ANGPTL4 induction by prostaglandin E 2 under hypoxic conditions promotes colorectal cancer progression

Sun Hee Kim, Yun Yong Park, Sang Wook Kim, Ju Seog Lee, Dingzhi Wang, Raymond N. DuBois

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

Prostaglandin E 2 (PGE 2), 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 2 in tumor hypoxia is not well understood. Here, we show a synergistic effect of PGE 2 and hypoxia on enhancing angiopoietin-like protein 4 (ANGPTL4) expression and that elevation of ANGPTL4 promotes colorectal cancer growth. PGE 2 induces ANGPTL4 expression at both the mRNA and protein levels under hypoxic conditions. Moreover, hypoxia induces one of the PGE 2 receptors, namely EP1. Activation of EP1 enhances ANGPTL4 expression, whereas blockage of EP1 by an antagonist inhibits PGE 2 induction of ANGPTL4 under hypoxic conditions. Importantly, overexpression 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 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 2 plays an important role in promoting cancer cell proliferation via ANGPTL4 under hypoxic conditions.

Original languageEnglish (US)
Pages (from-to)7010-7020
Number of pages11
JournalCancer Research
Volume71
Issue number22
DOIs
StatePublished - Nov 15 2011
Externally publishedYes

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Angiopoietins
Prostaglandins E
Colorectal Neoplasms
Proteins
Angiopoietin-2
Cell Proliferation
Receptors, Prostaglandin E, EP2 Subtype
STAT1 Transcription Factor
Neoplasms
src-Family Kinases
Growth
Recombinant Proteins
Prostaglandins
Cell Survival

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

ANGPTL4 induction by prostaglandin E 2 under hypoxic conditions promotes colorectal cancer progression. / Kim, Sun Hee; Park, Yun Yong; Kim, Sang Wook; Lee, Ju Seog; Wang, Dingzhi; DuBois, Raymond N.

In: Cancer Research, Vol. 71, No. 22, 15.11.2011, p. 7010-7020.

Research output: Contribution to journalArticle

Kim, Sun Hee ; Park, Yun Yong ; Kim, Sang Wook ; Lee, Ju Seog ; Wang, Dingzhi ; DuBois, Raymond N. / ANGPTL4 induction by prostaglandin E 2 under hypoxic conditions promotes colorectal cancer progression. In: Cancer Research. 2011 ; Vol. 71, No. 22. pp. 7010-7020.
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abstract = "Prostaglandin E 2 (PGE 2), 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 2 in tumor hypoxia is not well understood. Here, we show a synergistic effect of PGE 2 and hypoxia on enhancing angiopoietin-like protein 4 (ANGPTL4) expression and that elevation of ANGPTL4 promotes colorectal cancer growth. PGE 2 induces ANGPTL4 expression at both the mRNA and protein levels under hypoxic conditions. Moreover, hypoxia induces one of the PGE 2 receptors, namely EP1. Activation of EP1 enhances ANGPTL4 expression, whereas blockage of EP1 by an antagonist inhibits PGE 2 induction of ANGPTL4 under hypoxic conditions. Importantly, overexpression 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 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 2 plays an important role in promoting cancer cell proliferation via ANGPTL4 under hypoxic conditions.",
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