The WNT/β-catenin signaling pathway and expression of survival promoting genes in luteinized granulosa cells: endometriosis as a paradigm for a dysregulated apoptosis pathway

Objective: To analyze the WNT/beta-catenin signaling pathway in luteinized granulosa cells from women with and without endometriosis in relation to cellular apoptosis. Design: Basic. Setting: University hospital. Patient(s): Patients with a laparoscopic diagnosis of endometriosis (n - 30) and women undergoing intracytoplasmic sperm injection for male infertility (control group n = 39). Intervention(s): Isolation of luteinized granulosa cells. Main Outcome Measure(s): Gene expression analysis of components of the WNT/beta-catenin pathway, protein expression levels of beta-catenin, and cell cycle studies in luteinized granulosa cells. Result(s): Compared with luteinized granulosa cells from control women, cells derived from endometriosis patients had significantly higher transcript levels of the beta-catenin-independent molecules WNT4 and WNT5a and lower levels of the beta-catenin-dependent molecule WNT1. A decrease of total beta-catenin as well as of its dephosphorylated active form, together with an aberrant gene expression of the downstream targets survivin and BMP4, was detected in cells from affected women. Flow cytometry analysis confirmed an enhanced apoptosis of luteinized granulosa cells from patients with endometriosis. Conclusion(s): The concomitant dysregulation of specific members of the WNT pathway and of its pivot molecule b-catenin in granulosa cells characterized by an increased apoptosis suggests that the WNT/beta-catenin signaling pathway might be involved in leading to granulosa cell atresia. (C) 2014 by American Society for Reproductive Medicine.