Microsomal prostaglandin E synthase-1 promotes hepatocarcinogenesis through activation of a novel EGR1/β-catenin signaling axis.
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.
Mesh Terms:
Animals, Blotting, Western, Carcinoma, Hepatocellular, Cell Line, Tumor, Cell Movement, Cell Proliferation, Dinoprostone, Early Growth Response Protein 1, Humans, Immunoprecipitation, Intramolecular Oxidoreductases, Liver Neoplasms, Male, Mice, Mice, Inbred NOD, Mice, SCID, Protein Binding, RNA Interference, Signal Transduction, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Tumor Burden, Xenograft Model Antitumor Assays, beta Catenin
Animals, Blotting, Western, Carcinoma, Hepatocellular, Cell Line, Tumor, Cell Movement, Cell Proliferation, Dinoprostone, Early Growth Response Protein 1, Humans, Immunoprecipitation, Intramolecular Oxidoreductases, Liver Neoplasms, Male, Mice, Mice, Inbred NOD, Mice, SCID, Protein Binding, RNA Interference, Signal Transduction, TCF Transcription Factors, Transcription Factor 7-Like 2 Protein, Tumor Burden, Xenograft Model Antitumor Assays, beta Catenin
Oncogene
Date: Feb. 16, 2012
PubMed ID: 21743491
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