Up-regulation of Bcl-2 by CD147 Through ERK Activation Results in Abnormal Cell Survival in Human Endometriosis

Abstract

Human endometriosis (EMS) is characterized by insufficient apoptosis. Our previous studies have shown elevated CD147 expression in human endometriotic tissues and its involvement in endometrial cell apoptosis. However, the exact underlying mechanism remains elusive. The objective was to examine the correlation of the highly expressed CD147 with anti-apoptotic factor Bcl-2 in human endometriotic tissues and to determine the CD147-regulated apoptotic pathway in human endometrial epithelial cell line (HES). This was a laboratory study using human tissue analysis and HES cell culture. The setting was an academic research center and hospital. Patients were 30 women with ovarian EMS and 12 women without EMS. mRNA levels of CD147 and Bcl-2 were evaluated in endometriotic tissues by quantitative real-time PCR. HES cells were transfected with pcDNA3.0-CD147 overexpressing plasmid or immune-depleted by CD147 antibody. Main outcome measures were reverse transcription, quantitative real-time PCR, 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay, and Western blotting. In human endometriotic tissues, Bcl-2 was up-regulated and positively correlated with CD147 expression, accompanied by activated ERK signaling. In HES cells, overexpression of CD147 increased viable cells and up-regulated Bcl-2 expression by activation of ERK signaling. Interference with CD147 function suppressed ERK signaling and decreased Bcl-2 expression, followed by accumulation of apoptotic factors, including cleaved caspase-9, cleaved caspase-3, and cleaved poly ADP-ribose polymerase. The presently found strong correlations between Bcl-2 and CD147, ERK, and CD147 in human endometriotic lesions and the demonstrated reduced cell apoptosis through CD147-ERK-Bcl-2 intrinsic apoptosis signaling axis suggest that this CD147-regulated signaling may contribute to the enhanced cell survival in the progression of human EMS.