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

摘要

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 尾-catenin. Specifically, mPGES-1-derived PGE_(2) induces the formation of EGR1-尾-catenin complex, which interacts with T-cell factor 4/lymphoid enhancer factor 1 transcription factors and activates the expression of 尾-catenin downstream genes. Our findings depict a novel crosstalk between mPGES-1/PGE_(2) and EGR1/尾-catenin signaling that is critical for hepatocarcinogenesis.