title: Microsomal prostaglandin E synthase-1 promotes hepatocarcinogenesis through activation of a novel EGR1/β-catenin signaling axis.
abstract: Microsomal prostaglandin E synthase-1 (mPGES-1) is a key enzyme that couples with cyclooxygenase-2 (COX-2) for the production of PGE(2). Although COX-2 is known to mediate the growth and progression of several human cancers including hepatocellular carcinoma (HCC), the role of mPGES-1 in hepatocarcinogenesis is not well established. This study provides novel evidence for a key role of mPGES-1 in HCC growth and progression. Forced overexpression of mPGES-1 in two HCC cell lines (Hep3B and Huh7) increased tumor cell growth, clonogenic formation, migration and invasion, whereas knockdown of mPGES-1 inhibited these parameters, in vitro. In a mouse tumor xenograft model, mPGES-1-overexpressed cells formed palpable tumors at earlier time points and developed larger tumors when compared with the control (P<0.01); in contrast, mPGES-1 knockdown delayed tumor development and reduced tumor size (P<0.01). Mechanistically, mPGES-1-induced HCC cell proliferation, invasion and migration involve PGE(2) production and activation of early growth response 1 (EGR1) and β-catenin. Specifically, mPGES-1-derived PGE(2) induces the formation of EGR1-β-catenin complex, which interacts with T-cell factor 4/lymphoid enhancer factor 1 transcription factors and activates the expression of β-catenin downstream genes. Our findings depict a novel crosstalk between mPGES-1/PGE(2) and EGR1/β-catenin signaling that is critical for hepatocarcinogenesis.
authors: Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA 70112, USA.
authors: D
authors: D
authors: Lu
authors: C
authors: C
authors: Han
authors: T
authors: T
authors: Wu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D015232:Dinoprostone / Q000378:metabolism; D051766:Early Growth Response Protein 1 / Q000378:metabolism*; D006801:Humans; D047468:Immunoprecipitation; D019746:Intramolecular Oxidoreductases / Q000235:genetics / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D000071876:Prostaglandin-E Synthases; D011485:Protein Binding; D034622:RNA Interference; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000378:metabolism; D058118:Transcription Factor 7-Like 2 Protein / Q000378:metabolism; D047368:Tumor Burden / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D058118:Transcription Factor 7-Like 2 Protein; D051176:beta Catenin; D019746:Intramolecular Oxidoreductases; C000605862:PTGES protein, human; D000071876:Prostaglandin-E Synthases; C000605865:Ptges protein, mouse; D015232:Dinoprostone