Abstract:
Background: Most gynecologic tumors originate from Müllerian ducts, which develop into the Fallopian tubes, uterus, cervix, proximal vagina, and from the surface epithelium of the ovary. Müllerian inhibiting substance (MIS), also known as anti-Müllerian hormone (AMH), has long been known for causing the regression of the embryonic Müllerian duct. MIS has been shown to inhibit tumor growth in vitro and in vivo, but its downstream regulated genes have not been fully elucidated. MIS initiates its effect by binding to the MIS type I and type II receptors. Since endometrial cancer is also a tumor of Müllerian duct origin and prior studies have reported antitumor properties of MIS against endometrial carcinoma cell lines, we sought to understand the molecular drivers of growth inhibition or apoptosis in endometrial cancer.We try to find out the mechanism of MIS-induced cell death in primary culture cells derived from endometrial cancer patients.
Methods: 3 patients with endometrial cancer FIGO stage IA were enrolled in the Department of Obstetrics and Gynecology of Seoul St. Mary’s Hospital in 2012. The specimens of patients after surgery were cultured primarily in vitro. We treated those cells with purified MIS, and then analyzed the cell death mechanism. To understand the genomewide effects of MIS on gene regulation, we performed serial gene expression analyses from 0 to 96 h at 24 h intervals after treating endometrial cancer cells with MIS.
Results: When the expressed genes were mapped to known biological processes, Wnt-, cancer-, proteolysis-, cytoskeleton-, cell cycle-, apoptosis-, and MAPK-signaling pathways emerged as the functions most significantly changed by MIS in endometrial cancer cells. Furthermore, western blot analysis validated that protein expression of cell cycle inhibitory genes.
Conclusions: MIS could be considered as a potential treatment of choice for endometrial cancer.
