Journal
ONCOTARGET
Volume 9, Issue 4, Pages 4998-5015Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.23578
Keywords
EndoMT; HIF-1 alpha; TCF12; eHSP90 alpha; cancer cell stemness
Categories
Funding
- National Health Research Institutes [CA-105-PP-10, CA-106-PP-10]
- Ministry of Science and Technology, Taiwan, Republic of China [NSC 102-2314-B-400-007-MY3]
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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 alpha(V)beta(3) rather than CD44 is involved in OPN-induced EndoMT. OPN-integrin alpha(V)beta(3) engagement induces HIF-1 alpha 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 alpha 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.
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