Integrin α6A splice variant regulates proliferation and the Wnt/β-catenin pathway in human colorectal cancer cells.
Bottom Line: The α6A silencing was also found to be associated with a significant repression of a number of Wnt/β-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 α6A variant is a pro-proliferative form of the α6 integrin subunit in CRC cells and appears to mediate its effects through the Wnt/β-catenin pathway.
Affiliation: Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology and Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.Show MeSH
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Mentions: We have shown previously that α6B/α6A integrin subunit ratios were significantly reduced in a relatively small set of human CRC samples at the transcript level (12). In an attempt to extend these observations, the mRNA levels of total α6 as well as the individual α6A and α6B variants were analyzed by qPCR in 97 CRCs and their corresponding resection margins (RMs). The level of total α6 subunit mRNA was found to be increased in CRC samples compared with RMs by more than 2-fold, as well as that of α6A, whereas the level of α6B remained stable (Figure 1A). Moreover, a close correlation was observed between the levels of α6 and α6A mRNA (P ≤ 0.0001, Pearson r = 0.588) in human CRC (Figure 1B). When each sample was analyzed individually, the expression of α6A in CRC compared with corresponding RMs was found to be increased in 69 patients, similar in 16 patients and reduced in 12 patients. Taking into consideration that significant levels of α6A are expressed in the crypt of the normal colonic mucosa of the RM, these results confirm that a large proportion of CRC cells express significant levels of α6A. Furthermore, up-regulation of α6A was observed for all tumour stages or grades (Supplementary Figure 1, available at Carcinogenesis Online) although the presence of somatic mutations of adenomatous polyposis coli (APC) had no impact on α6A expression (data not shown). Taken together, these data confirm a sustained up-regulation of the α6A splice variant in human CRC.
Affiliation: Laboratory of Intestinal Physiopathology, Department of Anatomy and Cell Biology and Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.