High integrin α3 expression is associated with poor prognosis in patients with non-small cell lung cancer.

Background: We previously showed that alpha 3 beta 1 integrin is a novel cancer biomarker and drug target in non small cell lung cancer (NSCLC). This study characterized the integrin alpha 3 (ITGA3) expression on patient specimens. Methods: Tissue microarrays (TMAs) were prepared from archival tissue blocks containing 161 patients, which included 91 adenocarcinoma (LUAD), 46 squamous carcinomas (LUSC), and 24 other histology types. TMA sections were stained and scored for ITGA3 expression by immunohistochemistry (IHC). Kaplan Meier curves and log-rank tests were used to compare overall survival (OS) between IHC score groups. Propensity-score-weighted Kaplan-Meier curves and weighted Cox models were used to adjust for covariate imbalance between IHC score groups. Logistic regression was used to determine ITGA3 transcriptome expression in NSCLC in The Cancer Genome Atlas (TCGA). Results: ITGA3 IHC expression (1+ to 3+) was detected in 107/161 (66.5%) of the NSCLC samples, and was associated with poor prognosis at the edge of significance (HR =1.30, 95% CI: 0.99-1.71, P=0.056), but significant (P<0.05) in subgroups of female patients, smokers and tumors with grade I and II differentiation using propensity-score-weighted survival analysis after adjusting for confounders. Multivariate survival analysis based on multiple imputation for missing variables showed ITGA3 expression, old age and metastasis were associated with poor prognosis (P<0.05). ITGA3 IHC expression was associated with poor prognosis in LUSC (HR =2.27, P<0.05) but not in LUAD (HR =1.49, P=0.16). Median ITGA3 expression was significantly higher in LUAD than LUSC (P<0.0001) in the TCGA transcriptome datasets. Using a higher cutoff than LUSC (70.6 vs. 19.5 FPKM), high ITGA3 RNA expression was also associated with poor prognosis in LUAD (P=0.023). ITGA3 interacted with key genes regulating epithelial to mesenchymal transition, angiogenesis, invasion and metastasis in both LUAD and LUSC. Conclusions: High ITGA3 IHC expression was associated with poor prognosis in NSCLC patients. Further study is warranted for targeting alpha 3 beta 1 integrin in NSCLC.