Osteopontin–integrin engagement induces HIF-1α–TCF12-mediated endothelial-mesenchymal transition to exacerbate colorectal cancer

// Chi-Shuan Fan 1, 2 , Wei-Shone Chen 3 , Li-Li Chen 2 , Chia-Chi Chen 2 , Yu-Ting Hsu 2 , Kee Voon Chua 2 , Horng-Dar Wang 1 and Tze-Sing Huang 2, 4 1 Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan 2 National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan 3 Division of Colorectal Surgery, Taipei Veterans General Hospital, and Department of Medicine, National Yang-Ming University, Taipei, Taiwan 4 Department of Biochemistry, School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan Correspondence to: Tze-Sing Huang, email: tshuang@nhri.org.tw Keywords: EndoMT; HIF-1α; TCF12; eHSP90α; cancer cell stemness Received: August 08, 2017      Accepted: December 04, 2017      Published: December 22, 2017 ABSTRACT Osteopontin (OPN) is a multi-functional phospho-glycoprotein that can stimulate angiogenesis through acting on endothelial cells. As angiogenic sprouting involves endothelial-to-mesenchymal transition (EndoMT), we are intrigued to know whether OPN exerts an effect on EndoMT. Clinically, we indeed detected EndoMT-derived cells next to OPN-expressing cells in colorectal cancer tissues. Furthermore, we treated OPN to primary cultures of endothelial cells to investigate the EndoMT-inducing activity and the underlying mechanisms. Integrin α V β 3 rather than CD44 is involved in OPN-induced EndoMT. OPN-integrin α V β 3 engagement induces HIF-1α expression through a PI3K/Akt/TSC2-mediated and mTORC1-dependent protein synthesis pathway, which in turn trans-activates TCF12 gene expression. TCF12 further interacts with EZH2 and histone deacetylases to transcriptionally repress VE-cadherin gene and thus facilitates EndoMT. Like cancer-associated fibroblasts, EndoMT-derived cells promote tumor growth and metastasis by secreting certain proteins. Secreted HSP90α is a candidate suggested by microwestern array assay, and is herein verified to induce stemness properties in colorectal cancer cells. As OPN is overexpressed in human cancers, OPN-induced EndoMT and EndoMT-derived cells can be potentially taken as cancer therapeutic targets.