Integrin αvβ6 predicts poor prognosis and promotes resistance to cisplatin in hilar cholangiocarcinoma

Objective: Integrin alpha v beta 6 is associated with an extremely aggressive cancer phenotype. However, little is known about the clinicopathological significance and prognostic value of integrin alpha v beta 6 in human hilar cholangiocarcinoma. Methods: In the present study, bioinformatics analysis demonstrated a significant increase of integrin beta 6 gene expression in cholangiocarcinoma tissues compared to non-tumorous tissues, which was further validated in clinical samples through RT-qPCR and western blotting analyses. Integrin alpha v beta 6 was observed to be expressed in 48.6% of tumors, and its expression was related to a poor tumor differentiation (p = 0.002), lymph node metastasis (p < 0.001) and advanced TNM stage (p=0.001). Furthermore, patients who were alpha v beta 6-positive showed a significantly shorter overall survival period than those who were alpha v beta 6-negative (p=0.004). Multivariate analysis confirmed that integrin alpha v beta 6 was an independent prognostic factor (p=0.002). In addition, loss- and gain-of-function assays showed integrin alpha v beta 6 not only played an important role in colony formation, but also protected cholangiocarcinoma cells from cisplatin-induced growth inhibition and apoptosis. ERK/MAPK signaling pathway was involved in integrin alpha v beta 6-mediated resistance of cholangiocarcinoma cells to cisplatin. Conclusions: Taken together, the present findings revealed that integrin alpha v beta 6 could serve as a potential prognostic predictor and contribute to cisplatin resistance, which might prove to be a promising target candidate for the clinical intervention of human hilar cholangiocarcinoma.