Systematic Analysis of the Prognostic Significance and Roles of the Integrin Alpha Family in Non-Small Cell Lung Cancers

Abstract

Introduction: Lung cancer is one of the most common cancer malignancies and the principal cause of cancer-associated deaths worldwide. Non-small cell lung cancers (NSCLCs) account for more than 80% of all lung cancer cases. Recent studies showed that the genes of the integrin alpha (α) (ITGA) subfamily play a fundamental role in various cancers. However, little is known about the expression and roles of distinct ITGA proteins in NSCLCs.

Methods: Gene Expression Profiling Interactive Analysis and UALCAN (University of ALabama at Birmingham CANcer) web resources and The Cancer Genome Atlas (TCGA), ONCOMINE, cBioPortal, GeneMANIA, and Tumor Immune Estimation Resource databases were used to evaluate differential expression, correlations between the expression levels of individual genes, the prognostic value of overall survival (OS) and stage, genetic alterations, protein-protein interactions, and the immune cell infiltration of ITGAs in NSCLCs. We used R (v. 4.0.3) software to conduct gene correlation, gene enrichment, and clinical correlation of RNA sequencing data of 1016 NSCLCs from TCGA. To evaluate the expression of ITGA5/8/9/L at the expression and protein levels, qRT-PCR, immunohistochemistry (IHC), and hematoxylin and eosin (H&E) were performed, respectively.

Results: Upregulated levels of ITGA11 messenger RNA and downregulated levels of ITGA1/3/5/7/8/9/L/M/X were observed in the NSCLC tissues. Lower expression of ITGA5/6/8/9/10/D/L was discovered to be expressively associated with advanced tumor stage or poor patient prognosis in patients with NSCLC. A high mutation rate (44%) of the ITGA family was observed in the NSCLCs. Gene Ontology functional enrichment analyses results revealed that the differentially expressed ITGAs could be involved in roles related to extracellular matrix (ECM) organization, collagen-containing ECM cellular components, and ECM structural constituent molecular functions. The results of the Kyoto Encyclopedia of Genes and Genomes analysis revealed that ITGAs may be involved in focal adhesion, ECM-receptor interaction, and amoebiasis; the expression of ITGAs was significantly correlated with the infiltration of diverse immune cells in NSCLCs. ITGA5/8/9/L was also highly correlated with PD-L1 expression. The validation results for marker gene expression in NSCLC tissues by qRT-PCR, IHC, and H&E staining indicated that the expression of ITGA5/8/9/L decreased compared with that in normal tissues.

Conclusion: As potential prognostic biomarkers in NSCLCs, ITGA5/8/9/L may fulfill important roles in regulating tumor progression and immune cell infiltration.

Keywords: Bioinformatics analysis; Biomarker; Integrin alpha family; NSCLCs; Prognosis.