MicroRNA-34a regulates WNT/TCF7 signaling and inhibits bone metastasis in Ras-activated prostate cancer
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Wei-Yu Chen1,2,*, Shih-Yang Liu3,*, Yung-Sheng Chang4, Juan Juan Yin5, Hsiu-lien Yeh6, Tarek H. Mouhieddine7, Ola Hadadeh7, Wassim Abou-Kheir7, Yen-Nien Liu4
1Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan
2Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan
3Department of Acupuncture and Manipulation, College of International Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
4Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
5Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
6Institute of Information System and Applications, National Tsing Hua University, HsinChu, Taiwan
7Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon
*These authors contributed equally to this work
Wassim Abou-Kheir, e-mail: email@example.com
Yen-Nien Liu, e-mail: firstname.lastname@example.org
Keywords: Prostate cancer, bone metastasis, miR-34a, TCF7, BIRC5
Received: August 15, 2014 Accepted: November 02, 2014 Published: November 25, 2014
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.
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