PTEN status on gonadotropin-releasing hormone (GnRH) metabolite, GnRH-(1–5), effects in endometrial cancer cell lines migration, & transcriptomic analysis of basal cell line and tumor gene expressions

Abstract

Previous studies have shown that the metabolite of gonadotropin-releasing hormone (GnRH), GnRH-(1–5), promotes migration and invasion in endometrial cancer cell lines through a non-canonical mechanism from its parental peptide. These studies showed that GnRH-(1–5) transactivates the epidermal growth factor receptor/extracellular signal–regulated kinases (EGFR/ERK) signaling pathway through an orphan G-protein-coupled receptor, GPR101, to stimulate matrix metalloproteinase-9 (MMP-9)-mediated EGF release to augment cellular migration and invasion. However, inhibition of the EGFR/ERK signaling pathway showed an incomplete ablation of the effects of GnRH-(1–5) in these studies to suggest that alternative signaling pathways are also involved. Given the incomplete inhibition of GnRH-(1–5) effects by EGFR/ERK pathway blockade, the present study sought to investigate the potential role of transforming growth factor beta (TGF-beta) in complementing the previously observed EGF effects on cellular function. As our previous studies were conducted in Phosphatase and Tensin homolog (PTEN)–negative cell lines, we sought to elucidate the involvement of the TGF-beta signaling pathway and the role of PTEN status in mediating the cellular responses to GnRH-(1–5). The present results show that cellular migration responses to GnRH-(1–5) involve both TGF-beta and EGF signaling pathways and are differentially regulated based on PTEN status. In addition to these cell line studies, we performed differential gene expression analysis of PTEN-positive and PTEN-negative cell lines and tumors using The Cancer Genome Atlas database. Identifying markers associated with PTEN status will allow for a more precise and rapid investigation of GnRH-(1–5) signaling mechanisms in endometrial cancer pathophysiology.