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

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)441-457
Number of pages17
JournalOncotarget
Volume6
Issue number1
Publication statusPublished - 2015

Keywords

  • BIRC5
  • Bone metastasis
  • miR-34a
  • Prostate cancer
  • TCF7

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Chen, W. Y., Liu, S. Y., Chang, Y. S., Yin, J. J., Yeh, H. L., Mouhieddine, T. H., Hadadeh, O., Abou-Kheir, W., & Liu, Y. N. (2015). MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer. Oncotarget, 6(1), 441-457.