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

Qianping Li; Weijie Ma; Shuai Chen; Eddie C Tian; Sixi Wei; Reggie R Fan; Tao Wang; Chihong Zhou; Tianhong Li

doi:10.21037/tlcr-19-633

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

Transl Lung Cancer Res. 2020 Aug;9(4):1361-1378. doi: 10.21037/tlcr-19-633.

Authors

Qianping Li¹, Weijie Ma¹, Shuai Chen², Eddie C Tian¹, Sixi Wei¹, Reggie R Fan¹, Tao Wang³, Chihong Zhou³, Tianhong Li^{1

4}

Affiliations

¹ Division of Hematology/Oncology, Department of Internal Medicine, University of California Davis School of Medicine, University of California Davis Comprehensive Cancer Center, Sacramento, California, USA.
² Division of Biostatistics, Department of Public Health Sciences, University of California, Davis, California, USA.
³ Department of Pathology and Laboratory Medicine, University of California Davis School of Medicine, Sacramento, CA, USA.
⁴ Department of Internal Medicine, Veterans Affairs Northern California Health Care System, Mather, California, USA.

Abstract

Background: We previously showed that α3β1 integrin is a novel cancer biomarker and drug target in non-small cell lung cancer (NSCLC). This study characterized the integrin α3 (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 α3β1 integrin in NSCLC.

Keywords: ITGA3; Integrin α3 subunit (ITGA3 subunit); non-small cell lung cancer (NSCLC); prognosis; tissue microarray (TMA).

Grants and funding

P30 CA093373/CA/NCI NIH HHS/United States