Elevated integrin α6β4 expression is associated with venous invasion and decreased overall survival in non-small cell lung cancer.
Lung cancer carries a poor prognosis and is the most common cause of cancer-related death worldwide. The integrin α6β4, a laminin receptor, promotes carcinoma progression in part by cooperating with various growth factor receptors to facilitate invasion and metastasis. In carcinoma cells with mutant TP53, the integrin α6β4 promotes cell survival. TP53 mutations and integrin α6β4 overexpression co-occur in many aggressive malignancies. Because of the high frequency of TP53 mutations in lung squamous cell carcinoma (SCC), we sought to investigate the association of integrin β4 expression with clinicopathologic features and survival in non-small cell lung cancer (NSCLC). We constructed a lung cancer tissue microarray and stained sections for integrin β4 subunit expression using immunohistochemistry. We found that integrin β4 expression is elevated in SCC compared with adenocarcinoma (P<.0001), which was confirmed in external gene expression data sets (P<.0001). We also determined that integrin β4 overexpression associates with the presence of venous invasion (P=.0048) and with reduced overall patient survival (hazard ratio, 1.46; 95% confidence interval, 1.01-2.09; P=.0422). Elevated integrin β4 expression was also shown to associate with reduced overall survival in lung cancer gene expression data sets (hazard ratio, 1.49; 95% confidence interval, 1.31-1.69; P<.0001). Using cBioPortal, we generated a network map demonstrating the 50 most highly altered genes neighboring ITGB4 in SCC, which included laminins, collagens, CD151, genes in the EGFR and PI3K pathways, and other known signaling partners. In conclusion, we demonstrate that integrin β4 is overexpressed in NSCLC where it is an adverse prognostic marker.
Department of Pathology, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Rachel L
RL
Stewart
Department of Pathology, University of Kentucky, Lexington, KY 40536, USA.
Dava
D
West
Department of Cancer Biostatistics, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Chi
C
Wang
Department of Cancer Biostatistics, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Heidi L
HL
Weiss
Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23220, USA.
Tamas
T
Gal
Department of Biomedical Informatics, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Eric B
EB
Durbin
Department of Pathology, University of Kentucky, Lexington, KY 40536, USA.
William
W
O'Connor
Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
Min
M
Chen
Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, KY 40506, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: kloconnor@uky.edu.
Kathleen L
KL
O'Connor
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D002289:Carcinoma, Non-Small-Cell Lung / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D019295:Computational Biology; D057225:Data Mining; D030541:Databases, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007150:Immunohistochemistry; D039503:Integrin alpha6 / Q000032:analysis* / Q000235:genetics; D039663:Integrin beta4 / Q000032:analysis* / Q000235:genetics; D053208:Kaplan-Meier Estimate; D008175:Lung Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D011379:Prognosis; D011667:Pulmonary Veins / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D013997:Time Factors; D046888:Tissue Array Analysis; D015854:Up-Regulation
D014408:Biomarkers, Tumor; C588002:ITGA6 protein, human; C059834:ITGB4 protein, human; D039503:Integrin alpha6; D039663:Integrin beta4; D012333:RNA, Messenger
CD44; Cell adhesion; Integrin signaling; NSCLC; Pulmonary adenocarcinoma