CCN3 promotes epithelial-mesenchymal transition in prostate cancer via FAK/Akt/HIF-1α-induced Twist expression

// Po-Chun Chen 1, 2, 3, * , Huai-Ching Tai 4, 5, 6, * , Tien-Huang Lin 7, 8 , Shih-Wei Wang 9 , Chih-Yang Lin 1 , Chia-Chia Chao 10 , Hong-Jeng Yu 4 , Yu-Chieh Tsai 11 , Yu-Wei Lai 12, 13 , Chiao-Wen Lin 14, 15 and Chih-Hsin Tang 1, 3, 16 1 Graduate Institute of Biomedical Science, China Medical University, Taichung, Taiwan 2 Department of Medical Research, Chung Shan Medical University Hospital, Chung Shan Medical University, Taichung, Taiwan 3 Department of Biotechnology, College of Health Science, Asia University, Taichung, Taiwan 4 Department of Urology, National Taiwan University Hospital, Taipei, Taiwan 5 Department of Urology, Fu-Jen Catholic University Hospital, New Taipei City, Taiwan 6 School of Medicine, Fu-Jen Catholic University, New Taipei City, Taiwan 7 Department of Urology, Buddhist Tzu Chi General Hospital Taichung Branch, Taichung, Taiwan 8 School of Post-Baccalaureate Chinese Medicine, Tzu Chi University, Hualien, Taiwan 9 Department of Medicine, Mackay Medical College, New Taipei City, Taiwan 10 Department of Respiratory Therapy, College of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan 11 Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan 12 Division of Urology, Taipei City Hospital Renai Branch, Taipei, Taiwan 13 Department of Urology, National Yang-Ming University School of Medicine, Taipei, Taiwan 14 Institute of Oral Sciences, Chung Shan Medical University, Taichung, Taiwan 15 Department of Dentistry, Chung Shan Medical University Hospital, Taichung, Taiwan 16 Department of Pharmacology, School of Medicine, China Medical University, Taichung, Taiwan * These authors have contributed equally to this work Correspondence to: Chih-Hsin Tang, email: chtang@mail.cmu.edu.tw Chiao-Wen Lin, email: cwlin@csmu.edu.tw Keywords: CCN3, epithelial-mesenchymal transition, prostate cancer, HIF-1α Received: May 10, 2017     Accepted: June 29, 2017     Published: August 10, 2017 ABSTRACT Epithelial-mesenchymal transition (EMT) has received considerable attention as a conceptual paradigm for explaining metastatic behavior during cancer progression. NOV/CCN3 is a matrix-associated protein involved in many cellular functions. Previous studies have shown that CCN3 expression is upregulated in prostate cancer (PCa) cells and in PCa patients. In this study, we have provided evidence of tumor promoting effects of CCN3, which includes induction of epithelial-to-mesenchymal transition (EMT) and tumor metastasis. We used an orthotopic in vivo model to demonstrate the prometastatic effects of CCN3. Overexpression or knockdown of CCN3 changed the EMT phenotype in PCa cells. Moreover, treatment with recombinant CCN3 promoted EMT in PCa cells. We also found that CCN3 may promote EMT by activating the FAK/Akt/HIF-1α pathway and this activation is responsible for Twist expression. IHC staining confirmed a positive correlation between the expression of CCN3, Twist, and tumor stage in PCa tissue. Our findings provide insight into the involvement of CCN3 in the EMT regulation of prostate cancer. CCN3 is a promising molecular target that may contribute to a novel therapeutic strategy against metastatic PCa.