title: Integrin α6A splice variant regulates proliferation and the Wnt/β-catenin pathway in human colorectal cancer cells.
abstract: The integrin α6 subunit pre-messenger RNA undergoes alternative splicing to generate two different splice variants, named α6A and α6B, 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 α6β4 integrin in colon adenocarcinomas as well as an increase in the α6A/α6B ratio, but little is known about the involvement of α6Aβ4 versus α6Bβ4 in this context. The aim of this study was to elucidate the function of the α6Aβ4 integrin in human colorectal cancer (CRC) cells. Expression studies on a panel of primary CRCs confirmed that the up-regulation of the α6 subunit in CRC is a direct consequence of the increase of the α6A variant. To investigate the functional significance of an α6A 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 α6A knockdown CRC cell lines studied. 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.
authors.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.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Groulx
authors.affiliation: Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors.forename: Véronique
authors.initials: V
authors.lastname: Giroux
authors.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.
authors.forename: Marco
authors.initials: M
authors.lastname: Beauséjour
authors.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.
authors.forename: Salah
authors.initials: S
authors.lastname: Boudjadi
authors.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.
authors.forename: Nuria
authors.initials: N
authors.lastname: Basora
authors.affiliation: Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Quebec J1H 5N4, Canada.
authors.forename: Julie C
authors.initials: JC
authors.lastname: Carrier
authors.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 jean-francois.beaulieu@usherbrooke.ca.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Beaulieu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D000072261:Dishevelled Proteins; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D000071679:Glycogen Synthase Kinase 3 beta; D064593:Heterografts; D006801:Humans; D039503:Integrin alpha6 / Q000235:genetics* / Q000378:metabolism; D042541:Intracellular Space / Q000378:metabolism; D051379:Mice; D010750:Phosphoproteins / Q000378:metabolism; D021122:Protein Subunits / Q000235:genetics; D021381:Protein Transport; D047368:Tumor Burden; D060449:Wnt Signaling Pathway
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000072261:Dishevelled Proteins; D039503:Integrin alpha6; D010750:Phosphoproteins; D021122:Protein Subunits; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3