Elevated integrin α6β4 expression is associated with venous invasion and decreased overall survival in non–small cell lung cancer

Abstract

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. Due to 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 to adenocarcinoma (P<0.0001), which was confirmed in external gene expression datasets (P<0.0001). We also determined that integrin β4 overexpression associates with the presence of venous invasion (P=0.0048), and with reduced overall patient survival (Hazard ratio 1.46, 95% confidence interval 1.01 to 2.09, P=0.0422). Elevated integrin β4 expression was also shown to associate with reduced overall survival in lung cancer gene expression datasets (Hazard ratio 1.49, 95% confidence interval 1.31 to 1.69, P<0.0001). 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.

Integrin-β4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells

“…We now demonstrate that ITGB4 mRNA alone can be used to stratify survival for TNBC patients that require chemotherapy; patients with tumors exhibiting high levels of ITGB4 mRNA had a significantly worse prognosis. These results were similar to those that have been reported in pancreatic ductal adenocarcinoma (17) and non-small cell lung cancer (18). Together, our results demonstrate that ITGB4 can be used to identify CSC-enriched TNBC cells and that high levels of ITGB4 mRNA can be used clinically to identify patients that may benefit from more aggressive therapeutic strategies.…”

Distinct mechanisms of regulation of the ITGA6 and ITGB4 genes by RUNX1 in myeloid cells

“…Furthermore, this integrin receptor plays a role in cell migration, and signaling through α6β4 has be shown to stimulate oncogenic pathways including p53 and PI3K signaling (reviewed in Stewart & O'Connor, ). These two integrin subunits promote metastatic potential and are frequently disrupted in a variety of solid tumors (Lu, Simin, Khan, & Mercurio, ; Stewart et al, ). In leukemia, where RUNX1 action is often disrupted, dysregulated expression of RUNX1 target genes is evident (Ichikawa et al, ).…”

Microdomain forming proteins in oncogenesis

“…Недавно показано, что при НМРЛ, особен-но в группе плоскоклеточного рака легкого, суперэкс-прессия интегрина β4 (ITGB4) строго ассоциирована с сосудистой инвазией и с уменьшением сроков общей выживаемости пациентов. На основании анализа па-нели из 50 генов, включающей компоненты EGFR-и PI3K-сигнальных путей, авторы, наряду с другими (например, мутантным р53), зафиксировали изменения экспрессии ламинина и CD151 [66]. Экспрессия CD151-α3β1 комплекса может служить прогностическим мар-кером при HER2-негативном РМЖ [67] и глиобластоме [64].…”