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: The Wnt/β-catenin pathway is one of the most important regulators of cell proliferation in various systems and is often strongly deregulated in human CRC (35,36), thus suggesting a possible link between α6A expression and Wnt/β-catenin activity in CRC cells. Wnt/β-catenin activity was first evaluated by determining the level of GSK3β phosphorylation of β-catenin at ser37/thr41 using an active β-catenin antibody. WB analyses of whole cell lysates showed a statistically significant decrease in the levels of active β-catenin in all shα6A cell lines relative to total β-catenin compared with shctl cells (Figure 5A). This overall decrease was also reflected in WB analyses of nuclear extracts, where β-catenin was reduced in α6A knockdown Caco-2/15, DLD-1 and T84 (Figure 5B). These results suggest that in these CRC cells, depletion of the α6A integrin variant interferes with the Wnt/β-catenin pathway by enhancing the phosphorylation of β-catenin by GSK3β, targeting it to proteasome degradation and consequently reducing its accumulation in the nucleus.
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.