Downregulation of miR-145 associated with cancer progression and VEGF transcriptional activation by targeting N-RAS and IRS1.

MicroRNA-145 (miR-145) is downregulated in various tumor types. However, its mechanism in inhibiting tumor growth and angiogenesis remains to be elucidated. In this study, we found that miR-145 was significantly downregulated in the plasma and cancer tumor tissues of colorectal cancer (CRC) patients, and overexpression of miR-145 inhibited cell proliferation, migration and invasion. To understand the potential mechanism of miR-145 in inhibiting tumor growth, we showed that miR-145 blocked the activation of AKT and ERK1/2 pathways, and the expression of HIF-1 and VEGF via directly targeting N-RAS and IRS1, and VEGF is an important effector for tumor growth. Forced expression of N-RAS and IRS1 restored VEGF expression via transcriptional activation. MiR-145 also inhibited N-RAS and IRS1 expression to suppress AKT and ERK1/2 activation, and VEGF expression in mouse xenograft tumors. To test the clinical relevance of these results, we used 60 pairs of colorectal cancer tissues and adjacent normal tissues, analyzed the levels of miR-145, N-RAS and IRS1 expression in these tissues, and found that miR-145 levels were significantly inversely correlated with N-RAS and IRS1 levels in these colorectal cancer tissues, suggesting the important implication of our findings in translational application for colorectal cancer diagnostics and treatment in the future.