Rocco Domenico, Tortora Anna, Marotta Vincenzo, Machado Aline Maria, Selistre-de-Araújo Heloisa S, Vitale Mario
Endocr Relat Cancer. 2025 Jun 5;32(6). doi: 10.1530/ERC-25-0101. Print 2025 Jun 1.
Integrins influence tumor growth, metastasis, and angiogenesis, making them potential targets for therapeutic intervention. In this study, we analyzed 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 an 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, which 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 signaling is a potential therapeutic target for disintegrins or other molecules with similar action.
整合素影响肿瘤生长、转移和血管生成，使其成为治疗干预的潜在靶点。在本研究中，我们分析了TCGA mRNA测序数据集，以评估纤连蛋白（FN1）和相关整合素亚基的表达水平，评估它们与甲状腺乳头状癌（PTC）临床特征的关系。这些发现进一步在细胞模型中得到验证。BRAFV600E阳性PTC中的FN1 mRNA水平是正常甲状腺组织（NT）的80倍，而具有RAS突变的PTC的FN1水平与NT相似。编码与β3配对形成FN受体的αv整合素亚基的ITGAV在PTC中也过表达。FN1表达升高，以及程度较轻的ITGAV，与淋巴结转移、癌症晚期、甲状腺外侵犯和较差的预后呈正相关。FN1表达处于最高四分位数的患者疾病复发风险增加（OR = 7.277，95% CI：2.019 - 26.191，P < 0.0024）。使用一种非肿瘤性甲状腺细胞系和两种PTC细胞系作为模型来验证mRNA测序结果。FN1敲除的PTC细胞突变体的增殖和迁移显著降低，添加可溶性FN后增殖恢复。DisBa - 01是一种源自交替锯鳞蝰蛇毒的重组RGD - 去整合素，作为FN/αvβ3相互作用的拮抗剂，抑制PTC细胞增殖和迁移。这些结果表明FN表达是PTC侵袭性的标志。FN/αvβ3相互作用在PTC中起关键作用，表明FN/αvβ3信号通路是去整合素或其他具有类似作用分子的潜在治疗靶点。
