Microsomal prostaglandin E synthase-1 (mPGES-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 SCID mouse tumor xenograft model, mPGES-1 overexpressed cells formed palpable tumors at earlier time points and developed larger tumors when compared to 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 TCF4/LEF1 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.