Data from ANGPTL4 Induction by Prostaglandin E<sub>2</sub> under Hypoxic Conditions Promotes Colorectal Cancer Progression

Abstract

<div>Abstract<p>Prostaglandin E<sub>2</sub> (PGE<sub>2</sub>), the most abundant COX-2–derived prostaglandin found in colorectal cancer, promotes tumor cell proliferation and survival via multiple signaling pathways. However, the role of PGE<sub>2</sub> in tumor hypoxia is not well understood. Here, we show a synergistic effect of PGE<sub>2</sub> and hypoxia on enhancing angiopoietin-like protein 4 (ANGPTL4) expression and that elevation of ANGPTL4 promotes colorectal cancer growth. PGE<sub>2</sub> induces ANGPTL4 expression at both the mRNA and protein levels under hypoxic conditions. Moreover, hypoxia induces one of the PGE<sub>2</sub> receptors, namely EP1. Activation of EP1 enhances ANGPTL4 expression, whereas blockage of EP1 by an antagonist inhibits PGE<sub>2</sub> induction of ANGPTL4 under hypoxic conditions. Importantly, overexpression of ANGPTL4 promotes cell proliferation and tumor growth <i>in vitro</i> and <i>in vivo</i>. In addition, treatment with ANGPTL4 recombinant protein increases colorectal carcinoma cell proliferation through effects on STAT1 signaling. The MAP kinase and Src pathways mediate ANGPTL4-induced STAT1 expression and activation. These results are relevant to human disease because we found that the expression of ANGPTL4 and STAT1 are elevated in 50% of human colorectal cancers tested and there is a positive correlation between COX-2 and ANGPTL4 as well STAT1 expression in colorectal carcinomas. Collectively, these findings suggest that PGE<sub>2</sub> plays an important role in promoting cancer cell proliferation via ANGPTL4 under hypoxic conditions. <i>Cancer Res; 71(22); 7010–20. ©2011 AACR</i>.</p></div>