Integrin α6Bβ4 inhibits colon cancer cell proliferation and c-Myc activity

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.
BMC Cancer (Impact Factor: 3.36). 02/2009; 9(1):223. DOI: 10.1186/1471-2407-9-223
Source: PubMed


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.
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.
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.
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.

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    • "Altered expression of integrins has also been reported in CRC [5,6]. For example, the integrin α9β1 was detected in 50% of the tumours [7] while expression of the pro-apoptotic α8β1 integrin was found to be down-regulated in CRC and the pro-proliferative variant form of the integrin α6β4 was exclusively found in CRC cells [8,9]. "
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    ABSTRACT: Background Colorectal cancer remains one of the leading causes of death from cancer in industrialized countries. Integrins are a family of heterodimeric glycoproteins involved in bidirectional cell signaling and participate in the regulation of cell shape, adhesion, migration, differentiation, gene transcription, survival and proliferation. The α1 subunit is known to be involved in RAS/ERK proliferative pathway activation and plays an important role in mammary carcinoma cell proliferation and migration. In the small intestine, α1 is present in the crypt proliferative compartment and absent in the villus, but nothing is known about its expression in the colon mucosa, or in colorectal cancer. Results In the present study, we demonstrated that in the colon mucosa, α1 is present in the basolateral domain of the proliferative cells of the crypt, and in the surrounding myofibroblasts. We found higher levels of α1 mRNA in 86% of tumours compared to their corresponding matched margin tissues. Immunohistochemical analysis showed that α1 staining was moderate to high in 65% of tumour cells and 97% of the reactive cells surrounding the tumour cells vs 23% of normal epithelial cells. Conclusion Our findings suggest an active role for the α1β1 integrin in colorectal cancer progression.
    03/2013; 1(1). DOI:10.1186/2050-7771-1-16
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    • "Our IHC analysis suggested that α 6β 4 could be a proper target for therapeutic Abs [52]. Trial for the development of therapeutic mAbs to α 6β 4 was reported [53]. "
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    ABSTRACT: Since the success of rituximab and trastuzumab for treatment of non-Hodgkin's lymphoma and breast cancer, respectively, a huge therapeutic potential of monoclonal antibodies (mAbs) was realized and development of therapeutic mAbs has been widely tried against various cancers. However, the successful examples are still limited and therapeutic mAbs are not yet available for the majority of human cancers. We established a procedure for comprehensive identification of tumor-associated antigens (TAAs) through the extensive isolation of human mAbs that may become therapeutic. Thirty-twoTAAs have been identified and 555 mAbs that bound to one of the TAAs have been isolated to date. Now we are trying to select TAAs as proper targets for therapy and candidate mAbs as drugs from among them. The immunohistochemical analysis using many fresh lung cancer specimens suggested probabilities of proper targets, and moreover, presence of cancer-specific epitopes that could be distinguished from normal epitopes on the same molecules by mAbs. For Abs to efficiently kill the cancer cells they should have the ability to induce immunological cytotoxicity such as ADCC and/or CDC. They should also be able to inhibit the function mediated by the target Ags. For clinical point of view, the continuous presence of the target molecule on the cell surface until cell death might be essential for successful treatment. Therefore, it will be required for targets TAAs to play essential roles in tumorigenesis. Otherwise the cancer cells that do not express them could selectively survive during treatment and finally become dominant. It was also suggested that even the same molecules could play different roles in tumorigenesis quite often in different patients. Therefore when we develop therapeutic Abs, we should obtain information about the conditions of patients including genetic background to whom the treatment will be effective. I will discuss how we can accomplish this purpose.
    Journal of Stem Cells and Regenerative Medicine 04/2011; 7(1):14-28.
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