2. Academic Validation
  3. 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†

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†

  • Biol Reprod. 2025 Jul 25:ioaf168. doi: 10.1093/biolre/ioaf168.
Madelaine Cho-Clark 1,  Gauthaman Sukumar 2,  Sorana Raiciulescu 3,  Clifton Dalgard 2 4,  Leonardo Mariño-Ramírez 5,  T John Wu 1
Affiliations

Affiliations

  • 1 Department of Gynecologic Surgery & Obstetrics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 2 Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 3 Preventive Medicine and Biostatistics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 4 Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 5 National Institute on Minority Health and Health Disparities, National Institutes of Health, Bethesda, MD, USA.
PMID: 40709821 DOI: 10.1093/biolre/ioaf168
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, with subsequent augmentation in 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 transforming growth factor beta (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 is 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.

Keywords

biomarkers; endometrial cancer; gonadotropin-releasing hormone (GnRH); phosphatase and tensin homolog (PTEN); signaling pathways; transforming growth factor-beta (TGF-beta).

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