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

// Wei-Yu Chen 1, 2, * , Shih-Yang Liu 3, * , Yung-Sheng Chang 4 , Juan Juan Yin 5 , Hsiu-lien Yeh 6 , Tarek H. Mouhieddine 7 , Ola Hadadeh 7 , Wassim Abou-Kheir 7 , Yen-Nien Liu 4 1 Department of Pathology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 2 Department of Pathology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan 3 Department of Acupuncture and Manipulation, College of International Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China 4 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 5 Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. 6 Institute of Information System and Applications, National Tsing Hua University, HsinChu, Taiwan 7 Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut, Lebanon * These authors contributed equally to this work Correspondence to: Wassim Abou-Kheir, e-mail: wa12@aub.edu.lb Yen-Nien Liu, e-mail: liuy@tmu.edu.tw Keywords: Prostate cancer, bone metastasis, miR-34a, TCF7, BIRC5 Received: August 15, 2014      Accepted: November 02, 2014      Published: November 25, 2014 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 anti-apoptotic signaling pathways thereby inducing TCF7 and BIRC5 expressions.