title: Microsomal prostaglandin E synthase-1 inhibits PTEN and promotes experimental cholangiocarcinogenesis and tumor progression.
abstract: OBJECTIVE
  Microsomal prostaglandin E synthase-1 (mPGES-1) is a rate-limiting enzyme that is coupled with cyclooxygenase (COX)-2 in the synthesis of prostaglandin E2. 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
authors.forename: Dongdong
authors.initials: D
authors.lastname: Lu
authors.forename: Chang
authors.initials: C
authors.lastname: Han
authors.forename: Tong
authors.initials: T
authors.lastname: Wu
mesh_terms: D020121:5' Untranslated Regions; D000818:Animals; D001650:Bile Duct Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D001653:Bile Ducts, Intrahepatic / Q000201:enzymology* / Q000473:pathology; D001665:Binding Sites; D015153:Blotting, Western; D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D018281:Cholangiocarcinoma / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D047468:Immunoprecipitation; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D051059:PTEN Phosphohydrolase / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D034622:RNA Interference; D025842:SUMO-1 Protein / Q000378:metabolism; D015398:Signal Transduction; D058207:Sumoylation; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D047368:Tumor Burden
chemical_list: D020121:5' Untranslated Regions; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D025842:SUMO-1 Protein; C495501:SUMO1 protein, human; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse