P354 - ECE_3594 - Triiodothyronine (T3) as a regulator of insulin receptor (INSR) expression in epithelial ovarian cancer

Abstract

Epidemiological and clinical data link thyroid dysfunction with ovarian cancer (OC) risk, progression, and prognosis, yet underlying molecular mechanisms remain unclear. Increasing evidence suggests that thyroid hormones, particularly triiodothyronine (T3), may modulate processes in OC not only through classical genomic mechanisms mediated by nuclear thyroid hormone receptors (TRα, TRβ), whose expression has been demonstrated in ovarian tissue, but also indirectly by regulating the expression and secretion of other metabolic hormones. A key component of these pathways is the insulin receptor (INSR), which regulates cellular metabolism and proliferation. The aim of this study was to assess the expression and prognostic significance of INSR, in OC and to investigate the dose-dependent effect of T3 on INSR mRNA expression level in epithelial ovarian cancer (EOC). SKOV-3 and COV318 cell lines, representing EOC, were cultured as 3D spheroids and treated with T3 at concentrations reflecting physiological (1 nM), hypothyroid (0.1 nM), and hyperthyroid (10 nM) conditions. Basal expression of TRα, TRβ, and INSR as well, as changes in INSR expression following T3 exposure in SKOV-3 and COV318 cells were quantified by RT-qPCR. Gene expression (mRNA level) in OC tissues was analyzed using GEPIA (http://gepia.cancer-pku.cn). Moreover, the association between INSR expression levels and the survival of OC patients was analyzed using the Kaplan–Meier plotter (https://kmplot.com/analysis). Basal expression analysis revealed expression of TRα and TRβ and INSR in both analyzed EOC cell lines. Higher levels of TRα and TRβ in SKOV-3 compared to COV318 was observed. INSR expression level was similar in both EOC lines. Additionally, bioinformatic analysis confirmed that INSR mRNA expression was significantly downregulated in OC tissue (n = 426) compared to normal tissue (n = 88; P < .05). However, survival analysis showed that high INSR expression was not significantly associated with overall survival (OS) or progression-free survival (PFS), although a protective trend was observed (HR < 1). Interestingly, exposure to T3 resulted in a reduction of INSR expression in both SKOV-3 and COV318 cell lines at concentrations of 1 nM and 10 nM, whereas at 0.1 nM only a non-significant downward trend was observed. To sum up, thyroid hormone signaling, particularly via T3, may influence on progression of EOC that express TRα and TRβ gene through modulation of INSR expression. T3 mediated regulation of INSR suggests involvement of metabolic signaling pathways, with potential prognostic and therapeutic implications.