Loss of EGFR signaling-regulated miR-203 promotes prostate cancer bone metastasis and tyrosine kinase inhibitors resistance
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Man Kit Siu1,2,*, Wassim Abou-Kheir3,*, Juan Juan Yin4,*, Yung-Sheng Chang1, Ben Barrett4, Florent Suau4, Orla Casey4, Wei-Yu Chen5, Lei Fang4, Paul Hynes4, Yao-Yu Hsieh1,6,9, Yen-Nien Liu1,7, Jiaoti Huang8 and Kathleen Kelly4
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
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
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.
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