Integrin alpha 6 is upregulated and drives hepatocellular carcinoma progression through integrin α6β4 complex

Abstract

Integrin α6 (ITGA6) forms integrin receptors with either integrin β1 (ITGB1) or integrin β4 (ITGB4). How it functions to regulate hepatocellular carcinoma (HCC) progression is not well‐elucidated. We found that ITGA6 RNA and protein expression levels are significantly elevated in human HCC tissues in comparison with paired adjacent nontumor tissues by RNA sequencing, RT‐qPCR, Western blotting and immunofluorescence staining. Stable knockdown of ITGA6 with different ITGA6 shRNA expression lentivectors significantly inhibited proliferation, migration and anchorage‐independent growth of HCC cell lines in vitro, and xenograft tumor growth in vivo. The inhibition of anchorage‐dependent and ‐independent growth of HCC cell lines was also confirmed with anti‐ITGA6 antibody. ITGA6 knockdown was shown to induce cell‐cycle arrest at G0/G1 phase. Immunoprecipitation assay revealed apparent interaction of ITGA6 with ITGB4, but not ITGB1. Expression studies showed that ITGA6 positively regulates the expression of ITGB4 with no or negative regulation of ITGB1 expression. Finally, while high levels of ITGA6 and ITGB4 together were associated with significantly worse survival of HCC patients in TCGA data set, the association was not significant for high levels of ITGA6 and ITGB1. In conclusion, ITGA6 is upregulated in HCC tumors and has a malignant promoting role in HCC cells through integrin α6β4 complex. Thus, integrin α6β4 may be a therapeutic target for treating patients with HCC.

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“…The rest of the tissues were cut into small pieces, flash frozen in liquid nitrogen and stored in a liquid nitrogen tank. Tissue RNA extraction and sequencing procedures are provided in the supplementary file and reported previously 46 . Due to limited amount of tissue samples, quality of samples, and various assays performed, the number of samples used for the various assays are different as shown in the figures.…”

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