Integrin ?6A splice variant regulates proliferation and the Wnt/?-catenin pathway in human colorectal cancer cells.

ABSTRACT: The integrin ?6 subunit pre-messenger RNA undergoes alternative splicing to generate two different splice variants, named ?6A and ?6B, having distinct cytoplasmic domains. In the human colonic gland, these splice variants display different patterns of expression suggesting specific functions for each variant. We have previously found an up-regulation of the ?6?4 integrin in colon adenocarcinomas as well as an increase in the ?6A/?6B ratio, but little is known about the involvement of ?6A?4 versus ?6B?4 in this context. The aim of this study was to elucidate the function of the ?6A?4 integrin in human colorectal cancer (CRC) cells. Expression studies on a panel of primary CRCs confirmed that the up-regulation of the ?6 subunit in CRC is a direct consequence of the increase of the ?6A variant. To investigate the functional significance of an ?6A up-regulation in CRC, we specifically knocked down its expression in well-established CRC cell lines using a small-hairpin RNA approach. Results showed a growth rate reduction in all ?6A knockdown CRC cell lines studied. The ?6A silencing was also found to be associated with a significant repression of a number of Wnt/?-catenin pathway end points. Moreover, it was accompanied by a reduction in the capacity of these cells to develop tumours in xenografts. Taken together, these results demonstrate that the ?6A variant is a pro-proliferative form of the ?6 integrin subunit in CRC cells and appears to mediate its effects through the Wnt/?-catenin pathway.

SUBMITTER: Groulx JF 

PROVIDER: S-EPMC4043246 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature