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

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 ?V?3 rather than CD44 is involved in OPN-induced EndoMT. OPN-integrin ?V?3 engagement induces HIF-1? 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 HSP90? 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.

SUBMITTER: Fan CS

PROVIDER: S-EPMC5797029 | biostudies-literature | 2018 Jan

REPOSITORIES: biostudies-literature

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

Fan Chi-Shuan CS Chen Wei-Shone WS Chen Li-Li LL Chen Chia-Chi CC Hsu Yu-Ting YT Chua Kee Voon KV Wang Horng-Dar HD Huang Tze-Sing TS

Oncotarget 20171222 4

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 ...[more]

PMID: 29435158

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Dataset Information

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

Publications

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

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