Integrin-fibronectin interaction is a pivotal biological and clinical determinant in papillary thyroid carcinoma.

Abstract

Integrins influence tumor growth, metastasis, and angiogenesis, making them potential targets for therapeutic intervention. In this study, we analysed the TCGA mRNA-seq dataset to assess the expression levels of fibronectin (FN1) and associated integrin subunits, evaluating their relationship with clinical features in papillary thyroid cancer (PTC). These findings were further validated in a cell model. FN1 mRNA levels in BRAFV600E-positive PTC were 80-fold compared to normal thyroid tissue (NT), whereas PTC with RAS mutations exhibited FN1 levels similar to NT. ITGAV, encoding the αv integrin subunit, which pairs with β3 to form a receptor for FN, was also overexpressed in PTC. Elevated FN1 expression, and to a lesser extent ITGAV, correlated positively with lymph node metastasis, advanced cancer stages, extrathyroidal extension, and poorer prognoses. Patients in the highest quartile of FN1 expression had increased risk of disease recurrence (OR=7.277, 95% CI: 2.019 - 26.191, p < 0.0024). A non-tumoral thyroid cell line and two PTC cell lines were used as models to validate the mRNA-seq results. The proliferation and migration of a FN1 knock-out PTC cell mutant were significantly reduced and proliferation was restored upon the addition of soluble FN. DisBa-01, a recombinant RGD-disintegrin derived from Bothrops alternatus snake venom, that acts as an antagonist to the FN/αvβ3 interaction, inhibited PTC cell proliferation and migration. These results demonstrate that FN expression is a hallmark of aggressiveness in PTC. FN/αvβ3 interaction plays a pivotal role in PTC, suggesting that the FN/αvβ3 signalling is a potential therapeutic target for disintegrins or other molecules with similar action.