MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer

Wei Yu Chen, Shih Yang Liu, Yung Sheng Chang, Juan Juan Yin, Hsiu Lien Yeh, Tarek H. Mouhieddine, Ola Hadadeh, Wassim Abou-Kheir, Yen Nien Liu

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74 引文 斯高帕斯(Scopus)

摘要

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 antiapoptotic signaling pathways thereby inducing TCF7 and BIRC5 expressions.
原文英語
頁(從 - 到)441-457
頁數17
期刊Oncotarget
6
發行號1
出版狀態已發佈 - 2015

ASJC Scopus subject areas

  • 腫瘤科

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