ANGPTL4 Induction by Prostaglandin E2 under Hypoxic Conditions Promotes Colorectal Cancer Progression

Abstract

Prostaglandin E2 (PGE2), 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 PGE2 in tumor hypoxia is not well understood. Here, we show a synergistic effect of PGE2 and hypoxia on enhancing ANGPTL4 expression and that elevation of ANGPTL4 promotes colorectal cancer growth. PGE2 induces ANGPTL4 expression at both the mRNA and protein levels under hypoxic conditions. Moreover, hypoxia induces one of the PGE2 receptors, namely EP1. Activation of EP1 enhances ANGPTL4 expression, whereas blockage of EP1 by its antagonist inhibits PGE2 induction of ANGPTL4 under hypoxic conditions. Importantly, over-expression of ANGPTL4 promotes cell proliferation and tumor growth in vitro and in vivo. In addition, treatment with ANGPTL4 recombinant protein increases colorectal carcinoma cell proliferation through effects on STAT1 signaling. The MAPK and Src pathways mediate ANGPTL4-induced STAT1 expression and activation. These results are relevant to human disease since 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 PGE2 plays an important role in promoting cancer cell proliferation via ANGPTL4 under hypoxic conditions.

Emerging Roles of Angiopoietin-like 4 in Human Cancer

“…Similarly, Huang and colleagues detected elevated cANGPTL4 from fine needle aspirates of breast tumors, basal cell carcinomas, melanomas, and in several cancer cell lines derived from breast, lung, and liver cancers (21). Consistent with the above findings, Kim and colleagues showed that colorectal cancer (CRC) cells only secrete cANGPTL4 proteins (25). A high ANGPTL4 expression in oral cancer correlates to an enhanced rate of tumorigenesis and a poor prognosis based on the tumor clinicopathology (Table 2; refs.…”

“…Recently, PPARs have been implicated in the development of tumors (24). Studies have shown that ANGPTL4 is one of the PPAR target genes and contains several putative PPAR response element consensus sequences within its promoter (25). Reports have proposed that ANGPTL4 may be regulated by all 3 PPAR isoforms (PPARa, PPARb/d, and PPARg), suggesting that ANGPTL4 may exert tissuedependent effects governed by the differential expression of the PPAR isoforms (15).…”

“…Girroir and colleagues suggested that PPARb/d modulates ANGPTL4 expression during tumorigenesis in human breast cancer and melanoma cell lines, although Zhu and colleagues reported no apparent correlation between the expression of PPARs and ANGPTL4 in SCC (11,26). A recent study suggested that prostaglandin E2 (PGE 2 ) may transactivate PPARb/d to regulate the expression of ANGPTL4 under hypoxic conditions (25). Because of the aberrant growth of tumor cells and poor vascularization, the tumor microenvironment tends to become hypoxic.…”

Familial colorectal cancer type X: genetic profiles and phenotypic features

“…24,25 'PTGER1 (prostaglandin E receptor 1 (subtype EP1), 42 kDa)' is activated by COX-2/PGE-2 signaling that is overexpressed in 90% of sporadic colon carcinomas and is induced by hypoxia. 78,79 Another target that has shown to directly upregulate COX-2 expression is the 'HIST1H1A (histone cluster 1, H1a)', whose overexpression had been significantly associated with a shorter colorectal cancer-specific and overall survival. 80 Through a SRC-dependent pathway, PTGER1 activates the 'ANGPTL4 (angiopoietin-like 4)' protein that may promote colorectal carcinogenesis.…”

“…80 Through a SRC-dependent pathway, PTGER1 activates the 'ANGPTL4 (angiopoietin-like 4)' protein that may promote colorectal carcinogenesis. 79 Upregulation of this pathway may drive FCCTX tumor development during anaerobic conditions, and this is supported by frequent findings of dirty necrosis during histological evaluations and downregulation of the aerobic oxidative phosphorylation metabolism genes such as 'ATP5L (ATP synthase, H þ transporting, mitochondrial Fo complex, subunit G),' 'ATP5A1 (ATP synthase, H þ transporting, mitochondrial F1 complex, a-subunit 1, cardiac muscle),' 'ATP5B (ATP synthase, H þ transporting, mitochondrial F1 complex, b-polypeptide),' and 'ATP5D (ATP synthase, H þ transporting, mitochondrial F1 complex, d-subunit)' (Figure 3). 25,37 Copy number gains and EGFR-mediated activation of SRC have been correlated to migration and invasion 81 ( Figure 3).…”