cells after 24h hypoxia from adenomyosis, Beclin 1 protein level was negatively related with the cell proliferation and migration, hypoxia-induced change of Beclin 1 might be related to the pathogenesis and progress of adenomyosis.
引文
[1]Parazzini F, Vercellini P, Panazza S, Chatenoud L, Oldani S,Crosignani PG. Risk factors for adenomyosis. Hum Reprod 1997; 12:1275-9.
[2]Devlieger R, D'Hooghe T, Timmerman D. Uterine adenomyosis in the infertility clinic. Hum Reprod Update 2003;9:139-47.
[3]Leyendecker G, Herbertz M, Kunz Q Mall G. Endometriosis results from the dislocation of basal endometrium. Hum Reprod 2002;17(10):2725-36.
[4]Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update 1998;4: 312-22.
[5]Lei ZM, Rao CV, Lincoln SR, Ackermann DM.Increased expression of human chorionic gonadotropin/human luteinizing hormone receptors in adenomyosis. J Clin Endocrinol Metab 1993;76(3):763-8.
[6]Yamamoto T, Noguchi T, Tamura T, Kitawaki J, Okada H. Evidence for estrogen synthesis in adenomyotic tissues. Am J Obstet Gynecol 1993;169(3):734-8.
[7]Takahashi K, Nagata H, Kitao M. Clinical usefulness of determination of estradiol level in menstrual blood for patients with endometriosis. Nippon Sanka Fujinka Gakkai Zasshi 1989;41:1849-50.
[8]Hever A, Roth RB, Hevezi PA, Lee J, Willhite D, White EC, et al.Molecular characterization of human adenomyosis.Mol Hum Reprod 2006;12(12):737-48.
[9]Edinger AL, Thompson CB. Death by design:apoptosis, necrosis and autophagy. Curr Opin Cell Biol 2004; 16:663-9.
[10]Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):57-70.
[11]Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E et al. Cloning and genomic structure of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 1999;59:59-65.
[12]Miracco C, Cosci E, Oliveri G, Luzi P, Pacenti L, Monciatti I et al. Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours, Int J Oncol 2007;30:429-36.
[13]Wang ZH, Xu L, Duan ZL, Zeng LQ, Yan NH, Peng ZL. Beclin 1-mediated macroautophagy involves regulation of caspase-9 expression in cervical cancer HeLa cells. Gynecol Oncol 2007; 107:107-13.
[14]Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672-6.
[15]Koneri K, Goi T, Hirono Y, Katayama K, Yamaguchi A. Beclin 1 gene inhibits tumor growth in colon cancer cell lines.Anticancer Res 2007;27(3B):1453-7.
[16]Ramakrishnan S, Nguyen TM, Subramanian IV, Kelekar A. Autophagy and angiogenesis inhibition. Autophagy 2007;3(5):512-5.
[17]Levine B, Sinha S, Kroemer G. Bcl-2 family members:dual regulators of apoptosis and autophagy. Autophagy 2008;4(5):600-6.
[18]Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122(6):927-39.
[19]Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 2007;26(10):2527-39.
[20]Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, et al. Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy 2007;3(6):561-8.
[21]Rashmi R, Pillai SG, Vijayalingam S, Ryerse J, Chinnadurai G BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 2008;27(10):1366-75.
[22]Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 2004;64(12):4286-93.
[23]Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 2007;14(1):146-57.
[24]Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A.Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ 2007;14(3):500-10.
[25]Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K, et al.Hypoxia-inducible factor (HIF1α and HIF2α), angiogenesis and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;53(5):1192-202.
[26]Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor la in common human cancers and their metastases. Cancer Res 1999;59(22):5830-5.
[27]Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G.Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000;60(17): 4693-6.
[28]Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, et al. Hypoxia inducible factor-1 dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A,and ZFHX1B. Cancer Res 2006;66(5):2725-31.
[29]Corley KM, Taylor CJ, Lilly B. Hypoxia inducible factor-1alpha modulates adhesion, migration, and FAK phosphorylation in vascular smooth muscle cells. J Cell Biochem 2005;96(5):971-85.
[30]Funasaka T, Yanagawa T, Hogan V, Raz A. Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J 2005;19(11):1422-30.
[31]Liu LZ, Hu XW, Xia C, He J. Reactive oxygen species regulate epidermal growth factor induced vascular endothelial growth factor and hypoxia inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radic Biol Med 2006;41(10):1521-33.
[32]Miyoshi A, Kitajima Y, Ide T, Ohtake K, Nagasawa H, Uto Y, et al. Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-lalpha independent manner, Int J Oncol 2006;29(6):1533-9.
[33]Hopfl G, Ogunshola O, Gassmann M. HIFs and tumor-causes and consequences. Am J Physiol Regul Integr Comp Physiol 2004;286(4):R608-23.
[34]Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward E, Israels SJ, et al. Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy 2008;4(2):195-204.
[35]Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008;283:10892-903.
[36]Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of 02 homeostasis by hypoxia-inducible factor 1α. Genes Dev 1998; 12(2):149-62.
[37]Brahimi-Horn MC, Pouyssegur J. Harnessing the hypoxia inducible factor in cancer and ischemic disease. Biochem Pharmacol 2007; 73:450-7.
[38]Bohensky J, Shapiro IM, Leshinsky S, Terkhorn SP, Adams CS, Srinivas V. HIF regulation of chondrocyte apoptosis:induction of the autophagic pathway. Autophagy 2007;3(3):207-14.
[39]Abaci HE, Truitt R, Luong E, Drazer G, Gerecht S. Adaptation to oxygen deprivation in cultures of human pluripotent stem cells, endothelial progenitor cells, and umbilical vein endothelial cells. Am J Physiol Cell Physiol 2010;298(6):C1527-37.
[40]Mazure NM, Pouyssegur J.Atypical BH3-domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy 2009;5(6):868-9.
[41]Chen Y, Lu Y, Lu C, Zhang L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1alpha expression. Pathol Oncol Res 2009;15(3):487-93.
[42]Wan XB, Fan XJ, Chen MY, Xiang J, Huang PY, Guo L, et al. Autophagy. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma.2010 Apr 26;6(3). [Epub ahead of print]
[1]Nap AW, Griffioen AW, Dunselman GA, Bouma-Ter Steege JC, Thijssen VL, Evers JL, et al. Antiangiogenesis therapy for endometriosis. J Clin Endocrinol Metab 2004;89 (3):1089-95.
[2]Kadomatsu K. The midkine family in cancer, inflammation and neural development. Nagoya J Med Sci 2005;67(3-4):71-82.
[3]Toth S, Nagy K, Palfia Z, Rez G. Cellular autophagic capacity changes during azaserine-induced tumour progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation. Cell Tissue Res 2002;309(3):409-16.
[4]Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):57-70.
[5]Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E et al. Cloning and genomic structure of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 1999;59:59-65.
[6]Miracco C, Cosci E, Oliveri G, Luzi P, Pacenti L, Monciatti I et al. Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours. Int J Oncol 2007;30:429-36.
[7]Wang ZH, Xu L, Duan ZL, Zeng LQ, Yan NH, Peng ZL. Beclin 1-mediated macroautophagy involves regulation of caspase-9 expression in cervical cancer HeLa cells. Gynecol Oncol 2007;107:107-13.
[8]Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672-6.
[9]Koneri K, Goi T, Hirono Y, Katayama K, Yamaguchi A. Beclin 1 gene inhibits tumor growth in colon cancer cell lines.Anticancer Res 2007;27(3B):1453-7.
[10]Ramakrishnan S, Nguyen TM, Subramanian IV, Kelekar A. Autophagy and angiogenesis inhibition. Autophagy 2007;3(5):512-5.
[11]Nguyen TM, Subramanian IV, Kelekar A, Ramakrishnan S. Kringle 5 of human plasminogen, an angiogenesis inhibitor, induces both autophagy and apoptotic death in endothelial cells. Blood 2007;109(11):4793-802.
[12]Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 2003;100(25):15077-82.
[13]Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.J Clin Invest 2003;112(12):1809-20.
[14]Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 2006;8:688-99.
[15]Furuya N, Yu J, ByWeld M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy 2005;1:46-52.
[16]Levine B, Sinha S, Kroemer G. Bcl-2 family members:dual regulators of apoptosis and autophagy. Autophagy 2008;4(5):600-6.
[17]Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell.2005;122(6): 927-39.
[18]Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 2007;26(10):2527-39.
[19]Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, et al. Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy 2007;3(6):561-8.
[20]Saeki K, Yuo A, Okuma E, Yazaki Y, Susin SA, Kroemer G, et al. Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells. Cell Death Differ 2000;7(12):1263-9.
[21]Akar U, Chaves-Reyez A, Barria M, Tari A, Sanguino A, Kondo Y, et al. Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy 2008;4(5):669-79.
[22]Rashmi R, Pillai SG, Vijayalingam S, Ryerse J, Chinnadurai G. BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 2008;27(10):1366-75.
[23]Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 2004;64(12):4286-93.
[24]Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 2007;14(1):146-57.
[25]Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A.Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ 2007;14(3):500-10.
[26]Oberstein A, Jeffrey PD, Shi Y.Crystal structure of the Bcl-XL-Beclin 1 peptide complex:Beclin 1 is a novel BH3-only protein. J Biol Chem 2007;282(17): 13123-32.
[27]Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435(7042):677-81.
[28]Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA, et al. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L).Autophagy 2007;3(4):374-6.
[29]Akar U, Chaves-Reyez A, Barria M, Tari A, Sanguino A, Kondo Y, et al. Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy 2008;4(5):669-79.
[30]Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, Ambral regulates autophagy and development of the nervous system. Nature 2007;447(7148):1121-5.
[31]Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, et al.Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007:1142-51.
[32]Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006;10(1):51-64.
[33]Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007;21(11):1367-81.
[34]Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, et al.Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. genes Dev 2007;21(13):1621-35.
[35]Ota H, Igarashi S, Hatazawa J, Tanaka T. Is adenomyosis an immune disease? Hum Reprod Update 1998;4:360-7.
[36]Wang F, Wen Z, Li H, Yang Z, Zhao X, Yao X. Human leukocyte antigen-G is expressed by the eutopic and ectopic endometrium of adenomyosis. Fertil Steril 2008;90:1599-604.
[37]Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D,Tuschl T et al. Endogenous MHC class Ⅱ processing of a viral nuclear antigen after autophagy. Science 2005;307:593-6.
[38]Parazzini F, Mais V, Cipriani S, Busacca M, Venturini P; GISE.Determinants of adenomyosis in women who underwent hysterectomy for benign gynecological conditions:results from a prospective multicentric study in Italy.Eur J Obstet Gynecol Reprod Biol 2009;143(2):103-6.
[39]Vercellini P, Vigano P, Somigliana E, et al. Adenomyosis:epidemiological factors. Best Pract Res Clin Obstet Gynaecol 2006;20:465-77.
[40]Vercellini P, Parazzini F, Oldani S, et al. Adenomyosis at hysterectomy:a study on frequency distribution and patient characteristics. Hum Reprod 1995;10:1160-2.
[41]Azziz R. Adenomyosis in pregnancy. A review. J Reprod Med 1986;31:224-7.
[42]Vavilis D, Agorastos T, Tzafetas J, Loufopoulos A, Vakiani M, Constantinidis T, et al. Adenomyosis at hysterectomy:prevalence and relationship to operative findings and reproductive and menstrual factors. Clin Exp Obstet Gynecol 1997;24(1):36-8.
[43]Kim DK, Yang JS, Maiti K, Hwang JI, Kim K, Seen D, et al. A gonadotropin-releasing hormone-Ⅱ antagonist induces autophagy of prostate cancer cells. Cancer Res 2009;69:923-31.
[44]Grundker C, Gunthert AR, Millar RP, Emons G. Expression of gonadotropin--releasing hormone Ⅱ (GnRH-Ⅱ) receptor in human endometrial and ovarian cancer cells and eVects of GnRH-Ⅱ on tumor cell proliferation. J Clin Endocrinol Metab 2002;87:1427-30.
[45]John S, Nayvelt I, Hsu HC, Yang P, Liu W, Das GM et al.Regulation of estrogenic effects by beclin 1 in breast cancer cells.Cancer Res 2008;68:7855-63.
[1]Nap AW, Dunselman GA, de Goeij AF, Evers JL, Groothuis PG. Inhibiting MMP activity prevents the development of endometriosis in the chicken chorioallantoic membrane model. Hum Reprod 2004;19(10):2180-7.
[2]Ruas JL, Poellinger L. Hypoxia-dependent activation of HIF into a transcriptional regulator. Semin Cell Dev Biol.2005;16(4-5):514-22.
[3]Lisy K, Peet DJ. Turn me on:regulating HIF transcriptional activity. Cell Death Differ 2008; 15(4):642-9.
[4]Mahon P C, Hirota K, Semenza GL. FIH-1:a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001; 15(20):2675-86.
[5]Semenza G L. HIF-1, O(2) and the 3 PHDs:How animal cells signal hypoxia to the nucleus. Cell 2001;107(1):123.
[6]Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K, et al. Hypoxia-inducible factor (HIF1α and HIF2α), angiogenesis and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;53(5):1192-202.
[7]Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 1999;59(22):5830-5.
[8]Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G.Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000;60(17): 4693-6.
[9]Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, et al. Hypoxia inducible factor-1 dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A,and ZFHX1B. Cancer Res 2006;66(5):2725-31.
[10]Corley KM, Taylor CJ, Lilly B. Hypoxia inducible factor-1alpha modulates adhesion, migration, and FAK phosphorylation in vascular smooth muscle cells. J Cell Biochem 2005;96(5):971-85.
[11]Funasaka T, Yanagawa T, Hogan V, Raz A. Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J 2005;19(11):1422-30.
[12]Liu LZ, Hu XW, Xia C, He J. Reactive oxygen species regulate epidermal growth factor induced vascular endothelial growth factor and hypoxia inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radic Biol Med 2006;41(10):1521-33.
[13]Miyoshi A, Kitajima Y, Ide T, Ohtake K, Nagasawa H, Uto Y, et al. Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-lalpha independent manner. Int J Oncol 2006;29(6):1533-9.
[14]Hopfl G, Ogunshola O, Gassmann M. HIFs and tumor-causes and consequences. Am J Physiol Regul Integr Comp Physiol 2004;286(4):R608-23.
[15]Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006;441(7092):437-43.
[16]Yang ZF, Poon RT, To J, Ho DW, Fan ST. The potential role of hypoxia inducible factor 1α in tumor progression after hypoxia and chemotherapy in hepatocellular carcinoma. Cancer Res 2004;64 (15):5496-503.
[17]Rankin EB, Giaccia AJ. The role of hypoxia inducible factors in tumorigenesis. Cell Death Differ 2008;15 (4):678-85.
[18]Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, et al. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 2003;22 (21):3213-20.
[19]Corn PG, Ricci MS, Scata KA, Arsham AM, Simon MC, Dicker DT, et al.Mxil is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol Ther 2005;4(11):1285-94.
[20]Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, et al.Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and-independent mechanisms and contributes to drug resistance. Mol Cell Biol 2004;24(7):2875-89.
[21]Peng XH, Kama P, Cao Z, Jiang BH, Zhou M, Yang L.Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-lalpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem 2006;281(36):25903-14.
[22]Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X, et al. Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc. J Biol Chem. 2006;281(20):13957-63.
[23]Kim JY, Ahn HJ, Ryu JH, Suk K, Park JH. BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor lalpha. J Exp Med 2004;199(1):113-24.
[24]Lee MJ, Kim JY, Suk K, Park JH.Identification of the hypoxia-inducible factor 1 alpha-responsive HGTD-P gene as a mediator in the mitochondrial apoptotic pathway. Mol Cell Biol 2004;24(9):3918-27.
[25]Hammond EM, Giaccia AJ. The role of p53 in hypoxia induced apoptosis. Biochem Biophys Res Commun 2005;331 (3):718-25.
[26]Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward E, Israels SJ, et al. Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy 2008;4(2):195-204.
[27]Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008;283:10892-903.
[28]Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of 02 homeostasis by hypoxia-inducible factor 1α. Genes Dev 1998; 12(2):149-62.
[29]Brahimi-Horn MC, Pouyssegur J. Harnessing the hypoxia inducible factor in cancer and ischemic disease. Biochem Pharmacol 2007; 73:450-7.
[30]Bohensky J, Shapiro IM, Leshinsky S, Terkhorn SP, Adams CS, Srinivas V. HIF regulation of chondrocyte apoptosis:induction of the autophagic pathway. Autophagy 2007;3(3):207-14.
[31]Abaci HE, Truitt R, Luong E, Drazer G, Gerecht S. Adaptation to oxygen deprivation in cultures of human pluripotent stem cells, endothelial progenitor cells, and umbilical vein endothelial cells. Am J Physiol Cell Physiol 2010;298(6):C1527-37.
[32]Mazure NM, Pouyssegur J.Atypical BH3-domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy 2009;5(6):868-9.
[33]Chen Y, Lu Y, Lu C, Zhang L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-lalpha expression. Pathol Oncol Res 2009;15(3):487-93.
[34]Wan XB, Fan XJ, Chen MY, Xiang J, Huang PY, Guo L, et al. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 2010 Apr 26;6(3). [Epub ahead of print]
[35]Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH et al. Autophagic and tumour suppressor activity of a novel Beclinl-binding protein UVRAG. Nat Cell Biol 2006;8:688-699.
[36]Furuya N, Yu J, ByWeld M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy 2005;1:46-52.
[37]Leyendecker G, Herbertz M, Kunz G, Mall G. Endometriosis results from the dislocation of basal endometrium. Hum Reprod 2002;17(10):2725-36.
[38]Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update 1998;4:312-22.
[39]Lei ZM, Rao CV, Lincoln SR, Ackermann DM.Increased expression of human chorionic gonadotropin/human luteinizing hormone receptors in adenomyosis. J Clin Endocrinol Metab 1993;76(3):763-8.
[40]Yamamoto T, Noguchi T, Tamura T, Kitawaki J, Okada H. Evidence for estrogen synthesis in adenomyotic tissues. Am J Obstet Gynecol 1993;169(3):734-8.
[41]Takahashi K, Nagata H, Kitao M. Clinical usefulness of determination of estradiol level in menstrual blood for patients with endometriosis. Nippon Sanka Fujinka Gakkai Zasshi 1989;41:1849-50.
[42]Hever A, Roth RB, Hevezi PA, Lee J, Willhite D, White EC, et al.Molecular characterization of human adenomyosis.Mol Hum Reprod 2006;12(12):737-48.
[43]Zhang L, Li J, Li M. Expression of bcl-2 protein in adenomyosis. Zhonghua Fu Chan Ke Za Zhi 2000;35(9):533-5.
[44]Goumenou A, Panayiotides I, Matalliotakis I, Vlachonikolis I, Tzardi M, Koumantakis E. Bcl-2 and Bax expression in human endometriotic and adenomyotic tissues. Eur J Obstet Gynecol Reprod Biol 2001;99(2):256-60.
[45]Otsuki Y, Misaki O, Sugimoto O, Ito Y, Tsujimoto Y, Akao Y. Cyclic bcl-2 gene expression in human uterine endometrium during menstrual cycle. Lancet 1994;344(8914):28-9.
[46]Yamashita H, Otsuki Y, Matsumoto K, Ueki K, Ueki M. Fas ligand, Fas antigen and Bcl-2 expression in human endometrium during the menstrual cycle. Mol Hum Reprod 1999;5(4):358-64.
[47]Watanabe H, Kanzaki H, Narukawa S, Inoue T, Katsuragawa H, Kaneko Y, et al.Bcl-2 and Fas expression in eutopic and ectopic human endometrium during the menstrual cycle in relation to endometrial cell apoptosis. Am J Obstet Gynecol 1997;176(2):360-8.
[48]Jones RK, Searle RF, Bulmer JN. Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Hum Reprod 1998; 13(12):3496-502.
[49]Goteri G, Lucarini G, Montik N, Zizzi A, Stramazzotti D, Fabris G,et al. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1alpha (HIF-1alpha), and microvessel density in endometrial tissue in women with adenomyosis.Int J Gynecol Pathol 2009;28(2):157-63.
[50]Critchley HO, Osei J, Henderson TA, Boswell L, Sales KJ, Jabbour HN, et al. Hypoxia-inducible factor-1alpha expression in human endometrium and its regulation by prostaglandin E-series prostanoid receptor 2 (EP2). Endocrinology 2006;147(2):744-53.
[51]Zhang J, Salamonsen LA. Expression of hypoxia-inducible factors in human endometrium and suppression of matrix metalloproteinases under hypoxic conditions do not support a major role for hypoxia in regulating tissue breakdown at menstruation. Hum Reprod 2002; 17:265-74.
[52]Sharkey AM, Day K, McPherson A, Malik S, Licence D, Smith SK, et al. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endocrinol Metab 2000;85:402-9.
[53]Wu MH, Chen KF, Lin SC, Lgu CW, Tsai SJ. Aberrant Expression of Leptin in Human Endometriotic Stromal Cells Is Induced by Elevated Levels of Hypoxia Inducible Factor-la. Am J Pathol.2007 Feb;170(2):590-8.
[54]任旭,何援利,潘石蕾,彭冬。缺氧诱导因子HIF-1α在子宫内膜异位症的表达及意义。南方医科大学学报2007；27(4)：538-40.
[1]Schlemmer SR, Kaufman DG. Endometrial stromal cells regulate gap-junction function in normal human endometrial epithelial cells but not in endometrial carcinoma cells. Mol Carcinog 2000;28(2):70-5.
[2]Mai KT, Yazdi HM, Perkins DG, Parks W. Pathogenetic role of the stromal cells in endometriosis and adenomyosis. Histopathology 1997;30(5):430-42.
[3]NisolleM, Casanas-Roux F, Donnez J. Early-stage eddometriosis:adhesion and growth of human menstrual endometrium in nude mice. Fertil Steril 2000;74: 306-12.
[4]Solaini G, Baracca A, Lenaz G, Sgarbi G. Hypoxia and mitochondrial oxidative metabolism. Biochim Biophys Acta 2010 Feb 11. [Epub ahead of print]
[5]Mazure NM, Pouyssegur J. Hypoxia-induced autophagy:cell death or cell survival? Curr Opin Cell Biol 2009 Dec 18. [Epub ahead of print]
[6]Semenza GL. Mitochondrial autophagy:life and breath of the cell. Autophagy 2008;16;4(4):534-6.
[7]Zhang H, Bosch-Marce M, Shimoda LA et al.Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008;283:10892-903.
[8]Band M, Joel A, Hernandez A, Avivi A. Hypoxia-induced BNIP3 expression and mitophagy:in vivo comparison of the rat and the hypoxia-tolerant mole rat, Spalax ehrenbergi. FASEB J 2009;23(7):2327-35.
[9]Hamacher-Brady A, Brady NR, Gottlieb RA. Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 2006;281(40):29776-87.
[10]Indelicato M, Pucci B, Schito L, Reali V, Aventaggiato M, Mazzarino MC, et al. Role of hypoxia and autophagy in MDA-MB-231 invasiveness. J Cell Physiol 2010;223(2):359-68.
[11]Fyles A,Milosevic M, Hedley D, Pintilie M, Levin W, Manchul L, et al.Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer. J Clin Oncol 2002;20(3):680-7.
[12]Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007;117(2):326-36
[13]Daniel F, Legrand A, Pessayre D, Vadrot N, Descatoire V, Bernuau D. Partial Beclin 1 silencing aggravates doxorubicin-and Fas-induced apoptosis in HepG2 cells. World J Gastroenterol 2006;12(18):2895-900.
[14]Ahn CH, Jeong EG, Lee JW, Kim MS, Kim SH, Kim SS, et al. Expression of beclin-1, an autophagy-related protein, in gastric and colorectal cancers.APMIS 2007;115(12):1344-9.
[15]Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 2007;117(7):1782-93.
[16]Decker RS, Wildenthal K. Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am J Pathol 1980;98(2):425-44.
[17]Yan L, Vatner DE, Kim SJ, Ge H, Masurekar M, Massover WH, et al. Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci U S A 2005;102(39):13807-12.
[18]Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 2007;14(1):146-57.
[19]Bohensky J, Shapiro IM, Leshinsky S, Terkhorn SP, Adams CS, Srinivas V. HIF-1 regulation of chondrocyte apoptosis:induction of the autophagic pathway. Autophagy 2007;3(3):207-14.
[20]Indelicato M, Pucci B, Schito L, Reali V, Aventaggiato M, Mazzarino MC, et al. Role of hypoxia and autophagy in MDA-MB-231 invasiveness. J Cell Physiol 2010;223(2):359-68.
[21]Meijer AJ, Codogno P. Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol 2004;36(12):2445-62.
[22]Yeh CH, Hsu SP, Yang CC, Chien CT, Wang NP.Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy. Life Sci 2010;86(3-4): 115-23.
[1]Berkley KJ, Rapkin AJ, Papka RE.The pains of endometriosis. Science. 2005;308:1587-9.
[2]Vigano P, Parazzini F, Somigliana E, Vercellini P. Endometriosis:epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol.2004; 18:177-200.
[3]Nap AW, Groothuis PG, Demir AY, Evers JL, Dunselman GA.Pathogenesis of endometriosis. Best Pract Res Clin Obstet Gynaecol.2004; 18:233-44.
[4]Braun DP, Ding J, Shen J, Rana N, Fernandez BB, Dmowski WP.Relationship between apoptosis and the number of macrophages in eutopic endometrium from women with and without endometriosis. Fertil Steril.2002;78:830-5.
[5]Jones RK, Bulmer JN, Searle RF. Phenotypic and functional studies of leukocytes in human endometrium and endometriosis. Hum Reprod Update. 1998;4:702-9.
[6]Gazvani R, Smith L, Fowler PA. Effect of interleukin-8 (IL-8), anti-IL-8, and IL-12 on endometrial cell survival in combined endometrial gland and stromal cell cultures derived from women with and without endometriosis. Fertil Steril. 2002;77:62-7.
[7]Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends in Molec Med. 2003;9:223-8.
[8]Ferrero S, Gillott DJ, Remorgida V, Anserini P, Ragni N, Grudzinskas JG. Proteomic analysis of peritoneal fluid in fertile and infertile women with endometriosis. J Reprod Med.2009;54:32-40.
[9]Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril.2001;75:1-10.
[10]Alpay Z, Saed GM, and Diamond MP. Female infertility and free radicals: potential role in adhesions and endometriosis. J Soc Gynecol Investig. 2006; 13:390-8.
[11]Iborra A, Palacio JR, and Martinez P. Oxidative stress and autoimmune response in the infertile woman. Chem Immunol Allergy.2005;88:150-62.
[12]Samlaska CP, Winfield EA. Pentoxifylline. J Am Acad Dermatol.1994;30: 603-21.
[13]Nothnick WB, Curry TE, Vernon MW. Immunomodulation of rat endometriotic implant growth and protein production. Am J Reprod Immunol.1994;31:151-62.
[14]Mohammadzadeh A, Heidari M, Soltanghoraee H, Jeddi-Tehrani M, Ghaffari Novin M, Akhondi MM, et al. Evaluation of the effect of pentoxifylline on white blood cell count in serum and peritoneal fluid in female rats with endometriosis. J Obstet Gynaecol Res.2008;34:307-13.
[15]Vlahos NF, Gregoriou O, Deliveliotou A, Perrea D, Vlachos A, Zhao Y, et al. Effect of pentoxifylline on vascular endothelial growth factor C and flk-1 expression on endometrial implants in the rat endometriosis model. Fertil Steril. 2009; in press.
[16]Steinleitner A, Lambert H, Roy S. Immunomodulation with pentoxifylline abrogates macrophage-mediated infertility in an in vivo model:a paradigm for a novel approach to the treatment of endometriosis-associated subfertility. Fertil Steril.1991;55:26-31.
[17]Steinleitner A, Lambert H, Suarez M, Serpa N, Roy S. Immunomodulation in the treatment of endometriosis-associated subfertility:use of pentoxifylline to reverse the inhibition of fertilization by surgically induced endometriosis in a rodent model. Fertil Steril.1991;56:975-9.
[18]Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials:Is blinding necessary? Control Clin Trials.1996;17:1-12.
[19]Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet.1998;352:609-13.
[20]Balasch J, Creus M, Fabregues F, Carmona F, Martinez-Roman S, Manau D,et al. Pentoxifylline versus placebo in the treatment of infertility associated with minimal or mild endometriosis:a pilot randomized clinical trial. Hum Reprod. 1997;12:2046-50.
[21]Alborzi S, Ghotbi S, Parsanezhad ME, Dehbashi S, Alborzi S, Alborzi M. Pentoxifylline therapy after laparoscopic surgery for different stages of endometriosis:a prospective, double-blind, randomized, placebo-controlled study. J Minim Invasive Gynecol.2007; 14:54-8.
[22]Kamencic H, Thiel JA. Pentoxifylline after conservative surgery for endometriosis:a randomized, controlled trial. J Minim Invasive Gynecol. 2008;15:62-6.
[23]Creus M, Fabregues F, Carmona F, del Pino M, Manau D, Balasch J. Combined laparoscopic surgery and pentoxifylline therapy for treatment of endometriosis-associated infertility:a preliminary trial. Hum Reprod. 2008;23:1910-6.
[24]Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med.1997;337:217-22.
[25]Parazzini F. Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women:a randomized trial. Gruppo Italiano per lo Studio dell'Endometriosi. Hum Reprod.1999;14:1332-4.
[26]Kennedy S, Bergqvist A, Chapron C, D'Hooghe T, Dunselman G, Greb R, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698-704.
[27]The Practice Committee of the Amercian Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril.2006;86:S156-S160.
[28]ESHRE Capri Workshop Group. Diagnosis and management of the infertile couple:missing information. Hum Reprod Update.2004;10:295-307.
[29]Hughes E, Brown J, Collins JJ, Farquhar C, Fedorkow DM, Vandekerckhove P.
Ovulation suppression for endometriosis. Cochrane Database Syst Rev. 2007;(3):CD000155.
[30]Steinleitner A, Lambert H, Suarez M:Immunomodulation in the treatment of endometriosis-associated subfertility:Use of pentoxifylline to reverse the inhibition of fertilization by surgically induced endometriosis in a rodent model. Fertil Steril.1991;55:975-9
[31]Zhang X, Sharma RK, Agarwal A, and Falcone T. Effect of pentoxifylline in reducing oxidative stress-induced embryotoxicity. J Assist Reprod Genet. 2005;22:415-7.
[32]Ramey JW, Starke ME, Gibbons WE, Archer DF. The influence of pentoxifylline (Trental) on the antifertility effect of intrauterine devices in rats. Fertil Steril.1994;62:181-5.
[33]Shukla V, Gude RP. Amelioration of B16F10 melanoma cells induced oxidative stress in DBA/2 mice by pentoxifylline. J Exp Clin Cancer Res.2003;22:407-10.
[34]Kwiecien S, Brzozowski T, Konturek PC, Pawlik MW, Pawlik WW, Kwiecien N, et al. Gastroprotection by pentoxyfilline against stress-induced gastric damage. Role of lipid peroxidation, antioxidizing enzymes and proinflammatory cytokines. J Physiol Pharmacol.2004;55:337-55.
[35]Laurent C, Voisin P, Pouget JP. DNA damage in cultured skin microvascular endothelial cells exposed to gamma rays and treated by the combination pentoxifylline and alpha-tocopherol. Int J Radiat Biol.2006;82:309-21.
[36]Delanian S, Porcher R, Balla-Mekias S, Lefaix JL:Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation induced fibrosis. J Clin Oncol.2003; 21: 2545-50
[37]Ozturk B, Egehan I, Atavci S, Kitapci M:Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer:a double-blind randomized trial. Int J Radiat Oncol Biol Phys.2004;58:213-9.
[38]Williamson R, Kondziolka D, Kanaan H, Lunsford LD, Flickinger JC. Adverse radiation effects after radiosurgery may benefit from oral vitamin E and pentoxifylline therapy:a pilot study. Stereotact Funct Neurosurg.2008;86: 359-66.
[39]Liu H, Xiong M, Xia YF, Cui NJ, Lu RB, Deng L, et al. Studies on pentoxifylline and tocopherol combination for radiation-induced heart disease in rats. Int J Radiat Oncol Biol Phys.2009;73:1552-9.
[40]Ledee-Bataille N, Olivennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Reprod. 2002;17:1249-53.
[41]Kurtoglu S, Gunes T, Koklu E, Bastug O, Canoz O, Kula M, et al. Influence of maternal nicotine exposure on neonatal rat bone:protective effect of pentoxifylline. Exp Biol Med (Maywood).2007;232:398-405.
[42]Adamson GD, Hurd SJ, Pasta DJ, Rodriguez BD. Laparoscopic endometriosis treatment:is it better? Fertil Steril.1993;59:35-44.
[43]Guzick DS, Silliman NP, Adamson GD, Buttram-VC J, Canis M, Malinak LR, et al. Prediction of pregnancy in infertile women based on the American Society for Reproductive Medicine's revised classification of endometriosis. Fertil Steril. 1997;67:822-9.
[44]Osuga Y, Koga K, Tsutsumi O, Yano T, Maruyama M, Kugu K, et al. Role of laparoscopy in the treatment of endometriosis-associated infertility. Gynecol Obstet Invest.2002;53 Suppl 1:33-9.
[45]Ozawa Y, Murakami T, Terada Y, Yaegashi N, Okamura K, Kuriyama S, et al. Management of the pain associated with endometriosis:an update of the painful problems. Tohoku J Exp Med.2006;210:175-88.
[46]Roman H, Puscasiu L. Guidelines for the management of painful endometriosis. Chirurgia (Bucur).2008; 103:265-74.
[47]Wordliczek J, Szczepanik AM, Banach M, Turchan J, Zembala M, Siedlar M, et al. The effect of pentoxifylline on post-injury hyperalgesia in rats and postoperative pain in patients. Life Sci.2000;66:1155-64.
[48]Yap C, Furness S, Farquhar C. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev.2004;(3):CD003678.
[49]Ward A, Clissold SP. Pentoxifylline:a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs.1987;34:50-97.
[50]Sales AM, de Matos HJ, Nery JAC, Duppre NC, Sampaio EP, Sarno EN. Double-blind trial of the efficacy of pentoxifylline vs thalidomide for the treatment of type Ⅱ reaction in leprosy. Braz J Med Biol Res.2007;40:243-8.
[51]Rizk B, Fountain S, Avery S, Palmer C, Blayney M, Macnamee M, et al. Successful use of pentoxifylline in male-factor infertility and previous failure of in vitro fertilization:a prospective randomized study. J Assist Reprod Genet. 1995;12:710-4.
[2]Devlieger R, D'Hooghe T, Timmerman D. Uterine adenomyosis in the infertility clinic. Hum Reprod Update 2003;9:139-47.
[3]Leyendecker G, Herbertz M, Kunz Q Mall G. Endometriosis results from the dislocation of basal endometrium. Hum Reprod 2002;17(10):2725-36.
[4]Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update 1998;4: 312-22.
[5]Lei ZM, Rao CV, Lincoln SR, Ackermann DM.Increased expression of human chorionic gonadotropin/human luteinizing hormone receptors in adenomyosis. J Clin Endocrinol Metab 1993;76(3):763-8.
[6]Yamamoto T, Noguchi T, Tamura T, Kitawaki J, Okada H. Evidence for estrogen synthesis in adenomyotic tissues. Am J Obstet Gynecol 1993;169(3):734-8.
[7]Takahashi K, Nagata H, Kitao M. Clinical usefulness of determination of estradiol level in menstrual blood for patients with endometriosis. Nippon Sanka Fujinka Gakkai Zasshi 1989;41:1849-50.
[8]Hever A, Roth RB, Hevezi PA, Lee J, Willhite D, White EC, et al.Molecular characterization of human adenomyosis.Mol Hum Reprod 2006;12(12):737-48.
[9]Edinger AL, Thompson CB. Death by design:apoptosis, necrosis and autophagy. Curr Opin Cell Biol 2004; 16:663-9.
[10]Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):57-70.
[11]Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E et al. Cloning and genomic structure of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 1999;59:59-65.
[12]Miracco C, Cosci E, Oliveri G, Luzi P, Pacenti L, Monciatti I et al. Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours, Int J Oncol 2007;30:429-36.
[13]Wang ZH, Xu L, Duan ZL, Zeng LQ, Yan NH, Peng ZL. Beclin 1-mediated macroautophagy involves regulation of caspase-9 expression in cervical cancer HeLa cells. Gynecol Oncol 2007; 107:107-13.
[14]Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672-6.
[15]Koneri K, Goi T, Hirono Y, Katayama K, Yamaguchi A. Beclin 1 gene inhibits tumor growth in colon cancer cell lines.Anticancer Res 2007;27(3B):1453-7.
[16]Ramakrishnan S, Nguyen TM, Subramanian IV, Kelekar A. Autophagy and angiogenesis inhibition. Autophagy 2007;3(5):512-5.
[17]Levine B, Sinha S, Kroemer G. Bcl-2 family members:dual regulators of apoptosis and autophagy. Autophagy 2008;4(5):600-6.
[18]Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell. 2005;122(6):927-39.
[19]Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 2007;26(10):2527-39.
[20]Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, et al. Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy 2007;3(6):561-8.
[21]Rashmi R, Pillai SG, Vijayalingam S, Ryerse J, Chinnadurai G BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 2008;27(10):1366-75.
[22]Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 2004;64(12):4286-93.
[23]Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 2007;14(1):146-57.
[24]Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A.Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ 2007;14(3):500-10.
[25]Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K, et al.Hypoxia-inducible factor (HIF1α and HIF2α), angiogenesis and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;53(5):1192-202.
[26]Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor la in common human cancers and their metastases. Cancer Res 1999;59(22):5830-5.
[27]Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G.Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000;60(17): 4693-6.
[28]Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, et al. Hypoxia inducible factor-1 dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A,and ZFHX1B. Cancer Res 2006;66(5):2725-31.
[29]Corley KM, Taylor CJ, Lilly B. Hypoxia inducible factor-1alpha modulates adhesion, migration, and FAK phosphorylation in vascular smooth muscle cells. J Cell Biochem 2005;96(5):971-85.
[30]Funasaka T, Yanagawa T, Hogan V, Raz A. Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J 2005;19(11):1422-30.
[31]Liu LZ, Hu XW, Xia C, He J. Reactive oxygen species regulate epidermal growth factor induced vascular endothelial growth factor and hypoxia inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radic Biol Med 2006;41(10):1521-33.
[32]Miyoshi A, Kitajima Y, Ide T, Ohtake K, Nagasawa H, Uto Y, et al. Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-lalpha independent manner, Int J Oncol 2006;29(6):1533-9.
[33]Hopfl G, Ogunshola O, Gassmann M. HIFs and tumor-causes and consequences. Am J Physiol Regul Integr Comp Physiol 2004;286(4):R608-23.
[34]Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward E, Israels SJ, et al. Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy 2008;4(2):195-204.
[35]Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008;283:10892-903.
[36]Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of 02 homeostasis by hypoxia-inducible factor 1α. Genes Dev 1998; 12(2):149-62.
[37]Brahimi-Horn MC, Pouyssegur J. Harnessing the hypoxia inducible factor in cancer and ischemic disease. Biochem Pharmacol 2007; 73:450-7.
[38]Bohensky J, Shapiro IM, Leshinsky S, Terkhorn SP, Adams CS, Srinivas V. HIF regulation of chondrocyte apoptosis:induction of the autophagic pathway. Autophagy 2007;3(3):207-14.
[39]Abaci HE, Truitt R, Luong E, Drazer G, Gerecht S. Adaptation to oxygen deprivation in cultures of human pluripotent stem cells, endothelial progenitor cells, and umbilical vein endothelial cells. Am J Physiol Cell Physiol 2010;298(6):C1527-37.
[40]Mazure NM, Pouyssegur J.Atypical BH3-domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy 2009;5(6):868-9.
[41]Chen Y, Lu Y, Lu C, Zhang L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-1alpha expression. Pathol Oncol Res 2009;15(3):487-93.
[42]Wan XB, Fan XJ, Chen MY, Xiang J, Huang PY, Guo L, et al. Autophagy. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma.2010 Apr 26;6(3). [Epub ahead of print]
[1]Nap AW, Griffioen AW, Dunselman GA, Bouma-Ter Steege JC, Thijssen VL, Evers JL, et al. Antiangiogenesis therapy for endometriosis. J Clin Endocrinol Metab 2004;89 (3):1089-95.
[2]Kadomatsu K. The midkine family in cancer, inflammation and neural development. Nagoya J Med Sci 2005;67(3-4):71-82.
[3]Toth S, Nagy K, Palfia Z, Rez G. Cellular autophagic capacity changes during azaserine-induced tumour progression in the rat pancreas. Up-regulation in all premalignant stages and down-regulation with loss of cycloheximide sensitivity of segregation along with malignant transformation. Cell Tissue Res 2002;309(3):409-16.
[4]Hanahan D, Weinberg RA. The hallmarks of cancer. Cell 2000;100(1):57-70.
[5]Aita VM, Liang XH, Murty VV, Pincus DL, Yu W, Cayanis E et al. Cloning and genomic structure of beclin 1, a candidate tumor suppressor gene on chromosome 17q21. Genomics 1999;59:59-65.
[6]Miracco C, Cosci E, Oliveri G, Luzi P, Pacenti L, Monciatti I et al. Protein and mRNA expression of autophagy gene Beclin 1 in human brain tumours. Int J Oncol 2007;30:429-36.
[7]Wang ZH, Xu L, Duan ZL, Zeng LQ, Yan NH, Peng ZL. Beclin 1-mediated macroautophagy involves regulation of caspase-9 expression in cervical cancer HeLa cells. Gynecol Oncol 2007;107:107-13.
[8]Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H et al. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature 1999;402:672-6.
[9]Koneri K, Goi T, Hirono Y, Katayama K, Yamaguchi A. Beclin 1 gene inhibits tumor growth in colon cancer cell lines.Anticancer Res 2007;27(3B):1453-7.
[10]Ramakrishnan S, Nguyen TM, Subramanian IV, Kelekar A. Autophagy and angiogenesis inhibition. Autophagy 2007;3(5):512-5.
[11]Nguyen TM, Subramanian IV, Kelekar A, Ramakrishnan S. Kringle 5 of human plasminogen, an angiogenesis inhibitor, induces both autophagy and apoptotic death in endothelial cells. Blood 2007;109(11):4793-802.
[12]Yue Z, Jin S, Yang C, Levine AJ, Heintz N. Beclin 1, an autophagy gene essential for early embryonic development, is a haploinsufficient tumor suppressor. Proc Natl Acad Sci U S A 2003;100(25):15077-82.
[13]Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene.J Clin Invest 2003;112(12):1809-20.
[14]Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH et al. Autophagic and tumour suppressor activity of a novel Beclin1-binding protein UVRAG. Nat Cell Biol 2006;8:688-99.
[15]Furuya N, Yu J, ByWeld M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy 2005;1:46-52.
[16]Levine B, Sinha S, Kroemer G. Bcl-2 family members:dual regulators of apoptosis and autophagy. Autophagy 2008;4(5):600-6.
[17]Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N, et al. Bcl-2 antiapoptotic proteins inhibit Beclin 1-dependent autophagy. Cell.2005;122(6): 927-39.
[18]Maiuri MC, Le Toumelin G, Criollo A, Rain JC, Gautier F, Juin P, et al. Functional and physical interaction between Bcl-X(L) and a BH3-like domain in Beclin-1. EMBO J 2007;26(10):2527-39.
[19]Erlich S, Mizrachy L, Segev O, Lindenboim L, Zmira O, Adi-Harel S, et al. Differential interactions between Beclin 1 and Bcl-2 family members. Autophagy 2007;3(6):561-8.
[20]Saeki K, Yuo A, Okuma E, Yazaki Y, Susin SA, Kroemer G, et al. Bcl-2 down-regulation causes autophagy in a caspase-independent manner in human leukemic HL60 cells. Cell Death Differ 2000;7(12):1263-9.
[21]Akar U, Chaves-Reyez A, Barria M, Tari A, Sanguino A, Kondo Y, et al. Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy 2008;4(5):669-79.
[22]Rashmi R, Pillai SG, Vijayalingam S, Ryerse J, Chinnadurai G. BH3-only protein BIK induces caspase-independent cell death with autophagic features in Bcl-2 null cells. Oncogene 2008;27(10):1366-75.
[23]Daido S, Kanzawa T, Yamamoto A, Takeuchi H, Kondo Y, Kondo S. Pivotal role of the cell death factor BNIP3 in ceramide-induced autophagic cell death in malignant glioma cells. Cancer Res 2004;64(12):4286-93.
[24]Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 2007;14(1):146-57.
[25]Abedin MJ, Wang D, McDonnell MA, Lehmann U, Kelekar A.Autophagy delays apoptotic death in breast cancer cells following DNA damage. Cell Death Differ 2007;14(3):500-10.
[26]Oberstein A, Jeffrey PD, Shi Y.Crystal structure of the Bcl-XL-Beclin 1 peptide complex:Beclin 1 is a novel BH3-only protein. J Biol Chem 2007;282(17): 13123-32.
[27]Oltersdorf T, Elmore SW, Shoemaker AR, Armstrong RC, Augeri DJ, Belli BA, et al. An inhibitor of Bcl-2 family proteins induces regression of solid tumours. Nature 2005;435(7042):677-81.
[28]Maiuri MC, Criollo A, Tasdemir E, Vicencio JM, Tajeddine N, Hickman JA, et al. BH3-only proteins and BH3 mimetics induce autophagy by competitively disrupting the interaction between Beclin 1 and Bcl-2/Bcl-X(L).Autophagy 2007;3(4):374-6.
[29]Akar U, Chaves-Reyez A, Barria M, Tari A, Sanguino A, Kondo Y, et al. Silencing of Bcl-2 expression by small interfering RNA induces autophagic cell death in MCF-7 breast cancer cells. Autophagy 2008;4(5):669-79.
[30]Fimia GM, Stoykova A, Romagnoli A, Giunta L, Di Bartolomeo S, Nardacci R, Ambral regulates autophagy and development of the nervous system. Nature 2007;447(7148):1121-5.
[31]Takahashi Y, Coppola D, Matsushita N, Cualing HD, Sun M, Sato Y, et al.Bif-1 interacts with Beclin 1 through UVRAG and regulates autophagy and tumorigenesis. Nat Cell Biol 2007:1142-51.
[32]Degenhardt K, Mathew R, Beaudoin B, Bray K, Anderson D, Chen G, et al. Autophagy promotes tumor cell survival and restricts necrosis, inflammation, and tumorigenesis. Cancer Cell 2006;10(1):51-64.
[33]Mathew R, Kongara S, Beaudoin B, Karp CM, Bray K, Degenhardt K, et al. Autophagy suppresses tumor progression by limiting chromosomal instability. Genes Dev 2007;21(11):1367-81.
[34]Karantza-Wadsworth V, Patel S, Kravchuk O, Chen G, Mathew R, Jin S, et al.Autophagy mitigates metabolic stress and genome damage in mammary tumorigenesis. genes Dev 2007;21(13):1621-35.
[35]Ota H, Igarashi S, Hatazawa J, Tanaka T. Is adenomyosis an immune disease? Hum Reprod Update 1998;4:360-7.
[36]Wang F, Wen Z, Li H, Yang Z, Zhao X, Yao X. Human leukocyte antigen-G is expressed by the eutopic and ectopic endometrium of adenomyosis. Fertil Steril 2008;90:1599-604.
[37]Paludan C, Schmid D, Landthaler M, Vockerodt M, Kube D,Tuschl T et al. Endogenous MHC class Ⅱ processing of a viral nuclear antigen after autophagy. Science 2005;307:593-6.
[38]Parazzini F, Mais V, Cipriani S, Busacca M, Venturini P; GISE.Determinants of adenomyosis in women who underwent hysterectomy for benign gynecological conditions:results from a prospective multicentric study in Italy.Eur J Obstet Gynecol Reprod Biol 2009;143(2):103-6.
[39]Vercellini P, Vigano P, Somigliana E, et al. Adenomyosis:epidemiological factors. Best Pract Res Clin Obstet Gynaecol 2006;20:465-77.
[40]Vercellini P, Parazzini F, Oldani S, et al. Adenomyosis at hysterectomy:a study on frequency distribution and patient characteristics. Hum Reprod 1995;10:1160-2.
[41]Azziz R. Adenomyosis in pregnancy. A review. J Reprod Med 1986;31:224-7.
[42]Vavilis D, Agorastos T, Tzafetas J, Loufopoulos A, Vakiani M, Constantinidis T, et al. Adenomyosis at hysterectomy:prevalence and relationship to operative findings and reproductive and menstrual factors. Clin Exp Obstet Gynecol 1997;24(1):36-8.
[43]Kim DK, Yang JS, Maiti K, Hwang JI, Kim K, Seen D, et al. A gonadotropin-releasing hormone-Ⅱ antagonist induces autophagy of prostate cancer cells. Cancer Res 2009;69:923-31.
[44]Grundker C, Gunthert AR, Millar RP, Emons G. Expression of gonadotropin--releasing hormone Ⅱ (GnRH-Ⅱ) receptor in human endometrial and ovarian cancer cells and eVects of GnRH-Ⅱ on tumor cell proliferation. J Clin Endocrinol Metab 2002;87:1427-30.
[45]John S, Nayvelt I, Hsu HC, Yang P, Liu W, Das GM et al.Regulation of estrogenic effects by beclin 1 in breast cancer cells.Cancer Res 2008;68:7855-63.
[1]Nap AW, Dunselman GA, de Goeij AF, Evers JL, Groothuis PG. Inhibiting MMP activity prevents the development of endometriosis in the chicken chorioallantoic membrane model. Hum Reprod 2004;19(10):2180-7.
[2]Ruas JL, Poellinger L. Hypoxia-dependent activation of HIF into a transcriptional regulator. Semin Cell Dev Biol.2005;16(4-5):514-22.
[3]Lisy K, Peet DJ. Turn me on:regulating HIF transcriptional activity. Cell Death Differ 2008; 15(4):642-9.
[4]Mahon P C, Hirota K, Semenza GL. FIH-1:a novel protein that interacts with HIF-1α and VHL to mediate repression of HIF-1 transcriptional activity. Genes Dev 2001; 15(20):2675-86.
[5]Semenza G L. HIF-1, O(2) and the 3 PHDs:How animal cells signal hypoxia to the nucleus. Cell 2001;107(1):123.
[6]Koukourakis MI, Giatromanolaki A, Sivridis E, Simopoulos C, Turley H, Talks K, et al. Hypoxia-inducible factor (HIF1α and HIF2α), angiogenesis and chemoradiotherapy outcome of squamous cell head-and-neck cancer. Int J Radiat Oncol Biol Phys 2002;53(5):1192-202.
[7]Zhong H, De Marzo AM, Laughner E, Lim M, Hilton DA, Zagzag D, et al. Overexpression of hypoxia-inducible factor 1α in common human cancers and their metastases. Cancer Res 1999;59(22):5830-5.
[8]Birner P, Schindl M, Obermair A, Plank C, Breitenecker G, Oberhuber G.Overexpression of hypoxia-inducible factor 1α is a marker for an unfavorable prognosis in early-stage invasive cervical cancer. Cancer Res 2000;60(17): 4693-6.
[9]Krishnamachary B, Zagzag D, Nagasawa H, Rainey K, Okuyama H, Baek JH, et al. Hypoxia inducible factor-1 dependent repression of E-cadherin in von Hippel-Lindau tumor suppressor-null renal cell carcinoma mediated by TCF3, ZFHX1A,and ZFHX1B. Cancer Res 2006;66(5):2725-31.
[10]Corley KM, Taylor CJ, Lilly B. Hypoxia inducible factor-1alpha modulates adhesion, migration, and FAK phosphorylation in vascular smooth muscle cells. J Cell Biochem 2005;96(5):971-85.
[11]Funasaka T, Yanagawa T, Hogan V, Raz A. Regulation of phosphoglucose isomerase/autocrine motility factor expression by hypoxia. FASEB J 2005;19(11):1422-30.
[12]Liu LZ, Hu XW, Xia C, He J. Reactive oxygen species regulate epidermal growth factor induced vascular endothelial growth factor and hypoxia inducible factor-1alpha expression through activation of AKT and P70S6K1 in human ovarian cancer cells. Free Radic Biol Med 2006;41(10):1521-33.
[13]Miyoshi A, Kitajima Y, Ide T, Ohtake K, Nagasawa H, Uto Y, et al. Hypoxia accelerates cancer invasion of hepatoma cells by upregulating MMP expression in an HIF-lalpha independent manner. Int J Oncol 2006;29(6):1533-9.
[14]Hopfl G, Ogunshola O, Gassmann M. HIFs and tumor-causes and consequences. Am J Physiol Regul Integr Comp Physiol 2004;286(4):R608-23.
[15]Pouyssegur J, Dayan F, Mazure NM. Hypoxia signalling in cancer and approaches to enforce tumour regression. Nature 2006;441(7092):437-43.
[16]Yang ZF, Poon RT, To J, Ho DW, Fan ST. The potential role of hypoxia inducible factor 1α in tumor progression after hypoxia and chemotherapy in hepatocellular carcinoma. Cancer Res 2004;64 (15):5496-503.
[17]Rankin EB, Giaccia AJ. The role of hypoxia inducible factors in tumorigenesis. Cell Death Differ 2008;15 (4):678-85.
[18]Unruh A, Ressel A, Mohamed HG, Johnson RS, Nadrowitz R, Richter E, et al. The hypoxia-inducible factor-1 alpha is a negative factor for tumor therapy. Oncogene 2003;22 (21):3213-20.
[19]Corn PG, Ricci MS, Scata KA, Arsham AM, Simon MC, Dicker DT, et al.Mxil is induced by hypoxia in a HIF-1-dependent manner and protects cells from c-Myc-induced apoptosis. Cancer Biol Ther 2005;4(11):1285-94.
[20]Erler JT, Cawthorne CJ, Williams KJ, Koritzinsky M, Wouters BG, Wilson C, et al.Hypoxia-mediated down-regulation of Bid and Bax in tumors occurs via hypoxia-inducible factor 1-dependent and-independent mechanisms and contributes to drug resistance. Mol Cell Biol 2004;24(7):2875-89.
[21]Peng XH, Kama P, Cao Z, Jiang BH, Zhou M, Yang L.Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-lalpha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem 2006;281(36):25903-14.
[22]Mizukami Y, Fujiki K, Duerr EM, Gala M, Jo WS, Zhang X, et al. Hypoxic regulation of vascular endothelial growth factor through the induction of phosphatidylinositol 3-kinase/Rho/ROCK and c-Myc. J Biol Chem. 2006;281(20):13957-63.
[23]Kim JY, Ahn HJ, Ryu JH, Suk K, Park JH. BH3-only protein Noxa is a mediator of hypoxic cell death induced by hypoxia-inducible factor lalpha. J Exp Med 2004;199(1):113-24.
[24]Lee MJ, Kim JY, Suk K, Park JH.Identification of the hypoxia-inducible factor 1 alpha-responsive HGTD-P gene as a mediator in the mitochondrial apoptotic pathway. Mol Cell Biol 2004;24(9):3918-27.
[25]Hammond EM, Giaccia AJ. The role of p53 in hypoxia induced apoptosis. Biochem Biophys Res Commun 2005;331 (3):718-25.
[26]Azad MB, Chen Y, Henson ES, Cizeau J, McMillan-Ward E, Israels SJ, et al. Hypoxia induces autophagic cell death in apoptosis-competent cells through a mechanism involving BNIP3. Autophagy 2008;4(2):195-204.
[27]Zhang H, Bosch-Marce M, Shimoda LA, Tan YS, Baek JH, Wesley JB, et al. Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008;283:10892-903.
[28]Iyer NV, Kotch LE, Agani F, Leung SW, Laughner E, Wenger RH, et al. Cellular and developmental control of 02 homeostasis by hypoxia-inducible factor 1α. Genes Dev 1998; 12(2):149-62.
[29]Brahimi-Horn MC, Pouyssegur J. Harnessing the hypoxia inducible factor in cancer and ischemic disease. Biochem Pharmacol 2007; 73:450-7.
[30]Bohensky J, Shapiro IM, Leshinsky S, Terkhorn SP, Adams CS, Srinivas V. HIF regulation of chondrocyte apoptosis:induction of the autophagic pathway. Autophagy 2007;3(3):207-14.
[31]Abaci HE, Truitt R, Luong E, Drazer G, Gerecht S. Adaptation to oxygen deprivation in cultures of human pluripotent stem cells, endothelial progenitor cells, and umbilical vein endothelial cells. Am J Physiol Cell Physiol 2010;298(6):C1527-37.
[32]Mazure NM, Pouyssegur J.Atypical BH3-domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy 2009;5(6):868-9.
[33]Chen Y, Lu Y, Lu C, Zhang L. Beclin-1 expression is a predictor of clinical outcome in patients with esophageal squamous cell carcinoma and correlated to hypoxia-inducible factor (HIF)-lalpha expression. Pathol Oncol Res 2009;15(3):487-93.
[34]Wan XB, Fan XJ, Chen MY, Xiang J, Huang PY, Guo L, et al. Elevated Beclin 1 expression is correlated with HIF-1alpha in predicting poor prognosis of nasopharyngeal carcinoma. Autophagy 2010 Apr 26;6(3). [Epub ahead of print]
[35]Liang C, Feng P, Ku B, Dotan I, Canaani D, Oh BH et al. Autophagic and tumour suppressor activity of a novel Beclinl-binding protein UVRAG. Nat Cell Biol 2006;8:688-699.
[36]Furuya N, Yu J, ByWeld M, Pattingre S, Levine B. The evolutionarily conserved domain of Beclin 1 is required for Vps34 binding, autophagy and tumor suppressor function. Autophagy 2005;1:46-52.
[37]Leyendecker G, Herbertz M, Kunz G, Mall G. Endometriosis results from the dislocation of basal endometrium. Hum Reprod 2002;17(10):2725-36.
[38]Ferenczy A. Pathophysiology of adenomyosis. Hum Reprod Update 1998;4:312-22.
[39]Lei ZM, Rao CV, Lincoln SR, Ackermann DM.Increased expression of human chorionic gonadotropin/human luteinizing hormone receptors in adenomyosis. J Clin Endocrinol Metab 1993;76(3):763-8.
[40]Yamamoto T, Noguchi T, Tamura T, Kitawaki J, Okada H. Evidence for estrogen synthesis in adenomyotic tissues. Am J Obstet Gynecol 1993;169(3):734-8.
[41]Takahashi K, Nagata H, Kitao M. Clinical usefulness of determination of estradiol level in menstrual blood for patients with endometriosis. Nippon Sanka Fujinka Gakkai Zasshi 1989;41:1849-50.
[42]Hever A, Roth RB, Hevezi PA, Lee J, Willhite D, White EC, et al.Molecular characterization of human adenomyosis.Mol Hum Reprod 2006;12(12):737-48.
[43]Zhang L, Li J, Li M. Expression of bcl-2 protein in adenomyosis. Zhonghua Fu Chan Ke Za Zhi 2000;35(9):533-5.
[44]Goumenou A, Panayiotides I, Matalliotakis I, Vlachonikolis I, Tzardi M, Koumantakis E. Bcl-2 and Bax expression in human endometriotic and adenomyotic tissues. Eur J Obstet Gynecol Reprod Biol 2001;99(2):256-60.
[45]Otsuki Y, Misaki O, Sugimoto O, Ito Y, Tsujimoto Y, Akao Y. Cyclic bcl-2 gene expression in human uterine endometrium during menstrual cycle. Lancet 1994;344(8914):28-9.
[46]Yamashita H, Otsuki Y, Matsumoto K, Ueki K, Ueki M. Fas ligand, Fas antigen and Bcl-2 expression in human endometrium during the menstrual cycle. Mol Hum Reprod 1999;5(4):358-64.
[47]Watanabe H, Kanzaki H, Narukawa S, Inoue T, Katsuragawa H, Kaneko Y, et al.Bcl-2 and Fas expression in eutopic and ectopic human endometrium during the menstrual cycle in relation to endometrial cell apoptosis. Am J Obstet Gynecol 1997;176(2):360-8.
[48]Jones RK, Searle RF, Bulmer JN. Apoptosis and bcl-2 expression in normal human endometrium, endometriosis and adenomyosis. Hum Reprod 1998; 13(12):3496-502.
[49]Goteri G, Lucarini G, Montik N, Zizzi A, Stramazzotti D, Fabris G,et al. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-1alpha (HIF-1alpha), and microvessel density in endometrial tissue in women with adenomyosis.Int J Gynecol Pathol 2009;28(2):157-63.
[50]Critchley HO, Osei J, Henderson TA, Boswell L, Sales KJ, Jabbour HN, et al. Hypoxia-inducible factor-1alpha expression in human endometrium and its regulation by prostaglandin E-series prostanoid receptor 2 (EP2). Endocrinology 2006;147(2):744-53.
[51]Zhang J, Salamonsen LA. Expression of hypoxia-inducible factors in human endometrium and suppression of matrix metalloproteinases under hypoxic conditions do not support a major role for hypoxia in regulating tissue breakdown at menstruation. Hum Reprod 2002; 17:265-74.
[52]Sharkey AM, Day K, McPherson A, Malik S, Licence D, Smith SK, et al. Vascular endothelial growth factor expression in human endometrium is regulated by hypoxia. J Clin Endocrinol Metab 2000;85:402-9.
[53]Wu MH, Chen KF, Lin SC, Lgu CW, Tsai SJ. Aberrant Expression of Leptin in Human Endometriotic Stromal Cells Is Induced by Elevated Levels of Hypoxia Inducible Factor-la. Am J Pathol.2007 Feb;170(2):590-8.
[54]任旭,何援利,潘石蕾,彭冬。缺氧诱导因子HIF-1α在子宫内膜异位症的表达及意义。南方医科大学学报2007；27(4)：538-40.
[1]Schlemmer SR, Kaufman DG. Endometrial stromal cells regulate gap-junction function in normal human endometrial epithelial cells but not in endometrial carcinoma cells. Mol Carcinog 2000;28(2):70-5.
[2]Mai KT, Yazdi HM, Perkins DG, Parks W. Pathogenetic role of the stromal cells in endometriosis and adenomyosis. Histopathology 1997;30(5):430-42.
[3]NisolleM, Casanas-Roux F, Donnez J. Early-stage eddometriosis:adhesion and growth of human menstrual endometrium in nude mice. Fertil Steril 2000;74: 306-12.
[4]Solaini G, Baracca A, Lenaz G, Sgarbi G. Hypoxia and mitochondrial oxidative metabolism. Biochim Biophys Acta 2010 Feb 11. [Epub ahead of print]
[5]Mazure NM, Pouyssegur J. Hypoxia-induced autophagy:cell death or cell survival? Curr Opin Cell Biol 2009 Dec 18. [Epub ahead of print]
[6]Semenza GL. Mitochondrial autophagy:life and breath of the cell. Autophagy 2008;16;4(4):534-6.
[7]Zhang H, Bosch-Marce M, Shimoda LA et al.Mitochondrial autophagy is an HIF-1-dependent adaptive metabolic response to hypoxia. J Biol Chem 2008;283:10892-903.
[8]Band M, Joel A, Hernandez A, Avivi A. Hypoxia-induced BNIP3 expression and mitophagy:in vivo comparison of the rat and the hypoxia-tolerant mole rat, Spalax ehrenbergi. FASEB J 2009;23(7):2327-35.
[9]Hamacher-Brady A, Brady NR, Gottlieb RA. Enhancing macroautophagy protects against ischemia/reperfusion injury in cardiac myocytes. J Biol Chem 2006;281(40):29776-87.
[10]Indelicato M, Pucci B, Schito L, Reali V, Aventaggiato M, Mazzarino MC, et al. Role of hypoxia and autophagy in MDA-MB-231 invasiveness. J Cell Physiol 2010;223(2):359-68.
[11]Fyles A,Milosevic M, Hedley D, Pintilie M, Levin W, Manchul L, et al.Tumor hypoxia has independent predictor impact only in patients with node-negative cervix cancer. J Clin Oncol 2002;20(3):680-7.
[12]Amaravadi RK, Yu D, Lum JJ, Bui T, Christophorou MA, Evan GI, et al. Autophagy inhibition enhances therapy-induced apoptosis in a Myc-induced model of lymphoma. J Clin Invest 2007;117(2):326-36
[13]Daniel F, Legrand A, Pessayre D, Vadrot N, Descatoire V, Bernuau D. Partial Beclin 1 silencing aggravates doxorubicin-and Fas-induced apoptosis in HepG2 cells. World J Gastroenterol 2006;12(18):2895-900.
[14]Ahn CH, Jeong EG, Lee JW, Kim MS, Kim SH, Kim SS, et al. Expression of beclin-1, an autophagy-related protein, in gastric and colorectal cancers.APMIS 2007;115(12):1344-9.
[15]Zhu H, Tannous P, Johnstone JL, Kong Y, Shelton JM, Richardson JA, et al. Cardiac autophagy is a maladaptive response to hemodynamic stress. J Clin Invest 2007;117(7):1782-93.
[16]Decker RS, Wildenthal K. Lysosomal alterations in hypoxic and reoxygenated hearts. I. Ultrastructural and cytochemical changes. Am J Pathol 1980;98(2):425-44.
[17]Yan L, Vatner DE, Kim SJ, Ge H, Masurekar M, Massover WH, et al. Autophagy in chronically ischemic myocardium. Proc Natl Acad Sci U S A 2005;102(39):13807-12.
[18]Hamacher-Brady A, Brady NR, Logue SE, Sayen MR, Jinno M, Kirshenbaum LA, et al. Response to myocardial ischemia/reperfusion injury involves Bnip3 and autophagy. Cell Death Differ 2007;14(1):146-57.
[19]Bohensky J, Shapiro IM, Leshinsky S, Terkhorn SP, Adams CS, Srinivas V. HIF-1 regulation of chondrocyte apoptosis:induction of the autophagic pathway. Autophagy 2007;3(3):207-14.
[20]Indelicato M, Pucci B, Schito L, Reali V, Aventaggiato M, Mazzarino MC, et al. Role of hypoxia and autophagy in MDA-MB-231 invasiveness. J Cell Physiol 2010;223(2):359-68.
[21]Meijer AJ, Codogno P. Regulation and role of autophagy in mammalian cells. Int J Biochem Cell Biol 2004;36(12):2445-62.
[22]Yeh CH, Hsu SP, Yang CC, Chien CT, Wang NP.Hypoxic preconditioning reinforces HIF-alpha-dependent HSP70 signaling to reduce ischemic renal failure-induced renal tubular apoptosis and autophagy. Life Sci 2010;86(3-4): 115-23.
[1]Berkley KJ, Rapkin AJ, Papka RE.The pains of endometriosis. Science. 2005;308:1587-9.
[2]Vigano P, Parazzini F, Somigliana E, Vercellini P. Endometriosis:epidemiology and aetiological factors. Best Pract Res Clin Obstet Gynaecol.2004; 18:177-200.
[3]Nap AW, Groothuis PG, Demir AY, Evers JL, Dunselman GA.Pathogenesis of endometriosis. Best Pract Res Clin Obstet Gynaecol.2004; 18:233-44.
[4]Braun DP, Ding J, Shen J, Rana N, Fernandez BB, Dmowski WP.Relationship between apoptosis and the number of macrophages in eutopic endometrium from women with and without endometriosis. Fertil Steril.2002;78:830-5.
[5]Jones RK, Bulmer JN, Searle RF. Phenotypic and functional studies of leukocytes in human endometrium and endometriosis. Hum Reprod Update. 1998;4:702-9.
[6]Gazvani R, Smith L, Fowler PA. Effect of interleukin-8 (IL-8), anti-IL-8, and IL-12 on endometrial cell survival in combined endometrial gland and stromal cell cultures derived from women with and without endometriosis. Fertil Steril. 2002;77:62-7.
[7]Matarese G, De Placido G, Nikas Y, Alviggi C. Pathogenesis of endometriosis: natural immunity dysfunction or autoimmune disease? Trends in Molec Med. 2003;9:223-8.
[8]Ferrero S, Gillott DJ, Remorgida V, Anserini P, Ragni N, Grudzinskas JG. Proteomic analysis of peritoneal fluid in fertile and infertile women with endometriosis. J Reprod Med.2009;54:32-40.
[9]Lebovic DI, Mueller MD, Taylor RN. Immunobiology of endometriosis. Fertil Steril.2001;75:1-10.
[10]Alpay Z, Saed GM, and Diamond MP. Female infertility and free radicals: potential role in adhesions and endometriosis. J Soc Gynecol Investig. 2006; 13:390-8.
[11]Iborra A, Palacio JR, and Martinez P. Oxidative stress and autoimmune response in the infertile woman. Chem Immunol Allergy.2005;88:150-62.
[12]Samlaska CP, Winfield EA. Pentoxifylline. J Am Acad Dermatol.1994;30: 603-21.
[13]Nothnick WB, Curry TE, Vernon MW. Immunomodulation of rat endometriotic implant growth and protein production. Am J Reprod Immunol.1994;31:151-62.
[14]Mohammadzadeh A, Heidari M, Soltanghoraee H, Jeddi-Tehrani M, Ghaffari Novin M, Akhondi MM, et al. Evaluation of the effect of pentoxifylline on white blood cell count in serum and peritoneal fluid in female rats with endometriosis. J Obstet Gynaecol Res.2008;34:307-13.
[15]Vlahos NF, Gregoriou O, Deliveliotou A, Perrea D, Vlachos A, Zhao Y, et al. Effect of pentoxifylline on vascular endothelial growth factor C and flk-1 expression on endometrial implants in the rat endometriosis model. Fertil Steril. 2009; in press.
[16]Steinleitner A, Lambert H, Roy S. Immunomodulation with pentoxifylline abrogates macrophage-mediated infertility in an in vivo model:a paradigm for a novel approach to the treatment of endometriosis-associated subfertility. Fertil Steril.1991;55:26-31.
[17]Steinleitner A, Lambert H, Suarez M, Serpa N, Roy S. Immunomodulation in the treatment of endometriosis-associated subfertility:use of pentoxifylline to reverse the inhibition of fertilization by surgically induced endometriosis in a rodent model. Fertil Steril.1991;56:975-9.
[18]Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, et al. Assessing the quality of reports of randomized clinical trials:Is blinding necessary? Control Clin Trials.1996;17:1-12.
[19]Moher D, Pham B, Jones A, Cook DJ, Jadad AR, Moher M, et al. Does quality of reports of randomised trials affect estimates of intervention efficacy reported in meta-analyses? Lancet.1998;352:609-13.
[20]Balasch J, Creus M, Fabregues F, Carmona F, Martinez-Roman S, Manau D,et al. Pentoxifylline versus placebo in the treatment of infertility associated with minimal or mild endometriosis:a pilot randomized clinical trial. Hum Reprod. 1997;12:2046-50.
[21]Alborzi S, Ghotbi S, Parsanezhad ME, Dehbashi S, Alborzi S, Alborzi M. Pentoxifylline therapy after laparoscopic surgery for different stages of endometriosis:a prospective, double-blind, randomized, placebo-controlled study. J Minim Invasive Gynecol.2007; 14:54-8.
[22]Kamencic H, Thiel JA. Pentoxifylline after conservative surgery for endometriosis:a randomized, controlled trial. J Minim Invasive Gynecol. 2008;15:62-6.
[23]Creus M, Fabregues F, Carmona F, del Pino M, Manau D, Balasch J. Combined laparoscopic surgery and pentoxifylline therapy for treatment of endometriosis-associated infertility:a preliminary trial. Hum Reprod. 2008;23:1910-6.
[24]Marcoux S, Maheux R, Berube S. Laparoscopic surgery in infertile women with minimal or mild endometriosis. N Engl J Med.1997;337:217-22.
[25]Parazzini F. Ablation of lesions or no treatment in minimal-mild endometriosis in infertile women:a randomized trial. Gruppo Italiano per lo Studio dell'Endometriosi. Hum Reprod.1999;14:1332-4.
[26]Kennedy S, Bergqvist A, Chapron C, D'Hooghe T, Dunselman G, Greb R, et al. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005;20:2698-704.
[27]The Practice Committee of the Amercian Society for Reproductive Medicine. Endometriosis and infertility. Fertil Steril.2006;86:S156-S160.
[28]ESHRE Capri Workshop Group. Diagnosis and management of the infertile couple:missing information. Hum Reprod Update.2004;10:295-307.
[29]Hughes E, Brown J, Collins JJ, Farquhar C, Fedorkow DM, Vandekerckhove P.
Ovulation suppression for endometriosis. Cochrane Database Syst Rev. 2007;(3):CD000155.
[30]Steinleitner A, Lambert H, Suarez M:Immunomodulation in the treatment of endometriosis-associated subfertility:Use of pentoxifylline to reverse the inhibition of fertilization by surgically induced endometriosis in a rodent model. Fertil Steril.1991;55:975-9
[31]Zhang X, Sharma RK, Agarwal A, and Falcone T. Effect of pentoxifylline in reducing oxidative stress-induced embryotoxicity. J Assist Reprod Genet. 2005;22:415-7.
[32]Ramey JW, Starke ME, Gibbons WE, Archer DF. The influence of pentoxifylline (Trental) on the antifertility effect of intrauterine devices in rats. Fertil Steril.1994;62:181-5.
[33]Shukla V, Gude RP. Amelioration of B16F10 melanoma cells induced oxidative stress in DBA/2 mice by pentoxifylline. J Exp Clin Cancer Res.2003;22:407-10.
[34]Kwiecien S, Brzozowski T, Konturek PC, Pawlik MW, Pawlik WW, Kwiecien N, et al. Gastroprotection by pentoxyfilline against stress-induced gastric damage. Role of lipid peroxidation, antioxidizing enzymes and proinflammatory cytokines. J Physiol Pharmacol.2004;55:337-55.
[35]Laurent C, Voisin P, Pouget JP. DNA damage in cultured skin microvascular endothelial cells exposed to gamma rays and treated by the combination pentoxifylline and alpha-tocopherol. Int J Radiat Biol.2006;82:309-21.
[36]Delanian S, Porcher R, Balla-Mekias S, Lefaix JL:Randomized, placebo-controlled trial of combined pentoxifylline and tocopherol for regression of superficial radiation induced fibrosis. J Clin Oncol.2003; 21: 2545-50
[37]Ozturk B, Egehan I, Atavci S, Kitapci M:Pentoxifylline in prevention of radiation-induced lung toxicity in patients with breast and lung cancer:a double-blind randomized trial. Int J Radiat Oncol Biol Phys.2004;58:213-9.
[38]Williamson R, Kondziolka D, Kanaan H, Lunsford LD, Flickinger JC. Adverse radiation effects after radiosurgery may benefit from oral vitamin E and pentoxifylline therapy:a pilot study. Stereotact Funct Neurosurg.2008;86: 359-66.
[39]Liu H, Xiong M, Xia YF, Cui NJ, Lu RB, Deng L, et al. Studies on pentoxifylline and tocopherol combination for radiation-induced heart disease in rats. Int J Radiat Oncol Biol Phys.2009;73:1552-9.
[40]Ledee-Bataille N, Olivennes F, Lefaix JL, Chaouat G, Frydman R, Delanian S. Combined treatment by pentoxifylline and tocopherol for recipient women with a thin endometrium enrolled in an oocyte donation programme. Hum Reprod. 2002;17:1249-53.
[41]Kurtoglu S, Gunes T, Koklu E, Bastug O, Canoz O, Kula M, et al. Influence of maternal nicotine exposure on neonatal rat bone:protective effect of pentoxifylline. Exp Biol Med (Maywood).2007;232:398-405.
[42]Adamson GD, Hurd SJ, Pasta DJ, Rodriguez BD. Laparoscopic endometriosis treatment:is it better? Fertil Steril.1993;59:35-44.
[43]Guzick DS, Silliman NP, Adamson GD, Buttram-VC J, Canis M, Malinak LR, et al. Prediction of pregnancy in infertile women based on the American Society for Reproductive Medicine's revised classification of endometriosis. Fertil Steril. 1997;67:822-9.
[44]Osuga Y, Koga K, Tsutsumi O, Yano T, Maruyama M, Kugu K, et al. Role of laparoscopy in the treatment of endometriosis-associated infertility. Gynecol Obstet Invest.2002;53 Suppl 1:33-9.
[45]Ozawa Y, Murakami T, Terada Y, Yaegashi N, Okamura K, Kuriyama S, et al. Management of the pain associated with endometriosis:an update of the painful problems. Tohoku J Exp Med.2006;210:175-88.
[46]Roman H, Puscasiu L. Guidelines for the management of painful endometriosis. Chirurgia (Bucur).2008; 103:265-74.
[47]Wordliczek J, Szczepanik AM, Banach M, Turchan J, Zembala M, Siedlar M, et al. The effect of pentoxifylline on post-injury hyperalgesia in rats and postoperative pain in patients. Life Sci.2000;66:1155-64.
[48]Yap C, Furness S, Farquhar C. Pre and post operative medical therapy for endometriosis surgery. Cochrane Database Syst Rev.2004;(3):CD003678.
[49]Ward A, Clissold SP. Pentoxifylline:a review of its pharmacodynamic and pharmacokinetic properties, and its therapeutic efficacy. Drugs.1987;34:50-97.
[50]Sales AM, de Matos HJ, Nery JAC, Duppre NC, Sampaio EP, Sarno EN. Double-blind trial of the efficacy of pentoxifylline vs thalidomide for the treatment of type Ⅱ reaction in leprosy. Braz J Med Biol Res.2007;40:243-8.
[51]Rizk B, Fountain S, Avery S, Palmer C, Blayney M, Macnamee M, et al. Successful use of pentoxifylline in male-factor infertility and previous failure of in vitro fertilization:a prospective randomized study. J Assist Reprod Genet. 1995;12:710-4.
© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号 地址：北京市海淀区学院路29号 邮编：100083 电话：办公室：(+86 10)66554848；文献借阅、咨询服务、科技查新：66554700 |