Loss of EGFR signaling-regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance

// Man Kit Siu 1,2,* , Wassim Abou-Kheir 3,* , Juan Juan Yin 4,* , Yung-Sheng Chang 1 , Ben Barrett 4 , Florent Suau 4 , Orla Casey 4 , Wei-Yu Chen 5 , Lei Fang 4 , Paul Hynes 4 , Yao-Yu Hsieh 1,6,9 , Yen-Nien Liu 1,7 , Jiaoti Huang 8 and Kathleen Kelly 4 1 Graduate Institute of Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan 2 Department of Anesthesiology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan 3 Department of Anatomy, Cell Biology and Physiological Sciences Faculty of Medicine, American University of Beirut, Beirut, Lebanon 4 Cell and Cancer Biology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA 5 Department of Pathology, Wan Fang Hospital, College of Medicine, Taipei Medical University, Taipei, Taiwan 6 Division of Hematology and Oncology, Shuang Ho Hospital, Taipei Medical University, New Taipei City, Taiwan 7 Center of Excellence for Cancer Research, Wan Fang Hospital, College of Medicine, Taipei Medical University, Taipei, Taiwan 8 Department of Pathology and Laboratory Medicine, University of California, Los Angeles, CA, USA 9 Department of Internal Medicine, Division of Hematology and Oncology, School of Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan * These authors contributed equally to this work Correspondence: Yen-Nien Liu, email: // Keywords : Bone metastasis/Epidermal growth factor receptor (EGFR)/Prostate cancer/miR-203 /KRAS/Tyrosine kinase inhibitors (TKIs) resistance Received : February 20, 2014 Accepted : May 18, 2014 Published : May 20, 2014 Abstract Activation of EGFR signaling pathway leads to prostate cancer bone metastasis; however, therapies targeting EGFR have demonstrated limited effectiveness and led to drug resistance. miR-203 levels are down-regulated in clinical samples of primary prostate cancer and further reduced in metastatic prostate cancer. Here we show that ectopic miR-203 expression displayed reduced bone metastasis and induced sensitivity to tyrosine kinase inhibitors (TKIs) treatment in a xenograft model. Our results demonstrate that the induction of bone metastasis and TKI resistance require miR-203 down-regulation, activation of the EGFR pathway via altered expression of EGFR ligands ( EREG and TGFA ) and anti-apoptotic proteins (API5, BIRC2, and TRIAP1). Importantly, a sufficient reconstitution of invasiveness and resistance to TKIs treatment was observed in cells transfected with anti-miR-203. In prostate cancer patients, our data showed that miR-203 levels were inversely correlated with the expression of two EGFR ligands, EREG and TGFA, and an EGFR dependent gene signature. Our results support the existence of a miR-203, EGFR, TKIs resistance regulatory network in prostate cancer progression. We propose that the loss of miR-203 is a molecular link in the progression of prostate cancer metastasis and TKIs resistance characterized by high EGFR ligands output and anti-apoptotic proteins activation.