Research Paper|Volume 12, Issue 22|pp 23029—23046

ERRα inhibitor acts as a potential agonist of PPARγ to induce cell apoptosis and inhibit cell proliferation in endometrial cancer

Meimei Huang^1,², Lili Chen³, Xiaodan Mao², Guifen Liu^1,², Yuqin Gao^1,², Xiaoqing You⁴, Min Gao⁵, Jalid Sehouli⁶, Pengming Sun^1,²

¹Department of Gynecology and Obstetrics, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
²Laboratory of Gynecologic Oncology, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, China
³Reproductive Center, Fujian Maternity and Child Health Hospital, Affiliated Hospital of Fujian Medical University, Fuzhou 350001, Fujian, P.R. of China
⁴Department of Cell Biology and Genetics, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350108, Fujian, China
⁵Department of Gynecologic Oncology, Peking University Cancer Hospital, Beijing 100046, China
⁶Department of Gynecology, Campus Virchow Clinic, CharitéUniversitätsmedizin Berlin, Humboldt University of Berlin, Berlin 13353, Germany

Received: February 25, 2020Accepted: August 14, 2020Published: November 10, 2020

https://doi.org/10.18632/aging.104049

Copyright: © 2020 Huang et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Two transcriptional factors, peroxisome proliferator-activated receptor-γ (PPARγ) and estrogen-related receptor-α (ERRα), have been reported to be key regulators of cellular energy metabolism. However, the relationship between ERRα and PPARγ in the development of endometrial cancer (EC) is still unclear. The expression levels of PPARγ and ERRα in EC were evaluated by quantitative real-time PCR, western blot, tissue array and immunohistochemistry. A significant negative correlation was identified between PPARγ and ERRα expression in women with EC (ρ=-0.509, P<0.001). Bioinformatics analyses showed that PPARγ and ERRα can activate or inhibit the same genes involved in cell proliferation and apoptosis through a similar ModFit. ERRα activation or PPARγ inhibition could promote proliferation and inhibit apoptosis through the Bcl-2/Caspase3 pathways. Both PPARγ and ERRα can serve as serum tumor markers. Surprisingly, as evaluated by receiver operating characteristic (ROC) curves and a logistic model, a PPARγ/ERRα 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 PPARγ(-)/ERRα(+) had the worst overall survival and disease-free survival rates (both P<0.001). Thus, a dynamic imbalance between PPARγ and ERRα leads to endometrial carcinogenesis and predicts the EC prognosis.