Department of Urology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China.
Int J Cancer. 2011 Apr 15;128(8):1758-69. doi: 10.1002/ijc.25509.
Increasing evidence has suggested that dysregulation of certain microRNAs (miRNAs) may contribute to tumorigenesis. microRNA-125b (miR-125b) was implicated to have close relationship with cell proliferation and differentiation, and downregulation of miR-125b was observed in various types of cancers. However, the biological function of miR-125b in bladder tumorigenesis is still unknown. In our study, we showed that the expression of miR-125b was significantly decreased in bladder cancer tissues and four bladder cancer cell lines. Moreover, miR-125b could suppress bladder cancer cells to form colonies in vitro and to develop tumors in nude mice. E2F3, which was critical for G1/S transition and was overexpressed in most of poor-differentiated bladder cancers, was identified as a target of miR-125b by luciferase assay. The E2F3 mRNA and protein expression levels were detected in bladder cancer tissues and cell lines, and interestingly, inverse correlations between miR-125b and E2F3 protein level were found in bladder cancer tissues and four E2F3 nonamplified cell lines. Introduction of miR-125b could reduce the expression of E2F3 protein but not the E2F3 mRNA. In addition, we observed that transfection of miR-125b could inhibit the expression of Cyclin A2, one of the E2Fs-responsive genes involved in G1/S transition. These results suggest that miR-125b may regulate G1/S transition through the E2F3-Cyclin A2 signaling pathway. Taken together, miR-125b may act as a tumor suppressor in bladder urothelium, and downregulation of miR-125b may contribute to the tumorigenesis of bladder cancer.
越来越多的证据表明，某些 microRNAs（miRNAs）的失调可能与肿瘤发生有关。microRNA-125b（miR-125b）与细胞增殖和分化密切相关，在各种类型的癌症中观察到 miR-125b 的下调。然而，miR-125b 在膀胱癌发生中的生物学功能尚不清楚。在我们的研究中，我们表明 miR-125b 的表达在膀胱癌组织和四种膀胱癌细胞系中显著降低。此外，miR-125b 可以抑制膀胱癌细胞在体外形成集落并在裸鼠中形成肿瘤。E2F3 对于 G1/S 转换至关重要，并且在大多数低分化膀胱癌中过度表达，通过荧光素酶测定被鉴定为 miR-125b 的靶标。检测了膀胱癌组织和细胞系中的 E2F3 mRNA 和蛋白表达水平，有趣的是，在膀胱癌组织和四种 E2F3 非扩增细胞系中发现 miR-125b 与 E2F3 蛋白水平呈负相关。引入 miR-125b 可以降低 E2F3 蛋白的表达，但不影响 E2F3 mRNA 的表达。此外，我们观察到 miR-125b 的转染可以抑制 E2Fs 反应基因之一 Cyclin A2 的表达，该基因参与 G1/S 转换。这些结果表明，miR-125b 可能通过 E2F3-Cyclin A2 信号通路调节 G1/S 转换。总之，miR-125b 可能在膀胱尿路上皮中作为肿瘤抑制因子发挥作用，miR-125b 的下调可能有助于膀胱癌的发生。
