Fan Chi-Shuan, Chen Wei-Shone, Chen Li-Li, Chen Chia-Chi, Hsu Yu-Ting, Chua Kee Voon, Wang Horng-Dar, Huang Tze-Sing
Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan.
National Institute of Cancer Research, National Health Research Institutes, Miaoli, Taiwan.
Oncotarget. 2017 Dec 22;9(4):4998-5015. doi: 10.18632/oncotarget.23578. eCollection 2018 Jan 12.
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 αβ rather than CD44 is involved in OPN-induced EndoMT. OPN-integrin αβ engagement induces HIF-1α expression through a PI3K/Akt/TSC2-mediated and mTORC1-dependent protein synthesis pathway, which in turn trans-activates gene expression. TCF12 further interacts with EZH2 and histone deacetylases to transcriptionally repress 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.
骨桥蛋白（OPN）是一种多功能磷酸糖蛋白，可通过作用于内皮细胞来刺激血管生成。由于血管生成芽生涉及内皮向间充质转化（EndoMT），我们很想知道OPN是否对EndoMT有影响。在临床上，我们确实在结直肠癌组织中检测到在表达OPN的细胞旁有EndoMT来源的细胞。此外，我们将OPN作用于内皮细胞原代培养物，以研究其诱导EndoMT的活性及潜在机制。整合素αβ而非CD44参与了OPN诱导的EndoMT。OPN与整合素αβ结合通过PI3K/Akt/TSC2介导的和mTORC1依赖的蛋白质合成途径诱导HIF-1α表达，这反过来又反式激活基因表达。TCF12进一步与EZH2和组蛋白去乙酰化酶相互作用，以转录抑制基因，从而促进EndoMT。与癌症相关成纤维细胞一样，EndoMT来源的细胞通过分泌某些蛋白质促进肿瘤生长和转移。分泌的HSP90α是微西部阵列分析提出的一个候选物，本文证实其可诱导结直肠癌细胞的干性特性。由于OPN在人类癌症中过表达，OPN诱导的EndoMT和EndoMT来源的细胞可能被作为癌症治疗靶点。
