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Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins

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Abstract

O6-methylguanine DNA methyltransferase (MGMT) suppresses mutations and cell death that result from alkylation damage. MGMT expression is lost by epigenetic silencing in a variety of human cancers including nearly half of sporadic colorectal cancers, suggesting that this loss maybe causal. Using mice with a targeted disruption of the Mgmt gene, we tested whether Mgmt protects against azoxymethane (AOM)-induced colonic aberrant crypt foci (ACF), against AOM and dextran sulfate sodium (DSS)-induced colorectal adenomas and against spontaneous intestinal adenomas in ApcMin mice. We also examined the genetic interaction of the Mgmt null gene with a DNA mismatch repair null gene, namely Msh6. Both Mgmt and Msh6 independently suppress AOM-induced ACF, and combination of the two mutant alleles had a multiplicative effect. This synergism can be explained entirely by the suppression of alkylation-induced apoptosis when Msh6 is absent. In addition, following AOM+DSS treatment Mgmt protected against adenoma formation to the same degree as it protected against AOM-induced ACF formation. Finally, Mgmt deficiency did not affect spontaneous intestinal adenoma development in ApcMin/+ mice, suggesting that Mgmt suppresses intestinal cancer associated with exogenous alkylating agents, and that endogenous alkylation does not contribute to the rapid tumor development seen in ApcMin/+ mice.

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Abbreviations

ACF:

Aberrant crypt foci

AOM:

Azoxymethane

DSS:

Dextran sulfate sodium

Mgmt:

O6-methylguanine-DNA methyltransferase

O6MeG:

O6-methylguanine

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Acknowledgements

This research was supported by NIH Grants ES02109 and CA75576. We acknowledge the MIT CCR Histology facility (NCI Grant: CA14051), especially Alicia Caron. LDS is an American Cancer Society Research Professor.

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  1. Biological Engineering Department and Center for Environmental Health Sciences, Massachusetts Institute of Technology, Cambridge, MA, USA

    J M Bugni, L B Meira & L D Samson

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  1. J M Bugni
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  2. L B Meira
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  3. L D Samson
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Correspondence to L D Samson.

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Bugni, J., Meira, L. & Samson, L. Alkylation-induced colon tumorigenesis in mice deficient in the Mgmt and Msh6 proteins. Oncogene 28, 734–741 (2009). https://doi.org/10.1038/onc.2008.426

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  • DOI: https://doi.org/10.1038/onc.2008.426

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