Axin在全反式维甲酸抗胶质瘤细胞增殖及促凋亡作用中的机制研究
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摘要
研究背景:维甲酸类化合物(retinoids)是一类维生素A衍生物,包括维甲酸(retinoic?acid?RA)、维胺酸(retinamide)、维胺酯(retimid?ester)和天然维生素A(retinol)等。维生酸A对生命活动必不可少,它对胚胎发育、精子发生、视觉和细胞分化都有十分重要的作用。早期研究表明维生素A缺乏的动物易发生肿瘤。在饮食中加入药理学浓度的维生素能减少化学药物诱发肿瘤的发生率。维甲酸类化合物最引人注目的作用是预防及治疗一些恶性肿瘤,包括白血病、乳腺癌、皮肤癌、宫颈癌、中枢神经系统肿瘤等。给予RA或合成维甲酸类似物导致人的多种肿瘤细胞株或肿瘤异种移植物生长停止、凋亡和分化。全反式维甲酸属于第三代维甲酸,该维甲酸类化合物由于多烯肽侧链的改变及羧基方向不同分为两种异构体,即顺式维甲酸(cis-retinoic? acid? cisRA)及全反式维甲酸(all-trans? retinoic? acid?ATRA),其中全反式构型最为稳定和常见。RA及其衍生物主要通过其经典的核受体信号通路(RARs和RXRs)从三个方面发挥抗肿瘤作用:诱导肿瘤细胞分化,生长抑制和诱导肿瘤细胞的凋亡。大量的研究表明,RA介导的核受体信号转导通路与Wnt/beta-canetin等信号转导通路之间存在着的相互作用(talkcross),共同调控细胞的分化、增殖及凋亡。
Axin(Axis inhibition)是1997年发现的小鼠Fused基因的编码产物,它是Wnt信号通路的重要的构架蛋白,它将进入细胞的信号整合并传给下游的效应分子,从而实现相应的生物学功能。迄今为止,研究发现Axin至少通过Wnt、、JNK、TGF-β及p53等信号通路中发挥重要作用。其生物学功能涉及胚胎发育、糖原代谢、肿瘤形成、细胞分化、细胞凋亡等方面。特别是近年来,Axin作为肿瘤抑制因子,引起人们广泛的兴趣。Axin过表达的转基因小鼠中出现不同组织器官大量细胞死亡,腺病毒转染野生型Axin基因到肿瘤细胞,可导致肿瘤细胞凋亡。我们实验室以往研究证实野生型小鼠Axin基因的过表达可抑制胶质瘤细胞C6的增殖并诱导其凋亡。近期研究表明Axin参与全反式维甲酸(all-trans retinoic acid ATRA)促胚胎癌细胞株分化的调节,提示Axin可能是维甲酸类化合物调控细胞增殖、分化、凋亡的一个重要的调节分子。
胶质瘤是中枢神经系统最常见的肿瘤(约占原发性中枢神经系统肿瘤的42%),其中四分之三是恶性肿瘤。大量的临床及实验研究表明RA可以有效地降低胶质瘤的复发率,提高患者的生存率。明确Axin在ATRA调控胶质瘤的增殖、凋亡中的作用,将有助于我们进一步探讨胶质瘤的发病机理并为其生物学治疗提供依据。
目的:探讨Axin基因是否参与ATRA介导的胶质瘤细胞株的增殖、凋亡及其作用机制。
方法:(1)治疗量的ATRA处理胶质瘤C6、U251细胞株,采用MTT比色法绘制细胞生长曲线、平板克隆形成实验对细胞克隆形成能力进行了检测、BrdUrd掺入实验检测细胞的增殖能力、流式细胞仪测定细胞增殖、凋亡状态的变化。(2)应用免疫荧光检测β-catenin在细胞内的定位、RT-PCR及Western blot方法分别检测Axin、p53、β-catenin的mRNA及其蛋白质的表达的变化。(3)胶质瘤C6细胞用脂质体转染法瞬时转染rAxin,流式细胞仪检测细胞周期及凋亡的变化;采用免疫荧光染色定位β-catenin、RT-PCR及Western blot方法分别检测稳/瞬转C6细胞株细胞中Axin、p53、β-catenin的mRNA及其蛋白质的表达的变化,研究过表达Axin是否类似ATRA对细胞的作用。(4)AxinRNAi片断转染C6细胞,流式细胞仪检测细胞周期及凋亡的变化,RT-PCR及Western blot方法分别检测p53等的mRNA及其蛋白质的表达的变化。探讨AxinRNAi能否逆转ATRA对胶质瘤细胞的调节。
结果:(1) ATRA抑制胶质瘤细胞的增殖、促进其凋亡; ATRA激活Axin、p53的表达、稳定胞浆内β-catenin蛋白的表达而不影响其总蛋白量。(2)胶质瘤C6细胞过表达Axin与ATRA的作用类似:(i)抑制细胞增殖,促其凋亡;(ii)稳定胞浆β-catenin蛋白的表达;(iii)激活p53的表达。(3)Axin RNAi逆转ATRA对胶质瘤C6细胞的抑制作用:促进细胞增殖,抑制细胞凋亡并抑制p53的表达。
结论:Axin参与ATRA介导的胶质瘤细胞的增殖抑制及促凋亡作用; ATRA激活的Axin的表达,上调抑癌基因p53的表达,并促进β-catenin的核浆穿梭,增加胞浆内β-catenin蛋白的量。上述调节途径可能是ATRA发挥抗肿瘤作用的普遍存在的一种作用机制。
创新点:发现Axin是ATRA调控胶质瘤细胞增殖、凋亡的一个重要的分子。
Retinoids, including retinoic acid, retinamide and retimid ester, arederivants of vitamin A (retinol). It is essential for life and has important roles inembryonic development, spermatogenesis, vision and cellular differentiation.Early researches with vitamin A-deficient animals revealed a connectionbetween this vitamin and susceptibility to carcinogenesis. In the diet,pharmacological retinol can reduce the incidence of carcinogen-inducedcarcinoma. Retinoids play an important role in prevention and therapy of sometumors such as leukecythemia, breast cancer, skin cancer, cervix cancer andCNS tumors. Retinoids reduces the growth of certain tumor cells and inducestheir apoptosis and differentiation. All-trans retinoic acid is the third generationof retinoids. There are two isomerides classified as cis-retinoic acid and all-transretinoic acid according to the lateral chain of polyalkene peptide and the locationof carboxy. All-trans isoform is frequent and stable constitution. Retinoic acidand its derivations induce cells apoptosis and differentioation and reduceproliferation by nuclear receptor (NR) signaling pathway (RARs and RXRs).Many studies demonstrated it has a crosstalk between Wnt/beta-canetinsignaling and NR signaling pathway. They synergistically regulate development, proliferation and apoptosis.
Axin (Axis inhibition), the product of the mouse Fused (Fu) gene found in1997, is an important scaffold protein of the Wnt signaling pathway. It transmitscellular signaling to downstream effective molecule to regulate the signalingtransduction between different signaling pathways. To date, Axin has beenimplicated in at least four different signaling pathways: the Wnt, JNK, p53, andTGF-βsignaling pathways and take part in embryonic development, neurondifferentiation, carcinogenesis, cell apoptosis and glycometabolism. EspeciallyAxin as a tumor suppor has arose more peopleís interest to study the relationshipbetween Axin and human tumor. Over-expression of Axin in transgenic miceleads to massive cell death in different organs. Other studies demonstrated thatectopic expression of Axin induced apoptosis in some tumor cells. Our groupfound that over-expression of Axin by stable transfection induced apoptosis ofglioma C6 cell lines. Recent study reveals that Axin take part in ATRA-induceddifferentiation of embryonic carcinoma cells, suggesting Axin may play animportant role in ATRA-mediated cell fate. The introduction of wild-type Axininto heptocellular and colorectal cancer cells induces apoptosis.
Gliomas are the most common tumors in central nervous system (CNS)(account for 42% of primary CNS tumors and 3/4 of them are malignant). Theclinical and experimental researches have shown that retinoids cut down therecrudescent rate of glioma and improved its survival rate. It is not clear whetherAxin as a regulator of ATRA-mediated cell growth.
Objectives：To investigate in glioma cells whether Axin takes part inATRA-induced cell proliferative inhibition and apoptotic cell death.Methods: (1) C6 and U251 cell lines were treated with ATRA. The effect ofATRA on the proliferation of cells was determined by 3-(4, 5-dimethylthiazol-2-yl) -2, 5-diphenyl tetrazolium bromide (MTT) assay. Todetermine the effect of ATRA on clonal proliferation, plate colony formationassays were performed. The ability of ATRA to inhibit DNA synthesis wasdetermined by estimating the amount of BrdUrd incorporation into DNA byimmunocytochemistry staining. The change of cell cycle was analyzed by flowcytometry. (2) The subcellular localization ofβ-catenin was detected byimmunofluorescent staining. The mRNA and protein of Axin, p53,β-cateninwere examined by RT-PCR and Western blot respectively. (3) To investigatewether over-expression of Axin can mimice the role of ATRA, glioma C6 cellline was stably or transiently transfected with rAxin. Cell cycle were examinedby FCM. The subcellular localization ofβ-catenin was detected byimmunofluorescent staining. The mRNA and protein of Axin, p53,β-cateninwere examined by RT-PCR and Western blot respectively. (4) To investigatewhether Axin RNAi attenuate ATRA-induced cell cycle arrest and apoptosis,siRNA oligos of Axin were transfected into C6 cells. FCM, RT-PCR andWestern blot was use to examine the cell cycle and the expression of p53,respectively.
Results: (1) ATRA inhibited cell proliferation and induced cell apoptosis. ATRAactivated the expression of Axin and p53. ATRA accumulated cytoplasmicbeta-catenin without changing the level of total protein. (2) Over-expression ofAxin could mimice the role of ATRA: (i) inhibited cell proliferation and inducedapoptosis; (ii) accumulated cytoplasmic beta-catenin without altering the levelof protein; (iii) activated the expression of Axin and p53. (3) Axin RNAiattenuated ATRA-induced G1/S arrest and apoptosis and down-regulated theexpression of p53.
Conclusions: ATRA-activated the expression of Axin result in the accumulation of cytoplasmic beta-catenin and the activation of p53. This activationcontributed to ATRA-induced cell proliferative inhibition and apoptosis.Intereatingly, Axin-RNAi caused only moderate decrease of p53 with the ATRAtreatment, implying that there are other mechanisms to regulate ATRA-activatedp53.
Axin(Axis inhibition)是1997年发现的小鼠Fused基因的编码产物,它是Wnt信号通路的重要的构架蛋白,它将进入细胞的信号整合并传给下游的效应分子,从而实现相应的生物学功能。迄今为止,研究发现Axin至少通过Wnt、、JNK、TGF-β及p53等信号通路中发挥重要作用。其生物学功能涉及胚胎发育、糖原代谢、肿瘤形成、细胞分化、细胞凋亡等方面。特别是近年来,Axin作为肿瘤抑制因子,引起人们广泛的兴趣。Axin过表达的转基因小鼠中出现不同组织器官大量细胞死亡,腺病毒转染野生型Axin基因到肿瘤细胞,可导致肿瘤细胞凋亡。我们实验室以往研究证实野生型小鼠Axin基因的过表达可抑制胶质瘤细胞C6的增殖并诱导其凋亡。近期研究表明Axin参与全反式维甲酸(all-trans retinoic acid ATRA)促胚胎癌细胞株分化的调节,提示Axin可能是维甲酸类化合物调控细胞增殖、分化、凋亡的一个重要的调节分子。
胶质瘤是中枢神经系统最常见的肿瘤(约占原发性中枢神经系统肿瘤的42%),其中四分之三是恶性肿瘤。大量的临床及实验研究表明RA可以有效地降低胶质瘤的复发率,提高患者的生存率。明确Axin在ATRA调控胶质瘤的增殖、凋亡中的作用,将有助于我们进一步探讨胶质瘤的发病机理并为其生物学治疗提供依据。
目的:探讨Axin基因是否参与ATRA介导的胶质瘤细胞株的增殖、凋亡及其作用机制。
方法:(1)治疗量的ATRA处理胶质瘤C6、U251细胞株,采用MTT比色法绘制细胞生长曲线、平板克隆形成实验对细胞克隆形成能力进行了检测、BrdUrd掺入实验检测细胞的增殖能力、流式细胞仪测定细胞增殖、凋亡状态的变化。(2)应用免疫荧光检测β-catenin在细胞内的定位、RT-PCR及Western blot方法分别检测Axin、p53、β-catenin的mRNA及其蛋白质的表达的变化。(3)胶质瘤C6细胞用脂质体转染法瞬时转染rAxin,流式细胞仪检测细胞周期及凋亡的变化;采用免疫荧光染色定位β-catenin、RT-PCR及Western blot方法分别检测稳/瞬转C6细胞株细胞中Axin、p53、β-catenin的mRNA及其蛋白质的表达的变化,研究过表达Axin是否类似ATRA对细胞的作用。(4)AxinRNAi片断转染C6细胞,流式细胞仪检测细胞周期及凋亡的变化,RT-PCR及Western blot方法分别检测p53等的mRNA及其蛋白质的表达的变化。探讨AxinRNAi能否逆转ATRA对胶质瘤细胞的调节。
结果:(1) ATRA抑制胶质瘤细胞的增殖、促进其凋亡; ATRA激活Axin、p53的表达、稳定胞浆内β-catenin蛋白的表达而不影响其总蛋白量。(2)胶质瘤C6细胞过表达Axin与ATRA的作用类似:(i)抑制细胞增殖,促其凋亡;(ii)稳定胞浆β-catenin蛋白的表达;(iii)激活p53的表达。(3)Axin RNAi逆转ATRA对胶质瘤C6细胞的抑制作用:促进细胞增殖,抑制细胞凋亡并抑制p53的表达。
结论:Axin参与ATRA介导的胶质瘤细胞的增殖抑制及促凋亡作用; ATRA激活的Axin的表达,上调抑癌基因p53的表达,并促进β-catenin的核浆穿梭,增加胞浆内β-catenin蛋白的量。上述调节途径可能是ATRA发挥抗肿瘤作用的普遍存在的一种作用机制。
创新点:发现Axin是ATRA调控胶质瘤细胞增殖、凋亡的一个重要的分子。
Retinoids, including retinoic acid, retinamide and retimid ester, arederivants of vitamin A (retinol). It is essential for life and has important roles inembryonic development, spermatogenesis, vision and cellular differentiation.Early researches with vitamin A-deficient animals revealed a connectionbetween this vitamin and susceptibility to carcinogenesis. In the diet,pharmacological retinol can reduce the incidence of carcinogen-inducedcarcinoma. Retinoids play an important role in prevention and therapy of sometumors such as leukecythemia, breast cancer, skin cancer, cervix cancer andCNS tumors. Retinoids reduces the growth of certain tumor cells and inducestheir apoptosis and differentiation. All-trans retinoic acid is the third generationof retinoids. There are two isomerides classified as cis-retinoic acid and all-transretinoic acid according to the lateral chain of polyalkene peptide and the locationof carboxy. All-trans isoform is frequent and stable constitution. Retinoic acidand its derivations induce cells apoptosis and differentioation and reduceproliferation by nuclear receptor (NR) signaling pathway (RARs and RXRs).Many studies demonstrated it has a crosstalk between Wnt/beta-canetinsignaling and NR signaling pathway. They synergistically regulate development, proliferation and apoptosis.
Axin (Axis inhibition), the product of the mouse Fused (Fu) gene found in1997, is an important scaffold protein of the Wnt signaling pathway. It transmitscellular signaling to downstream effective molecule to regulate the signalingtransduction between different signaling pathways. To date, Axin has beenimplicated in at least four different signaling pathways: the Wnt, JNK, p53, andTGF-βsignaling pathways and take part in embryonic development, neurondifferentiation, carcinogenesis, cell apoptosis and glycometabolism. EspeciallyAxin as a tumor suppor has arose more peopleís interest to study the relationshipbetween Axin and human tumor. Over-expression of Axin in transgenic miceleads to massive cell death in different organs. Other studies demonstrated thatectopic expression of Axin induced apoptosis in some tumor cells. Our groupfound that over-expression of Axin by stable transfection induced apoptosis ofglioma C6 cell lines. Recent study reveals that Axin take part in ATRA-induceddifferentiation of embryonic carcinoma cells, suggesting Axin may play animportant role in ATRA-mediated cell fate. The introduction of wild-type Axininto heptocellular and colorectal cancer cells induces apoptosis.
Gliomas are the most common tumors in central nervous system (CNS)(account for 42% of primary CNS tumors and 3/4 of them are malignant). Theclinical and experimental researches have shown that retinoids cut down therecrudescent rate of glioma and improved its survival rate. It is not clear whetherAxin as a regulator of ATRA-mediated cell growth.
Objectives：To investigate in glioma cells whether Axin takes part inATRA-induced cell proliferative inhibition and apoptotic cell death.Methods: (1) C6 and U251 cell lines were treated with ATRA. The effect ofATRA on the proliferation of cells was determined by 3-(4, 5-dimethylthiazol-2-yl) -2, 5-diphenyl tetrazolium bromide (MTT) assay. Todetermine the effect of ATRA on clonal proliferation, plate colony formationassays were performed. The ability of ATRA to inhibit DNA synthesis wasdetermined by estimating the amount of BrdUrd incorporation into DNA byimmunocytochemistry staining. The change of cell cycle was analyzed by flowcytometry. (2) The subcellular localization ofβ-catenin was detected byimmunofluorescent staining. The mRNA and protein of Axin, p53,β-cateninwere examined by RT-PCR and Western blot respectively. (3) To investigatewether over-expression of Axin can mimice the role of ATRA, glioma C6 cellline was stably or transiently transfected with rAxin. Cell cycle were examinedby FCM. The subcellular localization ofβ-catenin was detected byimmunofluorescent staining. The mRNA and protein of Axin, p53,β-cateninwere examined by RT-PCR and Western blot respectively. (4) To investigatewhether Axin RNAi attenuate ATRA-induced cell cycle arrest and apoptosis,siRNA oligos of Axin were transfected into C6 cells. FCM, RT-PCR andWestern blot was use to examine the cell cycle and the expression of p53,respectively.
Results: (1) ATRA inhibited cell proliferation and induced cell apoptosis. ATRAactivated the expression of Axin and p53. ATRA accumulated cytoplasmicbeta-catenin without changing the level of total protein. (2) Over-expression ofAxin could mimice the role of ATRA: (i) inhibited cell proliferation and inducedapoptosis; (ii) accumulated cytoplasmic beta-catenin without altering the levelof protein; (iii) activated the expression of Axin and p53. (3) Axin RNAiattenuated ATRA-induced G1/S arrest and apoptosis and down-regulated theexpression of p53.
Conclusions: ATRA-activated the expression of Axin result in the accumulation of cytoplasmic beta-catenin and the activation of p53. This activationcontributed to ATRA-induced cell proliferative inhibition and apoptosis.Intereatingly, Axin-RNAi caused only moderate decrease of p53 with the ATRAtreatment, implying that there are other mechanisms to regulate ATRA-activatedp53.
引文
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