Microsomal Prostaglandin E Synthase-1 Inhibits PTEN and Promotes Experimental Cholangiocarcinogenesis and Tumor Progression

BACKGROUND & AIMS: Microsomal prostaglandin E synthase-1 (mPGES-1) is a rate-limiting enzyme that is coupled with cyclooxygenase (COX)-2 in the synthesis of prostaglandin E(2). Although COX-2 is involved in the development and progression of various human cancers, the role of mPGES-1 in carcinogenesis has not been determined. We investigated the role of mPGES-1 in human cholangiocarcinoma growth. METHODS: We used immunohistochemical analyses to examine the expression of mPGES-1 in formalin-fixed, paraffin-embedded human cholangiocarcinoma tissues. The effects of mPGES-1 on human cholangiocarcinoma cells were determined in vitro and in SCID mice. Immunoblotting and immunoprecipitation assays were performed to determine the levels of PTEN and related signaling molecules in human cholangiocarcinoma cells with overexpression or knockdown of mPGES-1. RESULTS: mPGES-1 is overexpressed in human cholangiocarcinoma tissues. Overexpression of mPGES-1 in human cholangiocarcinoma cells increased tumor cell proliferation, migration, invasion, and colony formation; in contrast, RNA interference knockdown of mPGES-1 inhibited tumor growth parameters. In SCID mice with tumor xenografts, mPGES-1 overexpression accelerated tumor formation and increased tumor weight (P<.01), whereas mPGES-1 knockdown delayed tumor formation and reduced tumor weight (P<.01). mPGES-1 inhibited the expression of phosphatase and tensin homologue deleted on chromosome 10 (PTEN), leading to activation of the epidermal growth factor/phosphoinositide 3-kinase/AKT/mammalian target of rapamycin signaling pathways in cholangiocarcinoma cells. mPGES-1-mediated inhibition of PTEN is regulated through blocking of early growth response-1 sumoylation and binding to the 5'-untranslated region of the PTEN gene. CONCLUSIONS: mPGES-1 promotes experimental cholangiocarcinogenesis and tumor progression by inhibiting PTEN.