Higher Integrin Alpha 3 Beta1 Expression in Papillary Thyroid Cancer Is Associated with Worst Outcome.

Lorenza Mautone,Mario Vitale,Roberta Tarallo,Alessandro Weisz,Carlo Ferravante,Anna Tortora,Giorgio Giurato

doi:10.3390/cancers13122937

Abstract

Simple SummaryIntegrins are cell-extracellular matrix adhesion molecules considered functionally related to the development of cancer metastasis. Starting from a large dataset of mRNA-seq of papillary thyroid carcinoma (PTC), we investigated the potential role of integrins in the clinical course of PTC patients. Results showed that the PTC “classical” and “tall cell” histology variants display a more similar integrin expression profile with respect to the ‘follicular’ variant. Interestingly, the BRAFV600E mutation was found to be associated with a higher expression of integrins compared to RAS mutations. The integrin subunit ITGA3 was associated with advanced disease stage, lymph node metastasis, extrathyroidal extension, high-risk, and a worst prognosis. In vitro assays with PTC cell lines demonstrated the role of the α3β1 integrin in cell motility and invasion, evidence that supports the role of this adhesion molecule in tumor progression. These results demonstrate the existence of a PTC-specific integrin expression signature that correlates with histopathology, specific driver gene mutations, and aggressiveness of the disease.Integrins are cell-extracellular matrix adhesion molecules whose expression level undergoes quantitative changes upon neoplastic transformation and are considered functionally related to the development of cancer metastasis. We analyzed the largest mRNA-seq dataset available to determine the expression pattern of integrin family subunits in papillary thyroid carcinomas (PTC). ITGA2, 3, 6, V, and ITGB1 integrin subunits were overexpressed in PTC compared to normal thyroid tissue. The PTC histology variants “classical” and “tall cell” displayed a similar integrin expression profile with a higher level of ITGA3, ITGAV, and ITGB1, which differed from that of the “follicular” variant. Interestingly, compared to RAS mutations, BRAFV600E mutation was associated with a significantly higher expression of integrins. Some integrin subunits were associated with advanced disease stage, lymph node metastasis, extrathyroidal extension, and high-risk groups. Among them, ITGA3 expression displayed the highest correlation with advanced disease and was associated with a negative prognosis. In vitro scratch assay and Matrigel invasion assay in two different PTC cell lines confirmed α3β1 role in cell motility and invasion, supporting its involvement during tumor progression. These results demonstrate the existence of a PTC-specific integrin expression signature correlated to histopathology, specific driver gene mutations, and aggressiveness of the disease.

Highlights

Survival of many eukaryotic cell, including epithelial cells, requires appropriate interactions between adhesion molecules and the extracellular matrix (ECM)
Some papillary thyroid carcinomas (PTC) samples of the The Cancer Genome Atlas (TCGA) dataset were contaminated by lymphocytes and stromal cells
Both these cells have their own integrin repertoire that can interfere with the correct assessment of integrin expression in tumoral cells

Summary

Introduction

Survival of many eukaryotic cell, including epithelial cells, requires appropriate interactions between adhesion molecules and the extracellular matrix (ECM). Integrins are the predominant cell surface receptors of ECM proteins such as fibronectin (FN), laminin, vitronectin (VN), and collagen (CO) [2]. These transmembrane heterodimers are composed of a common β1 chain noncovalently associated with a distinctive α-subunit, whose level of expression undergoes quantitative changes upon differentiation, neoplastic transformation, and hormone or cytokine induction [3,4]. Integrins bind to ECM cluster in subcellular structures known as focal adhesions These sites provide a structural link between the actin cytoskeleton and the extracellular matrix and control signal transduction pathways that modulate proliferation, differentiation, survival, migration, and tumorigenesis in many cell types

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