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题名	肿瘤细胞中视黄酸受体与孤生受体相互作用的不同模式; Distinct role and functional mode of retinoid receptors and orphan receptors in carcinoma cells
作者	叶晓峰
答辩日期	2004 ; 2004
导师	吴乔
关键词	全反式视黄酸 All-trans retinoic acid (ATRA) 视黄酸受体，凋亡，细胞周期 Retinoid receptors Apoptosis Cell cycle
英文摘要	全反式视黄酸ATRA 能够调节肿瘤细胞生长、分化和凋亡。ATRA 主要 通过它的受体RARs 和RXRs 发挥功能。在ATRA 存在下，RARs 和RXRs 形成异源二聚体，由此调节视黄酸应答元件RARE 下游靶基因的表达。此 外，还有一些孤生受体也参与了ATRA 的信号途径，例如TR3。这些受体 如何在不同细胞内介导ATRA 信号途径还有待于进一步研究。 本文研究发现，ATRA 能够同时抑制乳腺癌细胞MCF-7 和胃癌细胞 MGC80-3 的生长，但ATRA 抑制两种肿瘤细胞生长的机制却完全不同。运 用凋亡形态分析和流式细胞术，我们发现ATRA 是通过诱导MCF-7 细胞凋 亡来抑制乳腺癌细胞生长，而在胃癌MGC80-3 细胞中则通过诱导细胞停滞 在G0/G1 期来抑制细胞生长。进一步研究发现在MCF-7 细胞中，由于TR3 的高表达有利于RXRα与之形成异源二聚体而介导ATRA 的作用；但在 MGC80-3 细胞中，由于RARα的高表达有利于RARα/RXRα异源二聚体形 成而介导ATRA 作用。在乳腺癌细胞MCF-7 中，ATRA 能够诱导TR3/RXRα 从细胞核转运到细胞浆，并调控凋亡相关蛋白Βcl-2、Bcl-xl 和Bax 的表达， 进而诱导细胞凋亡；特异性的核蛋白输出抑制剂LMB 可以抑制ATRA 诱导 TR3 和RXRα的转运，同时抑制了ATRA 对Βcl-2、Bcl-xl 和Bax 表达的调 控，细胞的凋亡率也从38.4％下降到和对照组相近的水平5.2％。在胃癌细 胞中，ATRA 不能诱导RARα、RXRα和TR3 的转运，因此不能诱导胃癌细 胞凋亡。但是ATRA 通过RARα的介导诱导细胞停滞在G0/G1 期，从而抑 制细胞生长。当胃癌细胞转染反义RARα表达载体后，MGC80-3 细胞由对 ATRA 敏感转变为对ATRA 抗性。 本论文揭示了孤生受体TR3 对肿瘤细胞凋亡诱导的功能作用，阐明了 ATRA 通过对TR3 转录后水平的调控途径诱导乳腺癌细胞凋亡的新机制。 为视黄酸在肿瘤的临床治疗中提供了实验和理论依据。 ; Abstract All-trans retinoic acid (ATRA) affects cell proliferation, differentiation and apoptosis through its receptors, RARs and RXRs. Besides these, other receptors such as orphan receptor TR3 are also involved in the regulatory process of ATRA. However, how different receptors function in response to ATRA is still largely unknown. In the present study, we found that formation of TR3/RXRα heterodimers in the nucleus and their subsequent translocation into the cytoplasm, in association with regulation of apoptosis-related proteins Bcl-2, Bcl-xl and Bax, was critical for apoptosis induction by ATRA in breast cancer cells MCF-7. When translocation of TR3 and RXRα were blocked by Leptomycin B (LMB), ATRA-induced apoptosis was consequently abolished. However, in ATRA-induced gastric cancer cells MGC80-3, RXRα heterodimerised with RARα but not with TR3, and remained in the nucleus exerting its effect on cell cycle regulation. When transfected with antisense-RARα, MGC80-3 cells changed from ATRA-sensitive to ATRA-resistant and most cells were arrested in the S phase, implying the importance of RARα in cell cycle regulation. Furthermore, we demonstrated that the effects of ATRA depend on the relative levels of TR3, RARα and RXRα expression in cancer cells. In ATRA-induced MCF-7 cells, highly expressed TR3 favours the formation of TR3/RXRα and promotes the TR3/RXRα signaling pathway to cause apoptosis; while in ATRA-induced MGC80-3 cells, high expression of RARα favours the formation of RARα/RXRα and promotes the RARα/RXRα signaling pathway in mediating cell cycle regulation. In conclusion, these results reveal the novel mechanism that cellular expression and location of protein is associated with diverse signaling transduction pathways and the resultant physiological process. Also, those provide new treatment approaches for breast and gastric cancer in clinic. Keywords: All-trans retinoic acid (ATRA); Retinoid receptors；Apoptosis；Cell cycle; 学位：理学硕士; 院系专业：生命科学学院生物学系_细胞生物学; 学号：200126048
语种	zh_CN
出处	http://210.34.4.13:8080/lunwen/detail.asp?serial=8334
内容类型	学位论文
源URL	[http://dspace.xmu.edu.cn/handle/2288/46282]
专题	生命科学－学位论文
推荐引用方式 GB/T 7714	叶晓峰. 肿瘤细胞中视黄酸受体与孤生受体相互作用的不同模式, Distinct role and functional mode of retinoid receptors and orphan receptors in carcinoma cells[D]. 2004, 2004.

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