Sciellin mediates mesenchymal-to-epithelial transition in colorectal cancer hepatic metastasis

// Chuan-Kai Chou 1, * , Chi-Chen Fan 2, 3, * , Pei-Shan Lin 4 , Pei-Yu Liao 1 , Jia-Chen Tung 5 , Chang-Hsun Hsieh 6 , Mien-Chie Hung 4, 5, 7 , Chung-Hsuan Chen 8, 9, 10, 11 , Wei-Chao Chang 4, 5 1 National Applied Research Laboratories, National Laboratory Animal Center, Taipei, Taiwan 2 Superintendent Office, Mackay Memorial Hospital, Taipei, Taiwan 3 Department of Medical Laboratory Science and Biotechnology, Yuanpei University, Hsinchu, Taiwan 4 Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan 5 Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan 6 Department of Orthopaedic Surgery, National Taiwan University Hospital, National Taiwan University, Taipei, Taiwan 7 Department of Molecular and Cellular Oncology, The University of Texas MD, Anderson Cancer Center, Houston, TX, USA 8 Genomics Research Center, Academia Sinica, Taipei, Taiwan 9 Institute of Biochemistry & Molecular Biology, National Yang-Ming University, Taipei, Taiwan 10 Department of Chemistry, National Taiwan University, Taipei, Taiwan 11 Institute of Atomic & Molecular Sciences, Academia Sinica, Taipei, Taiwan * These authors have contributed equally to this work Correspondence to: Wei-Chao Chang, e-mail: proma@mail.cmu.edu.tw Keywords: colorectal cancer, hepatic metastasis, mesenchymal-to-epithelial transition, SCEL Received: September 14, 2015 Accepted: March 11, 2016 Published: March 22, 2016 ABSTRACT Hepatic metastasis is the major cause of mortality in colorectal cancer (CRC) patients. Using proteomic analysis, we found sciellin (SCEL) to be specifically expressed in hepatic metastatic CRC cell lines. SCEL knockdown increased CRC cell migration and invasion, while overexpression had the opposite effect. SCEL knockdown also caused cancer cells to form more invasive structures within 3D cultures, increased the mesenchymal marker vimentin, and attenuated the epithelial marker E-cadherin. SCEL increased WNT signaling by activating β-catenin and its downstream target c-myc, and activated mesenchymal-to-epithelial transition (MET) through a SCEL-β-catenin-E-cadherin axis. SCEL showed higher expression in late stage primary CRC than in its hepatic metastatic counterpart. SCEL expression is dynamically modulated by TGF-β1 and hypoxia, revealing a plastic MET mechanism for tumor colonization. Intrahepatic injection in immunodeficient mice revealed that SCEL is necessary for metastatic CRC tumor growth in the liver. These results demonstrate that SCEL is a MET inducer dynamically regulated through the metastasis process. They suggest SCEL may be a useful therapeutic target for preventing or eliminating CRC hepatic metastasis.