Err Alpha Inhibitor Acts As A Potential Agonist Of Ppar Gamma To Induce Cell Apoptosis And Inhibit Cell Proliferation In Endometrial Cancer

Two transcriptional factors, peroxisome proliferator-activated receptor-gamma (PPAR gamma) and estrogen-related receptor-alpha (ERR alpha), have been reported to be key regulators of cellular energy metabolism. However, the relationship between ERR alpha and PPAR gamma in the development of endometrial cancer (EC) is still unclear. The expression levels of PPAR gamma and ERR alpha in EC were evaluated by quantitative real-time PCR, western blot, tissue array and immunohistochemistry. A significant negative correlation was identified between PPAR gamma and ERR alpha expression in women with EC (rho=-0.509, P<0.001). Bioinformatics analyses showed that PPAR gamma and ERR alpha can activate or inhibit the same genes involved in cell proliferation and apoptosis through a similar ModFit. ERR alpha activation or PPAR gamma inhibition could promote proliferation and inhibit apoptosis through the Bcl-2/Caspase3 pathways. Both PPAR gamma and ERR alpha can serve as serum tumor markers. Surprisingly, as evaluated by receiver operating characteristic (ROC) curves and a logistic model, a PPAR gamma/ERR alpha ratio <= 1.86 (area under the ROC curve (AUC)=0.915, Youden index=0.6633, P<0.001) was an independent risk factor for endometrial carcinogenesis (OR=14.847, 95% CI= 1.6-137.748, P=0.018). EC patients with PPAR gamma(-)/ERR alpha(+) had the worst overall survival and disease-free survival rates (both P<0.001). Thus, a dynamic imbalance between PPAR gamma and ERR alpha leads to endometrial carcinogenesis and predicts the EC prognosis.