Integrin alpha6Bbeta4 inhibits colon cancer cell proliferation and c-Myc activity.
BACKGROUND
Integrins are known to be important contributors to cancer progression. We have previously shown that the integrin beta4 subunit is up-regulated in primary colon cancer. Its partner, the integrin alpha6 subunit, exists as two different mRNA splice variants, alpha6A and alpha6B, that differ in their cytoplasmic domains but evidence for distinct biological functions of these alpha6 splice variants is still lacking.


METHODS
In this work, we first analyzed the expression of integrin alpha6A and alpha6B at the protein and transcript levels in normal human colonic cells as well as colorectal adenocarcinoma cells from both primary tumors and established cell lines. Then, using forced expression experiments, we investigated the effect of alpha6A and alpha6B on the regulation of cell proliferation in a colon cancer cell line.


RESULTS
Using variant-specific antibodies, we observed that alpha6A and alpha6B are differentially expressed both within the normal adult colonic epithelium and between normal and diseased colonic tissues. Proliferative cells located in the lower half of the glands were found to predominantly express alpha6A, while the differentiated and quiescent colonocytes in the upper half of the glands and surface epithelium expressed alpha6B. A relative decrease of alpha6B expression was also identified in primary colon tumors and adenocarcinoma cell lines suggesting that the alpha6A/alpha6B ratios may be linked to the proliferative status of colonic cells. Additional studies in colon cancer cells showed that experimentally restoring the alpha6A/alpha6B balance in favor of alpha6B caused a decrease in cellular S-phase entry and repressed the activity of c-Myc.


CONCLUSIONS
The findings that the alpha6Bbeta4 integrin is expressed in quiescent normal colonic cells and is significantly down-regulated in colon cancer cells relative to its alpha6Abeta4 counterpart are consistent with the anti-proliferative influence and inhibitory effect on c-Myc activity identified for this alpha6Bbeta4 integrin. Taken together, these findings point out the importance of integrin variant expression in colon cancer cell biology.
Dydensborg
Anders Bondo
AB
CIHR Team on the Digestive Epithelium, Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke, Québec, J1H 5N4, Canada. andersbondo@gmail.com
Teller
Inga C
IC
Groulx
Jean-François
JF
Basora
Nuria
N
Paré
Fréderic
F
Herring
Elizabeth
E
Gauthier
Rémy
R
Jean
Dominique
D
Beaulieu
Jean-François
JF
D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism* / Q000628:therapy; D004847:Epithelial Cells / Q000166:cytology; D019084:Fluorescent Antibody Technique, Indirect; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039161:Integrin alpha6beta4 / Q000378:metabolism / Q000502:physiology*; D008875:Middle Aged; D008954:Models, Biological; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D016196:S Phase
D039161:Integrin alpha6beta4; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger