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

Abstract

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.

Keywords

• integrins
• thyroid cancer
• BRAF mutation