Filamin A expression levels modulates pathological markers of pituitary neuroendocrine tumors

PÉREZ PABLO; GUTIÉRREZ SILVINA; TOLEDO JONATHAN; MUKDSI JORGE HUMBERTO; DÍAZ-TORGA GRACIELA

Mar del Plata

Congreso; Reunión Conjunta SAIC SAB AAFE AACYTAL; 2023

Sociedad Argentina de Investigación Clínica

Aggressive pituitary neuroendocrine tumors (PitNETs) frequently prove resistant to treatment and pose a significant challenge due to the absence of predictive markers for their behavior. Over the last decade, the actin-binding protein Filamin A (FLNA) has been proposed as a pivotal player in tumor development due to its variety of functions. However, the role in PitNETs remains unknown. Thus, we aimed to analyze FLNA expression levels and its impact on aggressive markers of pituitary cells, using an integrative approach of in vivo and in vitro models and human samples. We utilized an in vivo model of hyperplastic adenomatous pituitary, an in vitro model for overexpression of FLNA in somatolactotropic cells (GH3), and a cohort of 20 PitNET human samples. Our techniques included flow cytometry; western blot; immunofluorescence, immunochemistry and immunogold labeling; clonogenic and traswell assay. Statistical analysis: Tukey post-test, T-test, Kruskall Wallis test. An increase in FLNA expression was observed in the advanced tumoral stages of the in vivo model, concomitantwith a decrease in cell proliferation and an incrementin the nuclear localization. Similarly, overexpression ofFLNA in GH3 cells induced a decrease in cell proliferation,colony formation, and the Ki-67 index. This overexpressionpromoted a fusiform phenotype with enhancedcell migration and decreased the prolactin secretion.Both models exhibited an increase in cyclin D1 and cyclin-dependent kinase 4 expression, correlating with theincrease in FLNA levels, implying potential non-canonicalfunctions for these proteins. In human samples a significant increase in FLNA was observed in tumors compared to normal pituitary, with heterogeneous intracellular localization. Interestingly, higher levels of FLNA expression were observed in invasive tumors. These results underline the crucial roles of FLNA as a modulator of pathological markers and as a potential prognostic marker in pituitary tumors.