ITGA5 and ITGB1 contribute to Sorafenib resistance by promoting vasculogenic mimicry formation in hepatocellular carcinoma.

Abstract

Hepatocellular carcinoma (HCC) is labeled with high mortality and tolerance to chemotherapy. Sorafenib has been the first-line treatment option in HCC patients for past decades, while the therapeutic effect was limited in almost HCC patients. In this study, we analyzed public omics data of HCC patients with different responses to Sorafenib treatment. To confirm the role of integrins A5 and B1 (ITGA5 and ITGB1) in Sorafenib resistance, we generated the Sorafenib-resistant (Sor-R) cell lines and cells overexpressing ITGA5 or ITGB1. Hypoxia level was measured using Hypoxy probe by flow cytometry, while vasculogenic mimicry was detected and quantified by CD31 and periodic acid schiff staining. Hypoxia was upregulated in non-responsive patients, accompanied with genes involved in encoding extracellular matrix components and angiogenesis such as ITGA5 and ITGB1. Sor-R hepatoma cell lines were constructed to measure expression and role of candidate genes. ITGA5 and ITGB1 were augmented in Sor-R cells. Upregulation of ITGA5 or ITGB1 reduced the sensitivity to Sorafenib in HepG2 and Huh7 cells, aggravated the hypoxic condition and resulted in formation of vascular mimicry. These findings suggested that hypoxia associated vascular mimicry account for non-response to Sorafenib treatment in HCC patients. ITGA5 and ITGB1 may serve as effective predictors of HCC patients' outcome after Sorafenib treatment, which also provides a new target for HCC patients resistant to Sorafenib.