MicroRNA-195 Suppresses Tumorigenicity and Regulates G1/S Transition of Human Hepatocellular Carcinoma Cells
MicroRNA-195 Suppresses Tumorigenicity and Regulates G1/S Transition of Human Hepatocellular Carcinoma Cells
复制标题
MicroRNA-195 抑制人肝细胞癌细胞的致瘤性并调节 G1/S 转变
DOI：
10.1002/hep.22919
复制
发表时间：
2009-07-01
期刊：
影响因子：
13.5
通讯作者：
Zhuang, Shi-Mei
中科院分区：
文献类型：
--
作者：
Xu, Teng;Zhu, Ying;Zhuang, Shi-Mei
越来越多的证据表明，microRNAs（miRNAs）的失调有助于肿瘤的发生。已经在各种类型的癌症中观察到miR-195的下调。然而，miR-195的生物学功能在很大程度上仍然未知。在这项研究中，我们旨在阐明miR-195的病理生理作用。我们的研究结果显示，miR-195的表达在高达85.7%的肝细胞癌（HCC）组织和所有五种HCC细胞系中显著降低。此外，miR-195的引入显著抑制了HCC和结直肠癌细胞在体外形成集落和在裸鼠中发展肿瘤的能力。此外，miR-195的异位表达阻断了G（1）/S转换，而miR-195的抑制促进了细胞周期进程。随后的研究将多种G（1）/S转换相关分子（包括细胞周期蛋白D1、CDK6和E2F3）作为miR-195的直接靶点。细胞周期蛋白D1、CDK6或E2F3的沉默表型模仿了miR-195的作用，而这些蛋白的过表达减弱了miR-195诱导的G（1）阻滞。此外，miR-195显著抑制Rb的磷酸化以及E2F下游靶基因的反式激活。这些结果表明，miR-195可能通过靶向多个分子（包括细胞周期蛋白D1、CDK6和E2F3）来抑制Rb-E2F信号传导，从而阻断G（1）/S转换。结论：我们的数据强调了miR-195在细胞周期控制和HCC分子病因学中的重要作用，并暗示了miR-195在癌症治疗中的潜在应用。（《肝脏学》2009; 50：113 - 121）
Growing evidence indicates that deregulation of microRNAs (miRNAs) contributes to tumorigenesis. Down-regulation of miR-195 has been observed in various types of cancers. However, the biological function of miR-195 is still largely unknown. In this study we aimed to elucidate the pathophysiologic role of miR-195. Our results showed that miR-195 expression was significantly reduced in as high as 85.7% of hepatocellular carcinoma (HCC) tissues and in all of the five HCC cell lines examined. Moreover, introduction of miR-195 dramatically suppressed the ability of HCC and colorectal carcinoma cells to form colonies in vitro and to develop tumors in nude mice. Furthermore, ectopic expression of miR-195 blocked G(1)/S transition, whereas inhibition of miR-195 promoted cell cycle progression. Subsequent investigation characterized multiple G(1)/S transition-related molecules, including cyclin D1, CDK6, and E2F3, as direct targets of miR-195. Silencing of cyclin D1, CDK6, or E2F3 phenocopied the effect of miR-195, whereas overexpression of these proteins attenuated miR-195-induced G(1) arrest. In addition, miR-195 significantly repressed the phosphorylation of Rb as well as the transactivation of downstream target genes of E2F. These results imply that miR-195 may block the G(1)/S transition by repressing Rb-E2F signaling through targeting multiple molecules, including cyclin D1, CDK6, and E2F3. Conclusion: Our data highlight an important role of miR-195 in cell cycle control and in the molecular etiology of HCC, and implicate the potential application of miR-195 in cancer therapy. (HEPATOLOGY 2009;50:113-121.)