Microsomal prostaglandin E synthase-1 promotes hepatocarcinogenesis through activation of a novel EGR1/β-catenin signaling axis

Oncogene. 2012 Feb 16;31(7):842-57. doi: 10.1038/onc.2011.287. Epub 2011 Jul 11.


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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Blotting, Western
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Cell Line, Tumor
  • Cell Movement
  • Cell Proliferation
  • Dinoprostone / metabolism
  • Early Growth Response Protein 1 / metabolism*
  • Humans
  • Immunoprecipitation
  • Intramolecular Oxidoreductases / genetics
  • Intramolecular Oxidoreductases / metabolism*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Prostaglandin-E Synthases
  • Protein Binding
  • RNA Interference
  • Signal Transduction*
  • TCF Transcription Factors / metabolism
  • Transcription Factor 7-Like 2 Protein / metabolism
  • Tumor Burden / genetics
  • Xenograft Model Antitumor Assays
  • beta Catenin / metabolism*


  • EGR1 protein, human
  • Early Growth Response Protein 1
  • TCF Transcription Factors
  • TCF7L2 protein, human
  • Transcription Factor 7-Like 2 Protein
  • beta Catenin
  • Intramolecular Oxidoreductases
  • PTGES protein, human
  • Prostaglandin-E Synthases
  • Ptges protein, mouse
  • Dinoprostone