FGFR1 EXPRESSION AND DNA METHYLATION LEVELS IN PitNETs ASSOCIATED WITH TUMOR PROLIFERATION AND INVASION

BRAVO, MELINA ROCIO; TURINA, ABRIL; CECENARRO, LAURA; CALAFAT, PATRICIA; DE BATISTA, JUAN; PETITI, JUAN; SOSA, LILIANA DEL VALLE

Mar del Plata

Congreso; REUNIÓN CONJUNTA SAIC SAB AAFE AACYTAL 2023; 2023

SAIC SAB AAFE AACYTAL

The genesis of pituitary neuroendocrine tumors (PitNETs) could be associated with numerous molecules. A common alteration involves the basic fibroblast growth factor receptor 1 (FGFR1), whose dysregulation was observed in numerous neoplasms. PitNETs are sporadic with no known alterations driving somatic mutations. Hence, epigenetic mechanisms have become more relevant, yet inducing signaling pathways have not been fully defined. In this context, FGFR1 signaling could modulate DNA methylation (5mC), to lead to differential gene expression associated with proliferation and invasion. The objective was to determine FGFR1 expression and DNA methylation levels in functioning (F) and nonfunctioning (NF) PitNETs and their association with proliferation and invasion. The FGFR1 and 5mC expression were evaluated in F- (n=16) and NF- PitNETs (n=22) by IHC and compared with clinical-pathological parameters. Expression of LINE-1, DNMT1, MMP9, B-integrin and Cdh2 were determined in control pituitary gland, primary tumor cell culture of somatotroph (H4) and silent somatotroph (R1) and a cell line (GH3), by PCR and FGFR1 by WB. Cell viability in GH3 stimulated with FGF2 (100 ng/ml), with or without FGFR1 inhibitor AZD4745 (AZD; 0.1-10 µM) for 24h was analyzed by MTT. Statistics: Pearson, Kruskal-Wallis or ANOVA-Tukey. FGFR1 expression was higher in NF vs F PitNETs (p=0,043), with a positive correlation between tumor volume and FGFR1 (p=0,04). In vitro, DNA hypomethylation was observed in tumor cells. FGFR1, MMP9 and Cdh2 expression was higher in R1 and GH3, with lower levels of DNMT1 and B-integrin vs control. FGF2 increased GH3 cell viability, which was reverted with AZD (p