HEPN1、RASSF3与垂体腺瘤发生发展的关系
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摘要
目的
垂体腺瘤是颅内第三大肿瘤。垂体腺瘤在病理上属于良性肿瘤，但部分病例具有向周围正常结构如颅骨、硬脑膜、海绵窦、蝶窦、鞍上、鞍旁等侵袭性生长的特点，故临床上将这一类垂体腺瘤称之为侵袭性垂体腺瘤。由于其侵袭性生长，导致其全切率低，复发率高，一直是该病治疗的难点。垂体腺瘤发生、发展、侵袭的机制尚不清楚。为此我们进行了以下实验以探索其发生发展和侵袭的机制：
（1）HEPN1在垂体腺瘤中的表达以及功能研究；
（2）DNA甲基化芯片筛选肿瘤相关基因；RASSF3在垂体腺瘤中的甲基化水平和表达水平以及功能研究研究。
方法
针对以上两个方面的研究，研究方法如下：
（1）选取人垂体腺瘤液氮冷冻标本27例和腺垂体组织4例。根据Hardy s分级，将垂体腺瘤分为2组，其中侵袭性组15例，非侵袭性组12例。
（2）检测HEPN1在垂体腺瘤中的表达情况。比较侵袭性组和非侵袭性组HEPN1mRNA及蛋白质表达水平的差异。构建HEPN1过表达和干扰的慢病毒载体，转染大鼠GH3和小鼠GT1.1垂体腺瘤细胞，观察HEPN1表达水平对GH3和GT1.1细胞增殖、凋亡和侵袭性的影响。检测HEPN1过表达和干扰对Bax、Bcl-2、p53、Casepase-3、Casepase-9、MMP-2、MMP-9表达水平的影响。
（3）运用DNA甲基化芯片筛选侵袭性组和非侵袭性组异常甲基化的基因，在生物学信息分析后，筛选重要基因进行功能研究。
（4）焦磷酸测序法验证RASSF3在垂体腺瘤中的甲基化水平。比较侵袭性组和非侵袭性组RASSF3mRNA及蛋白质表达水平的差异。在大鼠、小鼠正常垂体组织和GH3和小鼠GT1.1垂体腺瘤细胞中，检测RASSF3甲基化水平、表达水平。去甲基化药物5-阿扎胞苷处理GH3和GT1.1细胞，观察RASSF3甲基化水平、表达水平的变化。构建RASSF3过表达和干扰的慢病毒载体，转染GH3和GT1.1细胞，观察RASSF3表达水平对GH3和GT1.1细胞增殖、凋亡和侵袭性的影响。检测RASSF3过表达和干扰对Bax、Bcl-2、p53、Casepase-3、Casepase-9、MMP-2、MMP-9表达水平的影响。
结果
（1）垂体腺瘤中HEPN1表达水平低于正常垂体组织，侵袭性组中HEPN1表达水平低于非侵袭性组。在GH3和GT1.1细胞中过表达HEPN1可抑制腺瘤细胞增殖和侵袭，促进垂体腺瘤细胞凋亡。沉默HEPN1可促进腺瘤细胞增殖和侵袭，抑制垂体腺瘤细胞凋亡。
（2）人垂体腺瘤中RASSF3甲基化水平高于人正常垂体组织，侵袭性组和非侵袭性组RASSF3甲基化水平差异无统计学意义。人垂体腺瘤中RASSF3表达水平低于人正常垂体组织，侵袭性组和非侵袭性组RASSF3表达水平差异无统计学意义。
在大鼠GH3垂体瘤细胞系中，RASSF3甲基化水平高于与大鼠正常垂体组织，而表达水平低于正常垂体组织。小鼠GT1.1垂体瘤细胞RASSF3甲基化水平高于小鼠正常垂体组织，表达水平低于正常垂体组织。
对GH3和GT1.1细胞进行去甲基化药物5-阿扎胞苷处理，RASSF3甲基化水平降低，表达水平增高。在GH3和GT1.1细胞中过表达RASSF3可抑制腺瘤细胞增殖和侵袭，促进垂体腺瘤细胞凋亡，沉默RASSF3可促进腺瘤细胞增殖，抑制腺瘤细胞凋亡，但RASSF3表达水平与肿瘤侵袭性无明显关系。
结论
（1）HEPN1下调可促进垂体腺瘤侵袭。HEPN1表达下调可能是垂体瘤发生发展的重要因素
（2）垂体腺瘤中RASSF3甲基化水平高于正常垂体组织，RASSF3的甲基化水平与表达水平负相关，去甲基化处理可恢复RASSF3的表达，说明RASSF3启动子区域甲基化是其低表达的原因。RASSF3的甲基化可能与垂体腺瘤的发生有关。
Objects
The pituitary gland regulates many functions of other endocrine glands and theirtarget tissues throughout the body. Pituitary adenomas can cause mood disorders, sexualdysfunction, infertility, acromegaly, obesity, visual disturbances, hypertension, diabetesmellitus, and accelerated heart disease. Although pituitary adenomas are benign, somepituitary adenomas are considered to be aggressive or invasive, showing atypical behavior,such as invading adjacent tissues and proliferating rapidly. Invasion of surroundingstructures by pituitary adenomas increases the difficulty of complete resection and is animportant reason for post-operative recurrence. The pathogenic mechanisms underlyingpituitary adenoma formation, progression, and invasion are poorly understood. Mutationsin classic oncogenes and tumor suppressor genes (TSGs), which might be prognosticpredictors or gene therapy targets, are rarely found in pituitary tumors. Thus furtherinvestigation of new oncogenes and TSGs is needed.
To understand the candidate oncogenes and TSGs involved in the pathogenesis ofpituitary adenomas, we studied the machanisms related to pituitary adenomastumorigenesis and progress in the following three aspects:
(1) Expression and function of HEPN1in pituitary adenomas.
(2) Methylated DNA immunoprecipitation with comparative high-densitywhole-genome microarray analysis to identify silenced TSGs in pituitary adenomas.Methylation, expression level and function of RASSF3in pituitary adenomas.Methods
Based on the three aspects above of research,the experimental methods are as follows:
(1) Four normal human adenohypophyses were obtained at the time of autopsy frompatients with no evidence of endocrinopathies. Fifteen invasive somatotroph adenomas and12non-invasive adenomas were obtained at the time of surgery at Changzheng Hospitaland frozen in liquid nitrogen and stored at-80oC.
(2) We analysed the expression of HEPN1in pituitary adenomas andadenohypophyses. HEPN1reduction was more frequent in invasive adenomas. Tounderstand the function of HEPN1, the pituitary adenoma cell lines, GH3and GT1.1, werestably transfected with short hairpin RNA (shRNA) targeting HEPN1or ectogenic HEPN1 by lentivirus-mediated transfection. MTT colorimetric assay, Annexin V/propidium iodide(PI) apoptosis assay, and transwell assay were performed to analyse the effect of HEPN1on cell proliferation, apoptosis, and migration. We also studied the influence of HEPN1expression on the level of MMP-2, MMP-9, BAX, p53, caspase-3and Bcl-2.
(3) To identify candidate tumor suppressor genes involved in pituitary somatotrophadenoma tumorigenesis, we used HG18CpG plus Promoter Microarray in27humansomatotroph adenomas and4normal human adenohypophyses. After bioinformaticsanalysis, RASSF3was selected as a candidate TSG.
(4) Pyrosequencing analysis was used to confirm the result of HG18CpG plusPromoter Microarray. QRT-PCR was performed to study expression of RASSF3.5-Aza-2deoxycytidine and trichostatin-A treatment was used in GH3and GT1.1cell lines.Tounderstand the function of RASSF3, the pituitary adenoma cell lines, GH3and GT1.1,were stably transfected with short hairpin RNA (shRNA) targeting RASSF3or ectogenicRASSF3by lentivirus-mediated transfection.Results
(1) In qRT-PCR, HEPN1reduction was more frequent in the invasive group. HEPN1overexpression in GH3and GT1.1cells inhibited cell proliferation, induced apoptosis,and attenuated invasive capacity, whereas HEPN1silencing enhanced cell proliferationand invasion accompanied by decreased apoptosis. Western blot analysis revealed thatHEPN1overexpression decreased MMP-2, MMP-9, and Bcl-2expression, but increasedBAX, p53, and caspase-3expression. In contrast, HEPN1silencing increased MMP-2,MMP-9, and Bcl-2expression, but decreased BAX, p53, and caspase-3expression.
(2) RASSF3was found with frequent methylation of CpG island in its promoter regionin somatotroph adenomas but rarely in adenohypophyses. This result was confirmed bypyrosequencing analysis. We also found that RASSF3mRNA level correlated negativelyto its gene promoter methylation level. RASSF3hypermethylation and downregulationwas also observed in rat GH3and mouse GT1.1somatotroph adenoma cell lines.5-Aza-2deoxycytidine and trichostatin-A treatment induced RASSF3promoter demethylation, andrestored its expression in GH3and GT1.1cell lines. RASSF3overexpression in GH3andGT1.1cells inhibited proliferation, induced apoptosis accompanied by increased Bax, p53,and caspase-3protein and decreased Bcl-2protein expression. We also found that theantitumor effect of RASSF3was p53dependent, and p53knockdown blocked RASSF3-induced apoptosis and growth inhibition.
Conclusions
(1) HEPN1performs multiple functions as a TSG through suppression of proliferationand invasion, and induction to apoptosis. In conclusion, silencing of HEPN1maycontribute to the progress and invasion of human pituitary somatotroph adenomas. Inpituitary adenoma cell lines, HEPN1silencing promotes proliferation, inhibits apoptosis bydecreased p53, BAX, and caspase-3expression, and promotes invasiveness by increasingthe expression of MMP-2and-9. Our study indicates that HEPN1might be a potentialprognostic predictor or gene therapy target for patients with invasive somatotrophadenomas.
(2) RASSF3gene silencing by promoter methylation is an important early event insomatotroph adenoma tumorigenesis. Hypermethylation-induced silencing of RASSF3may contribute to tumor cell growth by apoptosis inhibition through the p53pathway. Inthe context of the data presented in this study,5-Aza induced re-expression of RASSF3might offer new avenues for treatment of somatotroph adenomas.
垂体腺瘤是颅内第三大肿瘤。垂体腺瘤在病理上属于良性肿瘤，但部分病例具有向周围正常结构如颅骨、硬脑膜、海绵窦、蝶窦、鞍上、鞍旁等侵袭性生长的特点，故临床上将这一类垂体腺瘤称之为侵袭性垂体腺瘤。由于其侵袭性生长，导致其全切率低，复发率高，一直是该病治疗的难点。垂体腺瘤发生、发展、侵袭的机制尚不清楚。为此我们进行了以下实验以探索其发生发展和侵袭的机制：
（1）HEPN1在垂体腺瘤中的表达以及功能研究；
（2）DNA甲基化芯片筛选肿瘤相关基因；RASSF3在垂体腺瘤中的甲基化水平和表达水平以及功能研究研究。
方法
针对以上两个方面的研究，研究方法如下：
（1）选取人垂体腺瘤液氮冷冻标本27例和腺垂体组织4例。根据Hardy s分级，将垂体腺瘤分为2组，其中侵袭性组15例，非侵袭性组12例。
（2）检测HEPN1在垂体腺瘤中的表达情况。比较侵袭性组和非侵袭性组HEPN1mRNA及蛋白质表达水平的差异。构建HEPN1过表达和干扰的慢病毒载体，转染大鼠GH3和小鼠GT1.1垂体腺瘤细胞，观察HEPN1表达水平对GH3和GT1.1细胞增殖、凋亡和侵袭性的影响。检测HEPN1过表达和干扰对Bax、Bcl-2、p53、Casepase-3、Casepase-9、MMP-2、MMP-9表达水平的影响。
（3）运用DNA甲基化芯片筛选侵袭性组和非侵袭性组异常甲基化的基因，在生物学信息分析后，筛选重要基因进行功能研究。
（4）焦磷酸测序法验证RASSF3在垂体腺瘤中的甲基化水平。比较侵袭性组和非侵袭性组RASSF3mRNA及蛋白质表达水平的差异。在大鼠、小鼠正常垂体组织和GH3和小鼠GT1.1垂体腺瘤细胞中，检测RASSF3甲基化水平、表达水平。去甲基化药物5-阿扎胞苷处理GH3和GT1.1细胞，观察RASSF3甲基化水平、表达水平的变化。构建RASSF3过表达和干扰的慢病毒载体，转染GH3和GT1.1细胞，观察RASSF3表达水平对GH3和GT1.1细胞增殖、凋亡和侵袭性的影响。检测RASSF3过表达和干扰对Bax、Bcl-2、p53、Casepase-3、Casepase-9、MMP-2、MMP-9表达水平的影响。
结果
（1）垂体腺瘤中HEPN1表达水平低于正常垂体组织，侵袭性组中HEPN1表达水平低于非侵袭性组。在GH3和GT1.1细胞中过表达HEPN1可抑制腺瘤细胞增殖和侵袭，促进垂体腺瘤细胞凋亡。沉默HEPN1可促进腺瘤细胞增殖和侵袭，抑制垂体腺瘤细胞凋亡。
（2）人垂体腺瘤中RASSF3甲基化水平高于人正常垂体组织，侵袭性组和非侵袭性组RASSF3甲基化水平差异无统计学意义。人垂体腺瘤中RASSF3表达水平低于人正常垂体组织，侵袭性组和非侵袭性组RASSF3表达水平差异无统计学意义。
在大鼠GH3垂体瘤细胞系中，RASSF3甲基化水平高于与大鼠正常垂体组织，而表达水平低于正常垂体组织。小鼠GT1.1垂体瘤细胞RASSF3甲基化水平高于小鼠正常垂体组织，表达水平低于正常垂体组织。
对GH3和GT1.1细胞进行去甲基化药物5-阿扎胞苷处理，RASSF3甲基化水平降低，表达水平增高。在GH3和GT1.1细胞中过表达RASSF3可抑制腺瘤细胞增殖和侵袭，促进垂体腺瘤细胞凋亡，沉默RASSF3可促进腺瘤细胞增殖，抑制腺瘤细胞凋亡，但RASSF3表达水平与肿瘤侵袭性无明显关系。
结论
（1）HEPN1下调可促进垂体腺瘤侵袭。HEPN1表达下调可能是垂体瘤发生发展的重要因素
（2）垂体腺瘤中RASSF3甲基化水平高于正常垂体组织，RASSF3的甲基化水平与表达水平负相关，去甲基化处理可恢复RASSF3的表达，说明RASSF3启动子区域甲基化是其低表达的原因。RASSF3的甲基化可能与垂体腺瘤的发生有关。
Objects
The pituitary gland regulates many functions of other endocrine glands and theirtarget tissues throughout the body. Pituitary adenomas can cause mood disorders, sexualdysfunction, infertility, acromegaly, obesity, visual disturbances, hypertension, diabetesmellitus, and accelerated heart disease. Although pituitary adenomas are benign, somepituitary adenomas are considered to be aggressive or invasive, showing atypical behavior,such as invading adjacent tissues and proliferating rapidly. Invasion of surroundingstructures by pituitary adenomas increases the difficulty of complete resection and is animportant reason for post-operative recurrence. The pathogenic mechanisms underlyingpituitary adenoma formation, progression, and invasion are poorly understood. Mutationsin classic oncogenes and tumor suppressor genes (TSGs), which might be prognosticpredictors or gene therapy targets, are rarely found in pituitary tumors. Thus furtherinvestigation of new oncogenes and TSGs is needed.
To understand the candidate oncogenes and TSGs involved in the pathogenesis ofpituitary adenomas, we studied the machanisms related to pituitary adenomastumorigenesis and progress in the following three aspects:
(1) Expression and function of HEPN1in pituitary adenomas.
(2) Methylated DNA immunoprecipitation with comparative high-densitywhole-genome microarray analysis to identify silenced TSGs in pituitary adenomas.Methylation, expression level and function of RASSF3in pituitary adenomas.Methods
Based on the three aspects above of research,the experimental methods are as follows:
(1) Four normal human adenohypophyses were obtained at the time of autopsy frompatients with no evidence of endocrinopathies. Fifteen invasive somatotroph adenomas and12non-invasive adenomas were obtained at the time of surgery at Changzheng Hospitaland frozen in liquid nitrogen and stored at-80oC.
(2) We analysed the expression of HEPN1in pituitary adenomas andadenohypophyses. HEPN1reduction was more frequent in invasive adenomas. Tounderstand the function of HEPN1, the pituitary adenoma cell lines, GH3and GT1.1, werestably transfected with short hairpin RNA (shRNA) targeting HEPN1or ectogenic HEPN1 by lentivirus-mediated transfection. MTT colorimetric assay, Annexin V/propidium iodide(PI) apoptosis assay, and transwell assay were performed to analyse the effect of HEPN1on cell proliferation, apoptosis, and migration. We also studied the influence of HEPN1expression on the level of MMP-2, MMP-9, BAX, p53, caspase-3and Bcl-2.
(3) To identify candidate tumor suppressor genes involved in pituitary somatotrophadenoma tumorigenesis, we used HG18CpG plus Promoter Microarray in27humansomatotroph adenomas and4normal human adenohypophyses. After bioinformaticsanalysis, RASSF3was selected as a candidate TSG.
(4) Pyrosequencing analysis was used to confirm the result of HG18CpG plusPromoter Microarray. QRT-PCR was performed to study expression of RASSF3.5-Aza-2deoxycytidine and trichostatin-A treatment was used in GH3and GT1.1cell lines.Tounderstand the function of RASSF3, the pituitary adenoma cell lines, GH3and GT1.1,were stably transfected with short hairpin RNA (shRNA) targeting RASSF3or ectogenicRASSF3by lentivirus-mediated transfection.Results
(1) In qRT-PCR, HEPN1reduction was more frequent in the invasive group. HEPN1overexpression in GH3and GT1.1cells inhibited cell proliferation, induced apoptosis,and attenuated invasive capacity, whereas HEPN1silencing enhanced cell proliferationand invasion accompanied by decreased apoptosis. Western blot analysis revealed thatHEPN1overexpression decreased MMP-2, MMP-9, and Bcl-2expression, but increasedBAX, p53, and caspase-3expression. In contrast, HEPN1silencing increased MMP-2,MMP-9, and Bcl-2expression, but decreased BAX, p53, and caspase-3expression.
(2) RASSF3was found with frequent methylation of CpG island in its promoter regionin somatotroph adenomas but rarely in adenohypophyses. This result was confirmed bypyrosequencing analysis. We also found that RASSF3mRNA level correlated negativelyto its gene promoter methylation level. RASSF3hypermethylation and downregulationwas also observed in rat GH3and mouse GT1.1somatotroph adenoma cell lines.5-Aza-2deoxycytidine and trichostatin-A treatment induced RASSF3promoter demethylation, andrestored its expression in GH3and GT1.1cell lines. RASSF3overexpression in GH3andGT1.1cells inhibited proliferation, induced apoptosis accompanied by increased Bax, p53,and caspase-3protein and decreased Bcl-2protein expression. We also found that theantitumor effect of RASSF3was p53dependent, and p53knockdown blocked RASSF3-induced apoptosis and growth inhibition.
Conclusions
(1) HEPN1performs multiple functions as a TSG through suppression of proliferationand invasion, and induction to apoptosis. In conclusion, silencing of HEPN1maycontribute to the progress and invasion of human pituitary somatotroph adenomas. Inpituitary adenoma cell lines, HEPN1silencing promotes proliferation, inhibits apoptosis bydecreased p53, BAX, and caspase-3expression, and promotes invasiveness by increasingthe expression of MMP-2and-9. Our study indicates that HEPN1might be a potentialprognostic predictor or gene therapy target for patients with invasive somatotrophadenomas.
(2) RASSF3gene silencing by promoter methylation is an important early event insomatotroph adenoma tumorigenesis. Hypermethylation-induced silencing of RASSF3may contribute to tumor cell growth by apoptosis inhibition through the p53pathway. Inthe context of the data presented in this study,5-Aza induced re-expression of RASSF3might offer new avenues for treatment of somatotroph adenomas.
引文
[1] Knosp E, Steiner E, Kitz K, et al. Pituitary adenomas with invasion of thecavernous sinus space: a magnetic resonance imaging classification compared withsurgical findings [J]. Neurosurgery,1993,33(4):610-7; discussion7-8.
[2] Moreau L, Cottier J P, Bertrand P, et al. MRI diagnosis of sinus cavernous invasionby pituitary adenomas][J]. Journal de radiologie,1998,79(3):241.
[3] Moh M C, Zhang T, Lee L H, et al. Expression of hepaCAM is downregulated incancers and induces senescence-like growth arrest via a p53/p21-dependentpathway in human breast cancer cells [J]. Carcinogenesis,2008,29(12):2298-305.
[4] Moh M C, Tian Q, Zhang T, et al. The immunoglobulin-like cell adhesion moleculehepaCAM modulates cell adhesion and motility through direct interaction with theactin cytoskeleton [J]. J Cell Physiol,2009,219(2):382-91.
[5] Zhang Q L, Luo C L, Wu X H, et al. HepaCAM induces G1phase arrest andpromotes c-Myc degradation in human renal cell carcinoma [J]. J Cell Biochem,2011,112(10):2910-9.
[6] Yang S, Wu X, Luo C, et al. Expression and clinical significance of hepaCAM andVEGF in urothelial carcinoma [J]. World journal of urology,2010,28(4):473-8.
[7] Xun C, Luo C, Wu X, et al. Expression of hepaCAM and its effect on proliferationof tumor cells in renal cell carcinoma [J]. Urology,2010,75(4):828-34.
[8] Moh M C, Lee L H, Yang X, et al. HEPN1, a novel gene that is frequentlydown-regulated in hepatocellular carcinoma, suppresses cell growth and inducesapoptosis in HepG2cells [J]. Journal of hepatology,2003,39(4):580-6.
[9] Asa S L, Ezzat S. The pathogenesis of pituitary tumors [J]. Annu Rev Pathol,2009,497-126.
[10] Melmed S. Pathogenesis of pituitary tumors [J]. Nat Rev Endocrinol,2011,7(5):257-66.
[11] Dworakowska D, Korbonits M, Aylwin S, et al. The pathology of pituitaryadenomas from a clinical perspective [J]. Frontiers in bioscience,2011,3105-16.
[12] Levy A, Hall L, Yeudall W A, et al. p53gene mutations in pituitary adenomas: rareevents [J]. Clin Endocrinol (Oxf),1994,41(6):809-14.
[13] Morris D G, Musat M, Czirjak S, et al. Differential gene expression in pituitaryadenomas by oligonucleotide array analysis [J]. Eur J Endocrinol,2005,153(1):143-51.
[14] Paez-Pereda M, Kuchenbauer F, Arzt E, et al. Regulation of pituitary hormones andcell proliferation by components of the extracellular matrix [J]. Braz J Med BiolRes,2005,38(10):1487-94.
[15] Sang Q X. Complex role of matrix metalloproteinases in angiogenesis [J]. Cellresearch,1998,8(3):171-7.
[16] Stetler-Stevenson W G, Liotta L A, Kleiner D E, Jr. Extracellular matrix6: role ofmatrix metalloproteinases in tumor invasion and metastasis [J]. FASEB J,1993,7(15):1434-41.
[17] Gong J, Zhao Y, Abdel-Fattah R, et al. Matrix metalloproteinase-9, a potentialbiological marker in invasive pituitary adenomas [J]. Pituitary,2008,11(1):37-48.
[18] Liu W, Matsumoto Y, Okada M, et al. Matrix metalloproteinase2and9expressioncorrelated with cavernous sinus invasion of pituitary adenomas [J]. J Med Invest,2005,52(3-4):151-8.
[19] Asa S L, Ezzat S. The cytogenesis and pathogenesis of pituitary adenomas [J].Endocrine reviews,1998,19(6):798-827.
[20] Michaelis K A, Knox A J, Xu M, et al. Identification of growth arrest andDNA-damage-inducible gene beta (GADD45beta) as a novel tumor suppressor inpituitary gonadotrope tumors [J]. Endocrinology,2011,152(10):3603-13.
[21] Asa S L, Ezzat S. The pathogenesis of pituitary tumours [J]. Nature reviews.Cancer,2002,2(11):836-49.
[22] Faglia G, Spada A. Genesis of pituitary adenomas: state of the art [J]. J Neurooncol,2001,54(2):95-110.
[23] Morris M R, Ricketts C J, Gentle D, et al. Genome-wide methylation analysisidentifies epigenetically inactivated candidate tumour suppressor genes in renal cellcarcinoma [J]. Oncogene,2011,30(12):1390-401.
[24] Simpson D J, Hibberts N A, McNicol A M, et al. Loss of pRb expression inpituitary adenomas is associated with methylation of the RB1CpG island [J].Cancer Res,2000,60(5):1211-6.
[25] Zhu X, Lee K, Asa S L, et al. Epigenetic silencing through DNA and histonemethylation of fibroblast growth factor receptor2in neoplastic pituitary cells [J].Am J Pathol,2007,170(5):1618-28.
[26] Tai K Y, Shiah S G, Shieh Y S, et al. DNA methylation and histone modificationregulate silencing of epithelial cell adhesion molecule for tumor invasion andprogression [J]. Oncogene,2007,26(27):3989-97.
[27] Qian Z R, Sano T, Yoshimoto K, et al. Inactivation of RASSF1A tumor suppressorgene by aberrant promoter hypermethylation in human pituitary adenomas [J]. LabInvest,2005,85(4):464-73.
[28] Qian Z R, Sano T, Yoshimoto K, et al. Tumor-specific downregulation andmethylation of the CDH13(H-cadherin) and CDH1(E-cadherin) genes correlatewith aggressiveness of human pituitary adenomas [J]. Mod Pathol,2007,20(12):1269-77.
[29] da Costa Prando E, Cavalli L R, Rainho C A. Evidence of epigenetic regulation ofthe tumor suppressor gene cluster flanking RASSF1in breast cancer cell lines [J].Epigenetics,2011,6(12):1413-24.
[30] Hesson L, Bieche I, Krex D, et al. Frequent epigenetic inactivation of RASSF1Aand BLU genes located within the critical3p21.3region in gliomas [J]. Oncogene,2004,23(13):2408-19.
[31] Hoque M O, Feng Q, Toure P, et al. Detection of aberrant methylation of four genesin plasma DNA for the detection of breast cancer [J]. Journal of clinical oncology:official journal of the American Society of Clinical Oncology,2006,24(26):4262-9.
[32] Kawai Y, Sakano S, Suehiro Y, et al. Methylation level of the RASSF1A promoteris an independent prognostic factor for clear-cell renal cell carcinoma [J]. Annals ofoncology: official journal of the European Society for Medical Oncology/ESMO,2010,21(8):1612-7.
[33] Martins A T, Monteiro P, Ramalho-Carvalho J, et al. High RASSF1A promotermethylation levels are predictive of poor prognosis in fine-needle aspirate washingsof breast cancer lesions [J]. Breast cancer research and treatment,2011,129(1):1-9.
[34] Meng W, Huebner A, Shabsigh A, et al. Combined RASSF1A and RASSF2APromoter Methylation Analysis as Diagnostic Biomarker for Bladder Cancer [J].Molecular biology international,2012,2012701814.
[35] Stutterheim J, Ichou F A, den Ouden E, et al. Methylated RASSF1a is the firstspecific DNA marker for minimal residual disease testing in neuroblastoma [J].Clin Cancer Res,2012,18(3):808-14.
[36] Tommasi S, Dammann R, Jin S G, et al. RASSF3and NORE1: identification andcloning of two human homologues of the putative tumor suppressor gene RASSF1[J]. Oncogene,2002,21(17):2713-20.
[37] Jacquemart I C, Springs A E, Chen W Y. Rassf3is responsible in part for resistanceto mammary tumor development in neu transgenic mice [J]. Int J Oncol,2009,34(2):517-28.
[38] Song M S, Song S J, Kim S Y, et al. The tumour suppressor RASSF1A promotesMDM2self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex [J].EMBO J,2008,27(13):1863-74.
[39] Calvisi D F, Donninger H, Vos M D, et al. NORE1A tumor suppressor candidatemodulates p21CIP1via p53[J]. Cancer Res,2009,69(11):4629-37.
[40] Chesnokova V, Zonis S, Zhou C, et al. Lineage-specific restraint of pituitarygonadotroph cell adenoma growth [J]. PLoS One,2011,6(3):e17924.
[41] Asa S L, Kovacs K. Functional morphology of the human fetal pituitary [J].Pathology annual,1984,19Pt1275-315.
[42] Ezzat S, Asa S L, Couldwell W T, et al. The prevalence of pituitary adenomas: asystematic review [J]. Cancer,2004,101(3):613-9.
[43] Alexander J M, Biller B M, Bikkal H, et al. Clinically nonfunctioning pituitarytumors are monoclonal in origin [J]. J Clin Invest,1990,86(1):336-40.
[44] Herman V, Fagin J, Gonsky R, et al. Clonal origin of pituitary adenomas [J]. J ClinEndocrinol Metab,1990,71(6):1427-33.
[45] Schulte H M, Oldfield E H, Allolio B, et al. Clonal composition of pituitaryadenomas in patients with Cushing's disease: determination by X-chromosomeinactivation analysis [J]. J Clin Endocrinol Metab,1991,73(6):1302-8.
[46] Gicquel C, Le Bouc Y, Luton J P, et al. Monoclonality of corticotrophmacroadenomas in Cushing's disease [J]. J Clin Endocrinol Metab,1992,75(2):472-5.
[47] Ezzat S, Asa S L. Mechanisms of disease: The pathogenesis of pituitary tumors [J].Nat Clin Pract Endocrinol Metab,2006,2(4):220-30.
[48] Yu S, Asa S L, Weigel R J, et al. Pituitary tumor AP-2alpha recognizes a crypticpromoter in intron4of fibroblast growth factor receptor4[J]. J Biol Chem,2003,278(22):19597-602.
[49] Ezzat S, Yu S, Asa S L. Ikaros isoforms in human pituitary tumors: distinctlocalization, histone acetylation, and activation of the5' fibroblast growth factorreceptor-4promoter [J]. Am J Pathol,2003,163(3):1177-84.
[50] Ezzat S, Zheng L, Asa S L. Pituitary tumor-derived fibroblast growth factorreceptor4isoform disrupts neural cell-adhesion molecule/N-cadherin signaling todiminish cell adhesiveness: a mechanism underlying pituitary neoplasia [J]. MolEndocrinol,2004,18(10):2543-52.
[51] Chandrasekharappa S C, Guru S C, Manickam P, et al. Positional cloning of thegene for multiple endocrine neoplasia-type1[J]. Science,1997,276(5311):404-7.
[52] Zhuang Z, Ezzat S Z, Vortmeyer A O, et al. Mutations of the MEN1tumorsuppressor gene in pituitary tumors [J]. Cancer Res,1997,57(24):5446-51.
[53] Asa S L, Somers K, Ezzat S. The MEN-1gene is rarely down-regulated in pituitaryadenomas [J]. J Clin Endocrinol Metab,1998,83(9):3210-2.
[54] Vierimaa O, Georgitsi M, Lehtonen R, et al. Pituitary adenoma predispositioncaused by germline mutations in the AIP gene [J]. Science,2006,312(5777):1228-30.
[55] Asa S L Tumors of the pituitary gland. Washington, D.C.: American Registry ofPathology;1998.
[56] Billestrup N, Swanson L W, Vale W. Growth hormone-releasing factor stimulatesproliferation of somatotrophs in vitro [J]. Proc Natl Acad Sci U S A,1986,83(18):6854-7.
[57] Godfrey P, Rahal J O, Beamer W G, et al. GHRH receptor of little mice contains amissense mutation in the extracellular domain that disrupts receptor function [J].Nature genetics,1993,4(3):227-32.
[58] Stefaneanu L, Kovacs K, Horvath E, et al. Adenohypophysial changes in micetransgenic for human growth hormone-releasing factor: a histological,immunocytochemical, and electron microscopic investigation [J]. Endocrinology,1989,125(5):2710-8.
[59] Thorner M O, Perryman R L, Cronin M J, et al. Somatotroph hyperplasia.Successful treatment of acromegaly by removal of a pancreatic islet tumorsecreting a growth hormone-releasing factor [J]. J Clin Invest,1982,70(5):965-77.
[60] Sano T, Asa S L, Kovacs K. Growth hormone-releasing hormone-producing tumors:clinical, biochemical, and morphological manifestations [J]. Endocrine reviews,1988,9(3):357-73.
[61] Levy A, Lightman S L. Growth hormone-releasing hormone transcripts in humanpituitary adenomas [J]. J Clin Endocrinol Metab,1992,74(6):1474-6.
[62] Joubert D, Benlot C, Lagoguey A, et al. Normal and growth hormone(GH)-secreting adenomatous human pituitaries release somatostatin andGH-releasing hormone [J]. J Clin Endocrinol Metab,1989,68(3):572-7.
[63] Thapar K, Kovacs K, Stefaneanu L, et al. Overexpression of thegrowth-hormone-releasing hormone gene in acromegaly-associated pituitarytumors. An event associated with neoplastic progression and aggressive behavior[J]. Am J Pathol,1997,151(3):769-84.
[64] Ezzat S, Asa S L, Stefaneanu L, et al. Somatotroph hyperplasia without pituitaryadenoma associated with a long standing growth hormone-releasinghormone-producing bronchial carcinoid [J]. J Clin Endocrinol Metab,1994,78(3):555-60.
[65] Hashimoto K, Koga M, Motomura T, et al. Identification of alternatively splicedmessenger ribonucleic acid encoding truncated growth hormone-releasing hormonereceptor in human pituitary adenomas [J]. J Clin Endocrinol Metab,1995,80(10):2933-9.
[66] Bertherat J, Chanson P, Dewailly D, et al. Somatostatin receptors, adenylate cyclaseactivity, and growth hormone (GH) response to octreotide in GH-secretingadenomas [J]. J Clin Endocrinol Metab,1993,77(6):1577-83.
[67] Danila D C, Haidar J N, Zhang X, et al. Somatostatin receptor-specific analogs:effects on cell proliferation and growth hormone secretion in human somatotrophtumors [J]. J Clin Endocrinol Metab,2001,86(7):2976-81.
[68] Ballare E, Persani L, Lania A G, et al. Mutation of somatostatin receptor type5inan acromegalic patient resistant to somatostatin analog treatment [J]. J ClinEndocrinol Metab,2001,86(8):3809-14.
[69] Levy L, Bourdais J, Mouhieddine B, et al. Presence and characterization of thesomatostatin precursor in normal human pituitaries and in growth hormonesecreting adenomas [J]. J Clin Endocrinol Metab,1993,76(1):85-90.
[70] Filopanti M, Ballare E, Lania A G, et al. Loss of heterozygosity at the SS receptortype5locus in human GH-and TSH-secreting pituitary adenomas [J]. J EndocrinolInvest,2004,27(10):937-42.
[71] Kola B, Korbonits M, Diaz-Cano S, et al. Reduced expression of the growthhormone and type1insulin-like growth factor receptors in human somatotrophtumours and an analysis of possible mutations of the growth hormone receptor [J].Clin Endocrinol (Oxf),2003,59(3):328-38.
[72] Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity inhuman GH-secreting pituitary adenomas [J]. Nature,1987,330(6148):566-8.
[73] Landis C A, Masters S B, Spada A, et al. GTPase inhibiting mutations activate thealpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours [J].Nature,1989,340(6236):692-6.
[74] Hayward B E, Barlier A, Korbonits M, et al. Imprinting of the G(s)alpha geneGNAS1in the pathogenesis of acromegaly [J]. J Clin Invest,2001,107(6):R31-6.
[75] Spada A, Arosio M, Bochicchio D, et al. Clinical, biochemical, and morphologicalcorrelates in patients bearing growth hormone-secreting pituitary tumors with orwithout constitutively active adenylyl cyclase [J]. J Clin Endocrinol Metab,1990,71(6):1421-6.
[76] Asa S L, Digiovanni R, Jiang J, et al. A growth hormone receptor mutation impairsgrowth hormone autofeedback signaling in pituitary tumors [J]. Cancer Res,2007,67(15):7505-11.
[77] Ezzat S, Kontogeorgos G, Redelmeier D A, et al. In vivo responsiveness ofmorphological variants of growth hormone-producing pituitary adenomas tooctreotide [J]. Eur J Endocrinol,1995,133(6):686-90.
[78] Bhayana S, Booth G L, Asa S L, et al. The implication of somatotroph adenomaphenotype to somatostatin analog responsiveness in acromegaly [J]. J ClinEndocrinol Metab,2005,90(11):6290-5.
[79] Asa S L, Coschigano K T, Bellush L, et al. Evidence for growth hormone (GH)autoregulation in pituitary somatotrophs in GH antagonist-transgenic mice and GHreceptor-deficient mice [J]. Am J Pathol,2000,156(3):1009-15.
[80] Delgrange E, Trouillas J, Maiter D, et al. Sex-related difference in the growth ofprolactinomas: a clinical and proliferation marker study [J]. J Clin EndocrinolMetab,1997,82(7):2102-7.
[81] Lohrer P, Gloddek J, Hopfner U, et al. Vascular endothelial growth factorproduction and regulation in rodent and human pituitary tumor cells in vitro [J].Neuroendocrinology,2001,74(2):95-105.
[82] Heaney A P, Fernando M, Melmed S. Functional role of estrogen in pituitary tumorpathogenesis [J]. J Clin Invest,2002,109(2):277-83.
[83] Shen E S, Hardenburg J L, Meade E H, et al. Estradiol induces galanin geneexpression in the pituitary of the mouse in an estrogen receptor alpha-dependentmanner [J]. Endocrinology,1999,140(6):2628-31.
[84] Lee E J, Jakacka M, Duan W R, et al. Adenovirus-directed expression of dominantnegative estrogen receptor induces apoptosis in breast cancer cells and regressionof tumors in nude mice [J]. Molecular medicine,2001,7(11):773-82.
[85] Molitch M E. Pituitary tumors and pregnancy [J]. Growth hormone&IGFresearch: official journal of the Growth Hormone Research Society and theInternational IGF Research Society,2003,13Suppl A S38-44.
[86] Kovacs K, Stefaneanu L, Ezzat S, et al. Prolactin-producing pituitary adenoma in amale-to-female transsexual patient with protracted estrogen administration. Amorphologic study [J]. Arch Pathol Lab Med,1994,118(5):562-5.
[87] Testa G, Vegetti W, Motta T, et al. Two-year treatment with oral contraceptives inhyperprolactinemic patients [J]. Contraception,1998,58(2):69-73.
[88] Schechter J, Goldsmith P, Wilson C, et al. Morphological evidence for the presenceof arteries in human prolactinomas [J]. J Clin Endocrinol Metab,1988,67(4):713-9.
[89] Kelly M A, Rubinstein M, Asa S L, et al. Pituitary lactotroph hyperplasia andchronic hyperprolactinemia in dopamine D2receptor-deficient mice [J]. Neuron,1997,19(1):103-13.
[90] Asa S L, Kelly M A, Grandy D K, et al. Pituitary lactotroph adenomas developafter prolonged lactotroph hyperplasia in dopamine D2receptor-deficient mice [J].Endocrinology,1999,140(11):5348-55.
[91] Fiorentini C, Guerra N, Facchetti M, et al. Nerve growth factor regulates dopamineD(2) receptor expression in prolactinoma cell lines via p75(NGFR)-mediatedactivation of nuclear factor-kappaB [J]. Mol Endocrinol,2002,16(2):353-66.
[92] Devost D, Boutin J M. Autoregulation of the rat prolactin gene in lactotrophs [J].Mol Cell Endocrinol,1999,158(1-2):99-109.
[93] Kelly P A, Binart N, Lucas B, et al. Implications of multiple phenotypes observedin prolactin receptor knockout mice [J]. Front Neuroendocrinol,2001,22(2):140-5.
[94] Schuff K G, Hentges S T, Kelly M A, et al. Lack of prolactin receptor signaling inmice results in lactotroph proliferation and prolactinomas by dopamine-dependentand-independent mechanisms [J]. J Clin Invest,2002,110(7):973-81.
[95] Scheithauer B W, Kovacs K, Randall R V, et al. Pituitary gland in hypothyroidism.Histologic and immunocytologic study [J]. Arch Pathol Lab Med,1985,109(6):499-504.
[96] Yamada M, Monden T, Satoh T, et al. Pituitary adenomas of patients withacromegaly express thyrotropin-releasing hormone receptor messenger RNA:cloning and functional expression of the human thyrotropin-releasing hormonereceptor gene [J]. Biochem Biophys Res Commun,1993,195(2):737-45.
[97] Brinkmeier M L, Stahl J H, Gordon D F, et al. Thyroid hormone-responsivepituitary hyperplasia independent of somatostatin receptor2[J]. Mol Endocrinol,2001,15(12):2129-36.
[98] Carey R M, Varma S K, Drake C R, Jr., et al. Ectopic secretion ofcorticotropin-releasing factor as a cause of Cushing's syndrome. A clinical,morphologic, and biochemical study [J]. The New England journal of medicine,1984,311(1):13-20.
[99] Stenzel-Poore M P, Cameron V A, Vaughan J, et al. Development of Cushing'ssyndrome in corticotropin-releasing factor transgenic mice [J]. Endocrinology,1992,130(6):3378-86.
[100] Scheithauer B W, Kovacs K, Randall R V. The pituitary gland in untreatedAddison's disease. A histologic and immunocytologic study of18adenohypophyses[J]. Arch Pathol Lab Med,1983,107(9):484-7.
[101] Bamberger C M, Schulte H M, Chrousos G P. Molecular determinants ofglucocorticoid receptor function and tissue sensitivity to glucocorticoids [J].Endocrine reviews,1996,17(3):245-61.
[102] Hurley D M, Accili D, Stratakis C A, et al. Point mutation causing a single aminoacid substitution in the hormone binding domain of the glucocorticoid receptor infamilial glucocorticoid resistance [J]. J Clin Invest,1991,87(2):680-6.
[103] Karl M, Lamberts S W, Koper J W, et al. Cushing's disease preceded by generalizedglucocorticoid resistance: clinical consequences of a novel, dominant-negativeglucocorticoid receptor mutation [J]. Proceedings of the Association of AmericanPhysicians,1996,108(4):296-307.
[104] Karl M, Von Wichert G, Kempter E, et al. Nelson's syndrome associated with asomatic frame shift mutation in the glucocorticoid receptor gene [J]. J ClinEndocrinol Metab,1996,81(1):124-9.
[105] Kovacs K, Horvath E, Rewcastle N B, et al. Gonadotroph cell adenoma of thepituitary in a women with long-standing hypogonadism [J]. Archives of gynecology,1980,229(1):57-65.
[106] Nicolis G, Shimshi M, Allen C, et al. Gonadotropin-producing pituitary adenoma ina man with long-standing primary hypogonadism [J]. J Clin Endocrinol Metab,1988,66(1):237-41.
[107] Karga H J, Alexander J M, Hedley-Whyte E T, et al. Ras mutations in humanpituitary tumors [J]. J Clin Endocrinol Metab,1992,74(4):914-9.
[108] Cai W Y, Alexander J M, Hedley-Whyte E T, et al. ras mutations in humanprolactinomas and pituitary carcinomas [J]. J Clin Endocrinol Metab,1994,78(1):89-93.
[109] Zou H, McGarry T J, Bernal T, et al. Identification of a vertebrate sister-chromatidseparation inhibitor involved in transformation and tumorigenesis [J]. Science,1999,285(5426):418-22.
[110] Pei L, Melmed S. Isolation and characterization of a pituitary tumor-transforminggene (PTTG)[J]. Mol Endocrinol,1997,11(4):433-41.
[111] Ramos-Morales F, Dominguez A, Romero F, et al. Cell cycle regulated expressionand phosphorylation of hpttg proto-oncogene product [J]. Oncogene,2000,19(3):403-9.
[112] Chesnokova V, Kovacs K, Castro A V, et al. Pituitary hypoplasia in Pttg-/-mice isprotective for Rb+/-pituitary tumorigenesis [J]. Mol Endocrinol,2005,19(9):2371-9.
[113] Martin A, Odajima J, Hunt S L, et al. Cdk2is dispensable for cell cycle inhibitionand tumor suppression mediated by p27(Kip1) and p21(Cip1)[J]. Cancer cell,2005,7(6):591-8.
[114] Gospodarowicz D, Ferrara N, Schweigerer L, et al. Structural characterization andbiological functions of fibroblast growth factor [J]. Endocrine reviews,1987,8(2):95-114.
[115] Ferrara N, Schweigerer L, Neufeld G, et al. Pituitary follicular cells produce basicfibroblast growth factor [J]. Proc Natl Acad Sci U S A,1987,84(16):5773-7.
[116] Scully K M, Rosenfeld M G. Pituitary development: regulatory codes inmammalian organogenesis [J]. Science,2002,295(5563):2231-5.
[117] Celli G, LaRochelle W J, Mackem S, et al. Soluble dominant-negative receptoruncovers essential roles for fibroblast growth factors in multi-organ induction andpatterning [J]. EMBO J,1998,17(6):1642-55.
[118] Ezzat S, Smyth H S, Ramyar L, et al. Heterogenous in vivo and in vitro expressionof basic fibroblast growth factor by human pituitary adenomas [J]. J ClinEndocrinol Metab,1995,80(3):878-84.
[119] Li Y, Koga M, Kasayama S, et al. Identification and characterization of highmolecular weight forms of basic fibroblast growth factor in human pituitaryadenomas [J]. J Clin Endocrinol Metab,1992,75(6):1436-41.
[120] Zimering M B, Katsumata N, Sato Y, et al. Increased basic fibroblast growth factorin plasma from multiple endocrine neoplasia type1: relation to pituitary tumor [J].J Clin Endocrinol Metab,1993,76(5):1182-7.
[121] Asa S L, Ramyar L, Murphy P R, et al. The endogenous fibroblast growth factor-2antisense gene product regulates pituitary cell growth and hormone production [J].Mol Endocrinol,2001,15(4):589-99.
[122] Heaney A P, Horwitz G A, Wang Z, et al. Early involvement of estrogen-inducedpituitary tumor transforming gene and fibroblast growth factor expression inprolactinoma pathogenesis [J]. Nature medicine,1999,5(11):1317-21.
[123] Abbass S A, Asa S L, Ezzat S. Altered expression of fibroblast growth factorreceptors in human pituitary adenomas [J]. J Clin Endocrinol Metab,1997,82(4):1160-6.
[124] Zhu X, Asa S L, Ezzat S. Fibroblast growth factor2and estrogen control thebalance of histone3modifications targeting MAGE-A3in pituitary neoplasia [J].Clin Cancer Res,2008,14(7):1984-96.
[125] Jacks T, Fazeli A, Schmitt E M, et al. Effects of an Rb mutation in the mouse [J].Nature,1992,359(6393):295-300.
[126] Cryns V L, Alexander J M, Klibanski A, et al. The retinoblastoma gene in humanpituitary tumors [J]. J Clin Endocrinol Metab,1993,77(3):644-6.
[127] Pei L, Melmed S, Scheithauer B, et al. Frequent loss of heterozygosity at theretinoblastoma susceptibility gene (RB) locus in aggressive pituitary tumors:evidence for a chromosome13tumor suppressor gene other than RB [J]. CancerRes,1995,55(8):1613-6.
[128] Woloschak M, Yu A, Xiao J, et al. Abundance and state of phosphorylation of theretinoblastoma gene product in human pituitary tumors [J]. Int J Cancer,1996,67(1):16-9.
[129] Tsai K Y, MacPherson D, Rubinson D A, et al. ARF mutation accelerates pituitarytumor development in Rb+/-mice [J]. Proc Natl Acad Sci U S A,2002,99(26):16865-70.
[130] Lasorella A, Rothschild G, Yokota Y, et al. Id2mediates tumor initiation,proliferation, and angiogenesis in Rb mutant mice [J]. Mol Cell Biol,2005,25(9):3563-74.
[131] Thapar K, Scheithauer B W, Kovacs K, et al. p53expression in pituitary adenomasand carcinomas: correlation with invasiveness and tumor growth fractions [J].Neurosurgery,1996,38(4):765-70; discussion70-1.
[132] Amar A P, Hinton D R, Krieger M D, et al. Invasive pituitary adenomas:significance of proliferation parameters [J]. Pituitary,1999,2(2):117-22.
[133] Sherr C J, Roberts J M. Inhibitors of mammalian G1cyclin-dependent kinases [J].Genes Dev,1995,9(10):1149-63.
[134] Kiyokawa H, Kineman R D, Manova-Todorova K O, et al. Enhanced growth ofmice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1)[J]. Cell,1996,85(5):721-32.
[135] Nakayama K, Ishida N, Shirane M, et al. Mice lacking p27(Kip1) display increasedbody size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors [J].Cell,1996,85(5):707-20.
[136] Fero M L, Rivkin M, Tasch M, et al. A syndrome of multiorgan hyperplasia withfeatures of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficientmice [J]. Cell,1996,85(5):733-44.
[137] Franklin D S, Godfrey V L, Lee H, et al. CDK inhibitors p18(INK4c) and p27(Kip1)mediate two separate pathways to collaboratively suppress pituitary tumorigenesis[J]. Genes Dev,1998,12(18):2899-911.
[138] Bamberger C M, Fehn M, Bamberger A M, et al. Reduced expression levels of thecell-cycle inhibitor p27Kip1in human pituitary adenomas [J]. Eur J Endocrinol,1999,140(3):250-5.
[139] Dahia P L, Aguiar R C, Honegger J, et al. Mutation and expression analysis of thep27/kip1gene in corticotrophin-secreting tumours [J]. Oncogene,1998,16(1):69-76.
[140] Woloschak M, Yu A, Post K D. Frequent inactivation of the p16gene in humanpituitary tumors by gene methylation [J]. Mol Carcinog,1997,19(4):221-4.
[141] Frost S J, Simpson D J, Clayton R N, et al. Transfection of an induciblep16/CDKN2A construct mediates reversible growth inhibition and G1arrest in theAtT20pituitary tumor cell line [J]. Mol Endocrinol,1999,13(11):1801-10.
[142] Zhang X, Sun H, Danila D C, et al. Loss of expression of GADD45gamma, agrowth inhibitory gene, in human pituitary adenomas: implications fortumorigenesis [J]. J Clin Endocrinol Metab,2002,87(3):1262-7.
[143] Bahar A, Bicknell J E, Simpson D J, et al. Loss of expression of the growthinhibitory gene GADD45gamma, in human pituitary adenomas, is associated withCpG island methylation [J]. Oncogene,2004,23(4):936-44.
[144] Zhao J, Dahle D, Zhou Y, et al. Hypermethylation of the promoter region isassociated with the loss of MEG3gene expression in human pituitary tumors [J]. JClin Endocrinol Metab,2005,90(4):2179-86.
[145] Bahar A, Simpson D J, Cutty S J, et al. Isolation and characterization of a novelpituitary tumor apoptosis gene [J]. Mol Endocrinol,2004,18(7):1827-39.
[146] Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros gene in lymphocytedevelopment and homeostasis [J]. Annual review of immunology,1997,15155-76.
[147] Ezzat S, Mader R, Fischer S, et al. An essential role for the hematopoietictranscription factor Ikaros in hypothalamic-pituitary-mediated somatic growth [J].Proc Natl Acad Sci U S A,2006,103(7):2214-9.
[148] Ezzat S, Yu S, Asa S L. The zinc finger Ikaros transcription factor regulatespituitary growth hormone and prolactin gene expression through distinct effects onchromatin accessibility [J]. Mol Endocrinol,2005,19(4):1004-11.
[149] Riley D J, Nikitin A Y, Lee W H. Adenovirus-mediated retinoblastoma gene therapysuppresses spontaneous pituitary melanotroph tumors in Rb+/-mice [J]. Naturemedicine,1996,2(12):1316-21.
[150] Freese A, During M J, Davidson B L, et al. Transfection of human lactotrophadenoma cells with an adenovirus vector expressing tyrosine hydroxylase decreasesprolactin release [J]. J Clin Endocrinol Metab,1996,81(6):2401-4.
[151] Ezzat S, Zheng L, Winer D, et al. Targeting N-cadherin through fibroblast growthfactor receptor-4: distinct pathogenetic and therapeutic implications [J]. MolEndocrinol,2006,20(11):2965-75.
[152] Cottier J P, Destrieux C, Brunereau L, et al. Cavernous Sinus Invasion by PituitaryAdenoma: MR Imaging1[J]. Radiology,2000,215(2):463.
[153] Vieira J O, Cukiert A, Liberman B. Evaluation of magnetic resonance imagingcriteria for cavernous sinus invasion in patients with pituitary adenomas: logisticregression analysis and correlation with surgical findings [J]. Surgical neurology,2006,65(2):130-5.
[154]马驰原,史继新.垂体腺瘤的术前影像学预判[J].中国医学影像技术,2005,21(004):649-52.
[155]霍钢.垂体腺瘤侵袭海绵窦的MRI判定标准[J].第四军医大学学报,2007,28(8):3.
[156]林富禄.垂体腺瘤侵袭海绵窦的术前MRI判断[J].中国临床神经外科杂志,2006,11(5):3.
[157]惠国祯垂体瘤.人民军医出版社;2004:302.
[158]王嵘.垂体腺瘤复发相关特性——高增殖和侵袭性[J].国外医学.神经病学神经外科学分册,1998,5
[159] Thapar K, Kovacs K, Scheithauer B W, et al. Proliferative activity and invasivenessamong pituitary adenomas and carcinomas: an analysis using the MIB-1antibody[J]. Neurosurgery,1996,38(1):99-106; discussion-7.
[160] Przhiialkovskaia E G, Abrosimov A, Grigor'ev A, et al.[Prognostic value of of theexpression Ki-67, CD31, and VEGF in somatotropinomas][J]. Arkh Patol,2010,72(1):35-8.
[161] Salehi F, Agur A, Scheithauer B W, et al. Ki-67in pituitary neoplasms: areview--part I [J]. Neurosurgery,2009,65(3):429-37; discussion37.
[162] Gejman R, Swearingen B, Hedley-Whyte E T. Role of Ki-67proliferation indexand p53expression in predicting progression of pituitary adenomas [J]. Hum Pathol,2008,39(5):758-66.
[163] Brito J, Saez L, Lemp M, et al.[Immunohistochemistry for pituitary hormones andKi-67in growth hormone producing pituitary adenomas][J]. Rev Med Chil,2008,136(7):831-6.
[164]沈晓黎. MRI推断垂体腺瘤质地、侵袭性与经蝶入路术中所见的比较[J].中国耳鼻咽喉颅底外科杂志,2004,10(4):4.
[165] Dolenc V V Anatomy and surgery of the cavernous sinus. Springer;1989.
[166] Destrieux C, Kakou M K, Velut S, et al. Microanatomy of the hypophyseal fossaboundaries [J]. J Neurosurg,1998,88(4):743-52.
[167] Yokoyama S, Hirano H, Moroki K, et al. Are nonfunctioning pituitary adenomasextending into the cavernous sinus aggressive and/or invasive?[J]. Neurosurgery,2001,49(4):857-63.
[168] Yasuda A, Campero A, Martins C, et al. The medial wall of the cavernous sinus:microsurgical anatomy [J]. Neurosurgery,2004,55(1):179.
[169]王永谦,丁美修,谭多盛,等.垂体囊的胚胎发育和显微解剖研究[J].中国临床解剖学杂志,2005,23(002):137-41.
[170]陆云涛,漆松涛,潘军,等.垂体的膜性结构及其临床意义[J].中华神经外科杂志,2010,26(10):
[2] Moreau L, Cottier J P, Bertrand P, et al. MRI diagnosis of sinus cavernous invasionby pituitary adenomas][J]. Journal de radiologie,1998,79(3):241.
[3] Moh M C, Zhang T, Lee L H, et al. Expression of hepaCAM is downregulated incancers and induces senescence-like growth arrest via a p53/p21-dependentpathway in human breast cancer cells [J]. Carcinogenesis,2008,29(12):2298-305.
[4] Moh M C, Tian Q, Zhang T, et al. The immunoglobulin-like cell adhesion moleculehepaCAM modulates cell adhesion and motility through direct interaction with theactin cytoskeleton [J]. J Cell Physiol,2009,219(2):382-91.
[5] Zhang Q L, Luo C L, Wu X H, et al. HepaCAM induces G1phase arrest andpromotes c-Myc degradation in human renal cell carcinoma [J]. J Cell Biochem,2011,112(10):2910-9.
[6] Yang S, Wu X, Luo C, et al. Expression and clinical significance of hepaCAM andVEGF in urothelial carcinoma [J]. World journal of urology,2010,28(4):473-8.
[7] Xun C, Luo C, Wu X, et al. Expression of hepaCAM and its effect on proliferationof tumor cells in renal cell carcinoma [J]. Urology,2010,75(4):828-34.
[8] Moh M C, Lee L H, Yang X, et al. HEPN1, a novel gene that is frequentlydown-regulated in hepatocellular carcinoma, suppresses cell growth and inducesapoptosis in HepG2cells [J]. Journal of hepatology,2003,39(4):580-6.
[9] Asa S L, Ezzat S. The pathogenesis of pituitary tumors [J]. Annu Rev Pathol,2009,497-126.
[10] Melmed S. Pathogenesis of pituitary tumors [J]. Nat Rev Endocrinol,2011,7(5):257-66.
[11] Dworakowska D, Korbonits M, Aylwin S, et al. The pathology of pituitaryadenomas from a clinical perspective [J]. Frontiers in bioscience,2011,3105-16.
[12] Levy A, Hall L, Yeudall W A, et al. p53gene mutations in pituitary adenomas: rareevents [J]. Clin Endocrinol (Oxf),1994,41(6):809-14.
[13] Morris D G, Musat M, Czirjak S, et al. Differential gene expression in pituitaryadenomas by oligonucleotide array analysis [J]. Eur J Endocrinol,2005,153(1):143-51.
[14] Paez-Pereda M, Kuchenbauer F, Arzt E, et al. Regulation of pituitary hormones andcell proliferation by components of the extracellular matrix [J]. Braz J Med BiolRes,2005,38(10):1487-94.
[15] Sang Q X. Complex role of matrix metalloproteinases in angiogenesis [J]. Cellresearch,1998,8(3):171-7.
[16] Stetler-Stevenson W G, Liotta L A, Kleiner D E, Jr. Extracellular matrix6: role ofmatrix metalloproteinases in tumor invasion and metastasis [J]. FASEB J,1993,7(15):1434-41.
[17] Gong J, Zhao Y, Abdel-Fattah R, et al. Matrix metalloproteinase-9, a potentialbiological marker in invasive pituitary adenomas [J]. Pituitary,2008,11(1):37-48.
[18] Liu W, Matsumoto Y, Okada M, et al. Matrix metalloproteinase2and9expressioncorrelated with cavernous sinus invasion of pituitary adenomas [J]. J Med Invest,2005,52(3-4):151-8.
[19] Asa S L, Ezzat S. The cytogenesis and pathogenesis of pituitary adenomas [J].Endocrine reviews,1998,19(6):798-827.
[20] Michaelis K A, Knox A J, Xu M, et al. Identification of growth arrest andDNA-damage-inducible gene beta (GADD45beta) as a novel tumor suppressor inpituitary gonadotrope tumors [J]. Endocrinology,2011,152(10):3603-13.
[21] Asa S L, Ezzat S. The pathogenesis of pituitary tumours [J]. Nature reviews.Cancer,2002,2(11):836-49.
[22] Faglia G, Spada A. Genesis of pituitary adenomas: state of the art [J]. J Neurooncol,2001,54(2):95-110.
[23] Morris M R, Ricketts C J, Gentle D, et al. Genome-wide methylation analysisidentifies epigenetically inactivated candidate tumour suppressor genes in renal cellcarcinoma [J]. Oncogene,2011,30(12):1390-401.
[24] Simpson D J, Hibberts N A, McNicol A M, et al. Loss of pRb expression inpituitary adenomas is associated with methylation of the RB1CpG island [J].Cancer Res,2000,60(5):1211-6.
[25] Zhu X, Lee K, Asa S L, et al. Epigenetic silencing through DNA and histonemethylation of fibroblast growth factor receptor2in neoplastic pituitary cells [J].Am J Pathol,2007,170(5):1618-28.
[26] Tai K Y, Shiah S G, Shieh Y S, et al. DNA methylation and histone modificationregulate silencing of epithelial cell adhesion molecule for tumor invasion andprogression [J]. Oncogene,2007,26(27):3989-97.
[27] Qian Z R, Sano T, Yoshimoto K, et al. Inactivation of RASSF1A tumor suppressorgene by aberrant promoter hypermethylation in human pituitary adenomas [J]. LabInvest,2005,85(4):464-73.
[28] Qian Z R, Sano T, Yoshimoto K, et al. Tumor-specific downregulation andmethylation of the CDH13(H-cadherin) and CDH1(E-cadherin) genes correlatewith aggressiveness of human pituitary adenomas [J]. Mod Pathol,2007,20(12):1269-77.
[29] da Costa Prando E, Cavalli L R, Rainho C A. Evidence of epigenetic regulation ofthe tumor suppressor gene cluster flanking RASSF1in breast cancer cell lines [J].Epigenetics,2011,6(12):1413-24.
[30] Hesson L, Bieche I, Krex D, et al. Frequent epigenetic inactivation of RASSF1Aand BLU genes located within the critical3p21.3region in gliomas [J]. Oncogene,2004,23(13):2408-19.
[31] Hoque M O, Feng Q, Toure P, et al. Detection of aberrant methylation of four genesin plasma DNA for the detection of breast cancer [J]. Journal of clinical oncology:official journal of the American Society of Clinical Oncology,2006,24(26):4262-9.
[32] Kawai Y, Sakano S, Suehiro Y, et al. Methylation level of the RASSF1A promoteris an independent prognostic factor for clear-cell renal cell carcinoma [J]. Annals ofoncology: official journal of the European Society for Medical Oncology/ESMO,2010,21(8):1612-7.
[33] Martins A T, Monteiro P, Ramalho-Carvalho J, et al. High RASSF1A promotermethylation levels are predictive of poor prognosis in fine-needle aspirate washingsof breast cancer lesions [J]. Breast cancer research and treatment,2011,129(1):1-9.
[34] Meng W, Huebner A, Shabsigh A, et al. Combined RASSF1A and RASSF2APromoter Methylation Analysis as Diagnostic Biomarker for Bladder Cancer [J].Molecular biology international,2012,2012701814.
[35] Stutterheim J, Ichou F A, den Ouden E, et al. Methylated RASSF1a is the firstspecific DNA marker for minimal residual disease testing in neuroblastoma [J].Clin Cancer Res,2012,18(3):808-14.
[36] Tommasi S, Dammann R, Jin S G, et al. RASSF3and NORE1: identification andcloning of two human homologues of the putative tumor suppressor gene RASSF1[J]. Oncogene,2002,21(17):2713-20.
[37] Jacquemart I C, Springs A E, Chen W Y. Rassf3is responsible in part for resistanceto mammary tumor development in neu transgenic mice [J]. Int J Oncol,2009,34(2):517-28.
[38] Song M S, Song S J, Kim S Y, et al. The tumour suppressor RASSF1A promotesMDM2self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex [J].EMBO J,2008,27(13):1863-74.
[39] Calvisi D F, Donninger H, Vos M D, et al. NORE1A tumor suppressor candidatemodulates p21CIP1via p53[J]. Cancer Res,2009,69(11):4629-37.
[40] Chesnokova V, Zonis S, Zhou C, et al. Lineage-specific restraint of pituitarygonadotroph cell adenoma growth [J]. PLoS One,2011,6(3):e17924.
[41] Asa S L, Kovacs K. Functional morphology of the human fetal pituitary [J].Pathology annual,1984,19Pt1275-315.
[42] Ezzat S, Asa S L, Couldwell W T, et al. The prevalence of pituitary adenomas: asystematic review [J]. Cancer,2004,101(3):613-9.
[43] Alexander J M, Biller B M, Bikkal H, et al. Clinically nonfunctioning pituitarytumors are monoclonal in origin [J]. J Clin Invest,1990,86(1):336-40.
[44] Herman V, Fagin J, Gonsky R, et al. Clonal origin of pituitary adenomas [J]. J ClinEndocrinol Metab,1990,71(6):1427-33.
[45] Schulte H M, Oldfield E H, Allolio B, et al. Clonal composition of pituitaryadenomas in patients with Cushing's disease: determination by X-chromosomeinactivation analysis [J]. J Clin Endocrinol Metab,1991,73(6):1302-8.
[46] Gicquel C, Le Bouc Y, Luton J P, et al. Monoclonality of corticotrophmacroadenomas in Cushing's disease [J]. J Clin Endocrinol Metab,1992,75(2):472-5.
[47] Ezzat S, Asa S L. Mechanisms of disease: The pathogenesis of pituitary tumors [J].Nat Clin Pract Endocrinol Metab,2006,2(4):220-30.
[48] Yu S, Asa S L, Weigel R J, et al. Pituitary tumor AP-2alpha recognizes a crypticpromoter in intron4of fibroblast growth factor receptor4[J]. J Biol Chem,2003,278(22):19597-602.
[49] Ezzat S, Yu S, Asa S L. Ikaros isoforms in human pituitary tumors: distinctlocalization, histone acetylation, and activation of the5' fibroblast growth factorreceptor-4promoter [J]. Am J Pathol,2003,163(3):1177-84.
[50] Ezzat S, Zheng L, Asa S L. Pituitary tumor-derived fibroblast growth factorreceptor4isoform disrupts neural cell-adhesion molecule/N-cadherin signaling todiminish cell adhesiveness: a mechanism underlying pituitary neoplasia [J]. MolEndocrinol,2004,18(10):2543-52.
[51] Chandrasekharappa S C, Guru S C, Manickam P, et al. Positional cloning of thegene for multiple endocrine neoplasia-type1[J]. Science,1997,276(5311):404-7.
[52] Zhuang Z, Ezzat S Z, Vortmeyer A O, et al. Mutations of the MEN1tumorsuppressor gene in pituitary tumors [J]. Cancer Res,1997,57(24):5446-51.
[53] Asa S L, Somers K, Ezzat S. The MEN-1gene is rarely down-regulated in pituitaryadenomas [J]. J Clin Endocrinol Metab,1998,83(9):3210-2.
[54] Vierimaa O, Georgitsi M, Lehtonen R, et al. Pituitary adenoma predispositioncaused by germline mutations in the AIP gene [J]. Science,2006,312(5777):1228-30.
[55] Asa S L Tumors of the pituitary gland. Washington, D.C.: American Registry ofPathology;1998.
[56] Billestrup N, Swanson L W, Vale W. Growth hormone-releasing factor stimulatesproliferation of somatotrophs in vitro [J]. Proc Natl Acad Sci U S A,1986,83(18):6854-7.
[57] Godfrey P, Rahal J O, Beamer W G, et al. GHRH receptor of little mice contains amissense mutation in the extracellular domain that disrupts receptor function [J].Nature genetics,1993,4(3):227-32.
[58] Stefaneanu L, Kovacs K, Horvath E, et al. Adenohypophysial changes in micetransgenic for human growth hormone-releasing factor: a histological,immunocytochemical, and electron microscopic investigation [J]. Endocrinology,1989,125(5):2710-8.
[59] Thorner M O, Perryman R L, Cronin M J, et al. Somatotroph hyperplasia.Successful treatment of acromegaly by removal of a pancreatic islet tumorsecreting a growth hormone-releasing factor [J]. J Clin Invest,1982,70(5):965-77.
[60] Sano T, Asa S L, Kovacs K. Growth hormone-releasing hormone-producing tumors:clinical, biochemical, and morphological manifestations [J]. Endocrine reviews,1988,9(3):357-73.
[61] Levy A, Lightman S L. Growth hormone-releasing hormone transcripts in humanpituitary adenomas [J]. J Clin Endocrinol Metab,1992,74(6):1474-6.
[62] Joubert D, Benlot C, Lagoguey A, et al. Normal and growth hormone(GH)-secreting adenomatous human pituitaries release somatostatin andGH-releasing hormone [J]. J Clin Endocrinol Metab,1989,68(3):572-7.
[63] Thapar K, Kovacs K, Stefaneanu L, et al. Overexpression of thegrowth-hormone-releasing hormone gene in acromegaly-associated pituitarytumors. An event associated with neoplastic progression and aggressive behavior[J]. Am J Pathol,1997,151(3):769-84.
[64] Ezzat S, Asa S L, Stefaneanu L, et al. Somatotroph hyperplasia without pituitaryadenoma associated with a long standing growth hormone-releasinghormone-producing bronchial carcinoid [J]. J Clin Endocrinol Metab,1994,78(3):555-60.
[65] Hashimoto K, Koga M, Motomura T, et al. Identification of alternatively splicedmessenger ribonucleic acid encoding truncated growth hormone-releasing hormonereceptor in human pituitary adenomas [J]. J Clin Endocrinol Metab,1995,80(10):2933-9.
[66] Bertherat J, Chanson P, Dewailly D, et al. Somatostatin receptors, adenylate cyclaseactivity, and growth hormone (GH) response to octreotide in GH-secretingadenomas [J]. J Clin Endocrinol Metab,1993,77(6):1577-83.
[67] Danila D C, Haidar J N, Zhang X, et al. Somatostatin receptor-specific analogs:effects on cell proliferation and growth hormone secretion in human somatotrophtumors [J]. J Clin Endocrinol Metab,2001,86(7):2976-81.
[68] Ballare E, Persani L, Lania A G, et al. Mutation of somatostatin receptor type5inan acromegalic patient resistant to somatostatin analog treatment [J]. J ClinEndocrinol Metab,2001,86(8):3809-14.
[69] Levy L, Bourdais J, Mouhieddine B, et al. Presence and characterization of thesomatostatin precursor in normal human pituitaries and in growth hormonesecreting adenomas [J]. J Clin Endocrinol Metab,1993,76(1):85-90.
[70] Filopanti M, Ballare E, Lania A G, et al. Loss of heterozygosity at the SS receptortype5locus in human GH-and TSH-secreting pituitary adenomas [J]. J EndocrinolInvest,2004,27(10):937-42.
[71] Kola B, Korbonits M, Diaz-Cano S, et al. Reduced expression of the growthhormone and type1insulin-like growth factor receptors in human somatotrophtumours and an analysis of possible mutations of the growth hormone receptor [J].Clin Endocrinol (Oxf),2003,59(3):328-38.
[72] Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity inhuman GH-secreting pituitary adenomas [J]. Nature,1987,330(6148):566-8.
[73] Landis C A, Masters S B, Spada A, et al. GTPase inhibiting mutations activate thealpha chain of Gs and stimulate adenylyl cyclase in human pituitary tumours [J].Nature,1989,340(6236):692-6.
[74] Hayward B E, Barlier A, Korbonits M, et al. Imprinting of the G(s)alpha geneGNAS1in the pathogenesis of acromegaly [J]. J Clin Invest,2001,107(6):R31-6.
[75] Spada A, Arosio M, Bochicchio D, et al. Clinical, biochemical, and morphologicalcorrelates in patients bearing growth hormone-secreting pituitary tumors with orwithout constitutively active adenylyl cyclase [J]. J Clin Endocrinol Metab,1990,71(6):1421-6.
[76] Asa S L, Digiovanni R, Jiang J, et al. A growth hormone receptor mutation impairsgrowth hormone autofeedback signaling in pituitary tumors [J]. Cancer Res,2007,67(15):7505-11.
[77] Ezzat S, Kontogeorgos G, Redelmeier D A, et al. In vivo responsiveness ofmorphological variants of growth hormone-producing pituitary adenomas tooctreotide [J]. Eur J Endocrinol,1995,133(6):686-90.
[78] Bhayana S, Booth G L, Asa S L, et al. The implication of somatotroph adenomaphenotype to somatostatin analog responsiveness in acromegaly [J]. J ClinEndocrinol Metab,2005,90(11):6290-5.
[79] Asa S L, Coschigano K T, Bellush L, et al. Evidence for growth hormone (GH)autoregulation in pituitary somatotrophs in GH antagonist-transgenic mice and GHreceptor-deficient mice [J]. Am J Pathol,2000,156(3):1009-15.
[80] Delgrange E, Trouillas J, Maiter D, et al. Sex-related difference in the growth ofprolactinomas: a clinical and proliferation marker study [J]. J Clin EndocrinolMetab,1997,82(7):2102-7.
[81] Lohrer P, Gloddek J, Hopfner U, et al. Vascular endothelial growth factorproduction and regulation in rodent and human pituitary tumor cells in vitro [J].Neuroendocrinology,2001,74(2):95-105.
[82] Heaney A P, Fernando M, Melmed S. Functional role of estrogen in pituitary tumorpathogenesis [J]. J Clin Invest,2002,109(2):277-83.
[83] Shen E S, Hardenburg J L, Meade E H, et al. Estradiol induces galanin geneexpression in the pituitary of the mouse in an estrogen receptor alpha-dependentmanner [J]. Endocrinology,1999,140(6):2628-31.
[84] Lee E J, Jakacka M, Duan W R, et al. Adenovirus-directed expression of dominantnegative estrogen receptor induces apoptosis in breast cancer cells and regressionof tumors in nude mice [J]. Molecular medicine,2001,7(11):773-82.
[85] Molitch M E. Pituitary tumors and pregnancy [J]. Growth hormone&IGFresearch: official journal of the Growth Hormone Research Society and theInternational IGF Research Society,2003,13Suppl A S38-44.
[86] Kovacs K, Stefaneanu L, Ezzat S, et al. Prolactin-producing pituitary adenoma in amale-to-female transsexual patient with protracted estrogen administration. Amorphologic study [J]. Arch Pathol Lab Med,1994,118(5):562-5.
[87] Testa G, Vegetti W, Motta T, et al. Two-year treatment with oral contraceptives inhyperprolactinemic patients [J]. Contraception,1998,58(2):69-73.
[88] Schechter J, Goldsmith P, Wilson C, et al. Morphological evidence for the presenceof arteries in human prolactinomas [J]. J Clin Endocrinol Metab,1988,67(4):713-9.
[89] Kelly M A, Rubinstein M, Asa S L, et al. Pituitary lactotroph hyperplasia andchronic hyperprolactinemia in dopamine D2receptor-deficient mice [J]. Neuron,1997,19(1):103-13.
[90] Asa S L, Kelly M A, Grandy D K, et al. Pituitary lactotroph adenomas developafter prolonged lactotroph hyperplasia in dopamine D2receptor-deficient mice [J].Endocrinology,1999,140(11):5348-55.
[91] Fiorentini C, Guerra N, Facchetti M, et al. Nerve growth factor regulates dopamineD(2) receptor expression in prolactinoma cell lines via p75(NGFR)-mediatedactivation of nuclear factor-kappaB [J]. Mol Endocrinol,2002,16(2):353-66.
[92] Devost D, Boutin J M. Autoregulation of the rat prolactin gene in lactotrophs [J].Mol Cell Endocrinol,1999,158(1-2):99-109.
[93] Kelly P A, Binart N, Lucas B, et al. Implications of multiple phenotypes observedin prolactin receptor knockout mice [J]. Front Neuroendocrinol,2001,22(2):140-5.
[94] Schuff K G, Hentges S T, Kelly M A, et al. Lack of prolactin receptor signaling inmice results in lactotroph proliferation and prolactinomas by dopamine-dependentand-independent mechanisms [J]. J Clin Invest,2002,110(7):973-81.
[95] Scheithauer B W, Kovacs K, Randall R V, et al. Pituitary gland in hypothyroidism.Histologic and immunocytologic study [J]. Arch Pathol Lab Med,1985,109(6):499-504.
[96] Yamada M, Monden T, Satoh T, et al. Pituitary adenomas of patients withacromegaly express thyrotropin-releasing hormone receptor messenger RNA:cloning and functional expression of the human thyrotropin-releasing hormonereceptor gene [J]. Biochem Biophys Res Commun,1993,195(2):737-45.
[97] Brinkmeier M L, Stahl J H, Gordon D F, et al. Thyroid hormone-responsivepituitary hyperplasia independent of somatostatin receptor2[J]. Mol Endocrinol,2001,15(12):2129-36.
[98] Carey R M, Varma S K, Drake C R, Jr., et al. Ectopic secretion ofcorticotropin-releasing factor as a cause of Cushing's syndrome. A clinical,morphologic, and biochemical study [J]. The New England journal of medicine,1984,311(1):13-20.
[99] Stenzel-Poore M P, Cameron V A, Vaughan J, et al. Development of Cushing'ssyndrome in corticotropin-releasing factor transgenic mice [J]. Endocrinology,1992,130(6):3378-86.
[100] Scheithauer B W, Kovacs K, Randall R V. The pituitary gland in untreatedAddison's disease. A histologic and immunocytologic study of18adenohypophyses[J]. Arch Pathol Lab Med,1983,107(9):484-7.
[101] Bamberger C M, Schulte H M, Chrousos G P. Molecular determinants ofglucocorticoid receptor function and tissue sensitivity to glucocorticoids [J].Endocrine reviews,1996,17(3):245-61.
[102] Hurley D M, Accili D, Stratakis C A, et al. Point mutation causing a single aminoacid substitution in the hormone binding domain of the glucocorticoid receptor infamilial glucocorticoid resistance [J]. J Clin Invest,1991,87(2):680-6.
[103] Karl M, Lamberts S W, Koper J W, et al. Cushing's disease preceded by generalizedglucocorticoid resistance: clinical consequences of a novel, dominant-negativeglucocorticoid receptor mutation [J]. Proceedings of the Association of AmericanPhysicians,1996,108(4):296-307.
[104] Karl M, Von Wichert G, Kempter E, et al. Nelson's syndrome associated with asomatic frame shift mutation in the glucocorticoid receptor gene [J]. J ClinEndocrinol Metab,1996,81(1):124-9.
[105] Kovacs K, Horvath E, Rewcastle N B, et al. Gonadotroph cell adenoma of thepituitary in a women with long-standing hypogonadism [J]. Archives of gynecology,1980,229(1):57-65.
[106] Nicolis G, Shimshi M, Allen C, et al. Gonadotropin-producing pituitary adenoma ina man with long-standing primary hypogonadism [J]. J Clin Endocrinol Metab,1988,66(1):237-41.
[107] Karga H J, Alexander J M, Hedley-Whyte E T, et al. Ras mutations in humanpituitary tumors [J]. J Clin Endocrinol Metab,1992,74(4):914-9.
[108] Cai W Y, Alexander J M, Hedley-Whyte E T, et al. ras mutations in humanprolactinomas and pituitary carcinomas [J]. J Clin Endocrinol Metab,1994,78(1):89-93.
[109] Zou H, McGarry T J, Bernal T, et al. Identification of a vertebrate sister-chromatidseparation inhibitor involved in transformation and tumorigenesis [J]. Science,1999,285(5426):418-22.
[110] Pei L, Melmed S. Isolation and characterization of a pituitary tumor-transforminggene (PTTG)[J]. Mol Endocrinol,1997,11(4):433-41.
[111] Ramos-Morales F, Dominguez A, Romero F, et al. Cell cycle regulated expressionand phosphorylation of hpttg proto-oncogene product [J]. Oncogene,2000,19(3):403-9.
[112] Chesnokova V, Kovacs K, Castro A V, et al. Pituitary hypoplasia in Pttg-/-mice isprotective for Rb+/-pituitary tumorigenesis [J]. Mol Endocrinol,2005,19(9):2371-9.
[113] Martin A, Odajima J, Hunt S L, et al. Cdk2is dispensable for cell cycle inhibitionand tumor suppression mediated by p27(Kip1) and p21(Cip1)[J]. Cancer cell,2005,7(6):591-8.
[114] Gospodarowicz D, Ferrara N, Schweigerer L, et al. Structural characterization andbiological functions of fibroblast growth factor [J]. Endocrine reviews,1987,8(2):95-114.
[115] Ferrara N, Schweigerer L, Neufeld G, et al. Pituitary follicular cells produce basicfibroblast growth factor [J]. Proc Natl Acad Sci U S A,1987,84(16):5773-7.
[116] Scully K M, Rosenfeld M G. Pituitary development: regulatory codes inmammalian organogenesis [J]. Science,2002,295(5563):2231-5.
[117] Celli G, LaRochelle W J, Mackem S, et al. Soluble dominant-negative receptoruncovers essential roles for fibroblast growth factors in multi-organ induction andpatterning [J]. EMBO J,1998,17(6):1642-55.
[118] Ezzat S, Smyth H S, Ramyar L, et al. Heterogenous in vivo and in vitro expressionof basic fibroblast growth factor by human pituitary adenomas [J]. J ClinEndocrinol Metab,1995,80(3):878-84.
[119] Li Y, Koga M, Kasayama S, et al. Identification and characterization of highmolecular weight forms of basic fibroblast growth factor in human pituitaryadenomas [J]. J Clin Endocrinol Metab,1992,75(6):1436-41.
[120] Zimering M B, Katsumata N, Sato Y, et al. Increased basic fibroblast growth factorin plasma from multiple endocrine neoplasia type1: relation to pituitary tumor [J].J Clin Endocrinol Metab,1993,76(5):1182-7.
[121] Asa S L, Ramyar L, Murphy P R, et al. The endogenous fibroblast growth factor-2antisense gene product regulates pituitary cell growth and hormone production [J].Mol Endocrinol,2001,15(4):589-99.
[122] Heaney A P, Horwitz G A, Wang Z, et al. Early involvement of estrogen-inducedpituitary tumor transforming gene and fibroblast growth factor expression inprolactinoma pathogenesis [J]. Nature medicine,1999,5(11):1317-21.
[123] Abbass S A, Asa S L, Ezzat S. Altered expression of fibroblast growth factorreceptors in human pituitary adenomas [J]. J Clin Endocrinol Metab,1997,82(4):1160-6.
[124] Zhu X, Asa S L, Ezzat S. Fibroblast growth factor2and estrogen control thebalance of histone3modifications targeting MAGE-A3in pituitary neoplasia [J].Clin Cancer Res,2008,14(7):1984-96.
[125] Jacks T, Fazeli A, Schmitt E M, et al. Effects of an Rb mutation in the mouse [J].Nature,1992,359(6393):295-300.
[126] Cryns V L, Alexander J M, Klibanski A, et al. The retinoblastoma gene in humanpituitary tumors [J]. J Clin Endocrinol Metab,1993,77(3):644-6.
[127] Pei L, Melmed S, Scheithauer B, et al. Frequent loss of heterozygosity at theretinoblastoma susceptibility gene (RB) locus in aggressive pituitary tumors:evidence for a chromosome13tumor suppressor gene other than RB [J]. CancerRes,1995,55(8):1613-6.
[128] Woloschak M, Yu A, Xiao J, et al. Abundance and state of phosphorylation of theretinoblastoma gene product in human pituitary tumors [J]. Int J Cancer,1996,67(1):16-9.
[129] Tsai K Y, MacPherson D, Rubinson D A, et al. ARF mutation accelerates pituitarytumor development in Rb+/-mice [J]. Proc Natl Acad Sci U S A,2002,99(26):16865-70.
[130] Lasorella A, Rothschild G, Yokota Y, et al. Id2mediates tumor initiation,proliferation, and angiogenesis in Rb mutant mice [J]. Mol Cell Biol,2005,25(9):3563-74.
[131] Thapar K, Scheithauer B W, Kovacs K, et al. p53expression in pituitary adenomasand carcinomas: correlation with invasiveness and tumor growth fractions [J].Neurosurgery,1996,38(4):765-70; discussion70-1.
[132] Amar A P, Hinton D R, Krieger M D, et al. Invasive pituitary adenomas:significance of proliferation parameters [J]. Pituitary,1999,2(2):117-22.
[133] Sherr C J, Roberts J M. Inhibitors of mammalian G1cyclin-dependent kinases [J].Genes Dev,1995,9(10):1149-63.
[134] Kiyokawa H, Kineman R D, Manova-Todorova K O, et al. Enhanced growth ofmice lacking the cyclin-dependent kinase inhibitor function of p27(Kip1)[J]. Cell,1996,85(5):721-32.
[135] Nakayama K, Ishida N, Shirane M, et al. Mice lacking p27(Kip1) display increasedbody size, multiple organ hyperplasia, retinal dysplasia, and pituitary tumors [J].Cell,1996,85(5):707-20.
[136] Fero M L, Rivkin M, Tasch M, et al. A syndrome of multiorgan hyperplasia withfeatures of gigantism, tumorigenesis, and female sterility in p27(Kip1)-deficientmice [J]. Cell,1996,85(5):733-44.
[137] Franklin D S, Godfrey V L, Lee H, et al. CDK inhibitors p18(INK4c) and p27(Kip1)mediate two separate pathways to collaboratively suppress pituitary tumorigenesis[J]. Genes Dev,1998,12(18):2899-911.
[138] Bamberger C M, Fehn M, Bamberger A M, et al. Reduced expression levels of thecell-cycle inhibitor p27Kip1in human pituitary adenomas [J]. Eur J Endocrinol,1999,140(3):250-5.
[139] Dahia P L, Aguiar R C, Honegger J, et al. Mutation and expression analysis of thep27/kip1gene in corticotrophin-secreting tumours [J]. Oncogene,1998,16(1):69-76.
[140] Woloschak M, Yu A, Post K D. Frequent inactivation of the p16gene in humanpituitary tumors by gene methylation [J]. Mol Carcinog,1997,19(4):221-4.
[141] Frost S J, Simpson D J, Clayton R N, et al. Transfection of an induciblep16/CDKN2A construct mediates reversible growth inhibition and G1arrest in theAtT20pituitary tumor cell line [J]. Mol Endocrinol,1999,13(11):1801-10.
[142] Zhang X, Sun H, Danila D C, et al. Loss of expression of GADD45gamma, agrowth inhibitory gene, in human pituitary adenomas: implications fortumorigenesis [J]. J Clin Endocrinol Metab,2002,87(3):1262-7.
[143] Bahar A, Bicknell J E, Simpson D J, et al. Loss of expression of the growthinhibitory gene GADD45gamma, in human pituitary adenomas, is associated withCpG island methylation [J]. Oncogene,2004,23(4):936-44.
[144] Zhao J, Dahle D, Zhou Y, et al. Hypermethylation of the promoter region isassociated with the loss of MEG3gene expression in human pituitary tumors [J]. JClin Endocrinol Metab,2005,90(4):2179-86.
[145] Bahar A, Simpson D J, Cutty S J, et al. Isolation and characterization of a novelpituitary tumor apoptosis gene [J]. Mol Endocrinol,2004,18(7):1827-39.
[146] Georgopoulos K, Winandy S, Avitahl N. The role of the Ikaros gene in lymphocytedevelopment and homeostasis [J]. Annual review of immunology,1997,15155-76.
[147] Ezzat S, Mader R, Fischer S, et al. An essential role for the hematopoietictranscription factor Ikaros in hypothalamic-pituitary-mediated somatic growth [J].Proc Natl Acad Sci U S A,2006,103(7):2214-9.
[148] Ezzat S, Yu S, Asa S L. The zinc finger Ikaros transcription factor regulatespituitary growth hormone and prolactin gene expression through distinct effects onchromatin accessibility [J]. Mol Endocrinol,2005,19(4):1004-11.
[149] Riley D J, Nikitin A Y, Lee W H. Adenovirus-mediated retinoblastoma gene therapysuppresses spontaneous pituitary melanotroph tumors in Rb+/-mice [J]. Naturemedicine,1996,2(12):1316-21.
[150] Freese A, During M J, Davidson B L, et al. Transfection of human lactotrophadenoma cells with an adenovirus vector expressing tyrosine hydroxylase decreasesprolactin release [J]. J Clin Endocrinol Metab,1996,81(6):2401-4.
[151] Ezzat S, Zheng L, Winer D, et al. Targeting N-cadherin through fibroblast growthfactor receptor-4: distinct pathogenetic and therapeutic implications [J]. MolEndocrinol,2006,20(11):2965-75.
[152] Cottier J P, Destrieux C, Brunereau L, et al. Cavernous Sinus Invasion by PituitaryAdenoma: MR Imaging1[J]. Radiology,2000,215(2):463.
[153] Vieira J O, Cukiert A, Liberman B. Evaluation of magnetic resonance imagingcriteria for cavernous sinus invasion in patients with pituitary adenomas: logisticregression analysis and correlation with surgical findings [J]. Surgical neurology,2006,65(2):130-5.
[154]马驰原,史继新.垂体腺瘤的术前影像学预判[J].中国医学影像技术,2005,21(004):649-52.
[155]霍钢.垂体腺瘤侵袭海绵窦的MRI判定标准[J].第四军医大学学报,2007,28(8):3.
[156]林富禄.垂体腺瘤侵袭海绵窦的术前MRI判断[J].中国临床神经外科杂志,2006,11(5):3.
[157]惠国祯垂体瘤.人民军医出版社;2004:302.
[158]王嵘.垂体腺瘤复发相关特性——高增殖和侵袭性[J].国外医学.神经病学神经外科学分册,1998,5
[159] Thapar K, Kovacs K, Scheithauer B W, et al. Proliferative activity and invasivenessamong pituitary adenomas and carcinomas: an analysis using the MIB-1antibody[J]. Neurosurgery,1996,38(1):99-106; discussion-7.
[160] Przhiialkovskaia E G, Abrosimov A, Grigor'ev A, et al.[Prognostic value of of theexpression Ki-67, CD31, and VEGF in somatotropinomas][J]. Arkh Patol,2010,72(1):35-8.
[161] Salehi F, Agur A, Scheithauer B W, et al. Ki-67in pituitary neoplasms: areview--part I [J]. Neurosurgery,2009,65(3):429-37; discussion37.
[162] Gejman R, Swearingen B, Hedley-Whyte E T. Role of Ki-67proliferation indexand p53expression in predicting progression of pituitary adenomas [J]. Hum Pathol,2008,39(5):758-66.
[163] Brito J, Saez L, Lemp M, et al.[Immunohistochemistry for pituitary hormones andKi-67in growth hormone producing pituitary adenomas][J]. Rev Med Chil,2008,136(7):831-6.
[164]沈晓黎. MRI推断垂体腺瘤质地、侵袭性与经蝶入路术中所见的比较[J].中国耳鼻咽喉颅底外科杂志,2004,10(4):4.
[165] Dolenc V V Anatomy and surgery of the cavernous sinus. Springer;1989.
[166] Destrieux C, Kakou M K, Velut S, et al. Microanatomy of the hypophyseal fossaboundaries [J]. J Neurosurg,1998,88(4):743-52.
[167] Yokoyama S, Hirano H, Moroki K, et al. Are nonfunctioning pituitary adenomasextending into the cavernous sinus aggressive and/or invasive?[J]. Neurosurgery,2001,49(4):857-63.
[168] Yasuda A, Campero A, Martins C, et al. The medial wall of the cavernous sinus:microsurgical anatomy [J]. Neurosurgery,2004,55(1):179.
[169]王永谦,丁美修,谭多盛,等.垂体囊的胚胎发育和显微解剖研究[J].中国临床解剖学杂志,2005,23(002):137-41.
[170]陆云涛,漆松涛,潘军,等.垂体的膜性结构及其临床意义[J].中华神经外科杂志,2010,26(10):