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

Chi Shuan Fan, Wei Shone Chen, Li Li Chen, Chia Chi Chen, Yu Ting Hsu, Kee Voon Chua, Horng Dar Wang, Tze Sing Huang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

30 Scopus citations

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 αVβ3 rather than CD44 is involved in OPNinduced EndoMT. OPN-integrin αVβ3 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.

Original languageEnglish
Pages (from-to)4998-5015
Number of pages18
JournalOncotarget
Volume9
Issue number4
DOIs
StatePublished - 2018

Keywords

  • Cancer cell stemness
  • EHSP90α
  • EndoMT
  • HIF-1α
  • TCF12

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