MicroRNA-125b suppresses the development of bladder cancer by targeting E2F3

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.