Aberrant activation of Ras and WNT signaling are key events that have been shown to be up-regulated in prostate cancer that has metastasized to the bone. However， the regulatory mechanism of combinatorial Ras and WNT signaling in advanced prostate cancer is still unclear. TCF7， a WNT signaling-related gene， has been implicated as a critical factor in bone metastasis， and here we show that TCF7 is a direct target of miR-34a. In samples of prostate cancer patients， miR-34a levels are inversely correlated with TCF7 expression and a WNT dependent gene signature. Ectopic miR-34a expression inhibited bone metastasis and reduced cancer cell proliferation in a Ras-dependent xenograft model. We demonstrate tha... More
Aberrant activation of Ras and WNT signaling are key events that have been shown to be up-regulated in prostate cancer that has metastasized to the bone. However， the regulatory mechanism of combinatorial Ras and WNT signaling in advanced prostate cancer is still unclear. TCF7， a WNT signaling-related gene， has been implicated as a critical factor in bone metastasis， and here we show that TCF7 is a direct target of miR-34a. In samples of prostate cancer patients， miR-34a levels are inversely correlated with TCF7 expression and a WNT dependent gene signature. Ectopic miR-34a expression inhibited bone metastasis and reduced cancer cell proliferation in a Ras-dependent xenograft model. We demonstrate that miR-34a can directly interfere with the gene expression of the anti-proliferative BIRC5， by targeting BIRC5 3'UTR. Importantly， BIRC5 overexpression was sufficient to reconstitute anti-apoptotic signaling in cells expressing high levels of miR-34a. In prostate cancer patients， we found that BIRC5 levels were positively correlated with a Ras signaling signature expression. Our data show that the bone metastasis and anti-apoptotic effects found in Ras signaling-activated prostate cancer cells require miR-34a deficiency， which in turn aids in cell survival by activating the WNT and anti-apoptotic signaling pathways thereby inducing TCF7 and BIRC5 expressions.
