Antisense integrin αV and β3 gene therapy suppresses subcutaneously implanted hepatocellular carcinomas

Abstract

Background Integrin αVβ3 plays a critical role in tumour angiogenesis and metastasis formation, and is recognized as a key therapeutic target in the treatment of cancer. Aim To investigate whether antisense αV and β3 gene therapy has utility in the treatment of hepatocellular carcinomas. Methods Antisense expression plasmids targeting integrin αV or β3 were constructed, and examined by immunohistochemistry and Western blot analyses for their ability to inhibit αV and β3 expression. The antisense αV and β3 expression vectors, either alone or in combination, were injected into HepG2 hepatomas established subcutaneously in nude mice and tumour growth, angiogenesis and apoptosis were monitored. Results Antisense αV and β3 downregulated the αV and β3 subunits expressed by human umbilical vein endothelial cells, and the αV subunit expressed by HepG2 cells. Gene transfer of antisense αV and β3 expression vectors downregulated αV and β3 in HepG2 tumours established in nude mice, inhibited tumour vascularization and growth, and enhanced tumour cell apoptosis. Antisense αV suppressed tumour growth more strongly than antisense β3; however antisense therapy that simultaneously targeted both integrin subunits was more effective than the respective monotherapies. Antisense αV and β3 inhibited tumour angiogenesis to similar extents, by a process that is independent of vascular endothelial growth factor. Conclusions Antisense gene therapy targeting αV integrins warrants consideration as an approach to treat hepatocellular carcinomas.