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. 2001 Oct 23;98(22):12566-71.
doi: 10.1073/pnas.221232998. Epub 2001 Oct 16.

Spontaneous Hepatocellular Carcinoma Is Reduced in Transgenic Mice Overexpressing Human O6- methylguanine-DNA Methyltransferase

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Free PMC article

Spontaneous Hepatocellular Carcinoma Is Reduced in Transgenic Mice Overexpressing Human O6- methylguanine-DNA Methyltransferase

Z Q Zhou et al. Proc Natl Acad Sci U S A. .
Free PMC article

Abstract

O(6)-methylguanine (O(6)mG) is a potent mutagenic and procarcinogenic DNA lesion. Organisms have evolved with a DNA repair mechanism that largely ameliorates the deleterious effects of O(6)mG through a direct reversal mechanism by a protein termed O(6)-methylguanine-DNA methyltransferase (MGMT). However, the contribution of O(6)mG to carcinogenesis, in the absence of known exposure to agents that produce it, has not been defined. Nontransgenic C3HeB male mice have a high frequency of spontaneous liver tumors. Transgenic CeHeB/FeJ mice expressing human MGMT (hMGMT) were generated that had elevated hepatic MGMT activity. The spontaneous development of hepatocellular carcinoma was significantly reduced in those mice expressing hMGMT compared with nontransgenic C3HeB/FeJ male mice. No differences were detected in spontaneous mutant frequencies in lacI transgenes in mice carrying hMGMT compared with that without hMGMT but the proportion of GC to AT transition mutations was lower in the transgenic mice carrying hMGMT as well as lacI. Tumors that arose in C3HeB/FeJ transgenic mice were largely deficient in hMGMT protein as determined by immunohistochemistry with a monoclonal antibody directed against hMGMT. Together these data indicate that spontaneous O(6)mG lesions induced hepatocellular carcinogenesis in C3HeB/FeJ male mice. These transgenic mice represent a rare example of reduced spontaneous carcinogenesis.

Figures

Figure 1
Figure 1
Immunohistochemical detection of hMGMT in liver. Cells expressing hMGMT are characterized by brown nuclei. (A) Nontransgenic liver. (B) LC22I liver. (C) LC26I liver. (D) Area of normal and tumor tissue from an LC28I animal. (Magnification: A and B, ×40; C, ×40; D, ×16.)
Figure 2
Figure 2
MGMT activity assays. (A) Results from a single MGMT assay by using extracts prepared from liver. (Upper) The amount of repaired oligonucleotide as an 8-mer band. (Lower) The efficiency of cutting by a control restriction endonuclease, HaeIII. (B) Means with standard error shown for each group. n = 5 animals for each line of mice. NT = nontransgenic.
Figure 3
Figure 3
Prevalence of spontaneous hepatocellular carcinoma. Frequencies were calculated by scoring the number of animals manifesting hepatocellular carcinoma divided by the total number of animals in the group, then multiplying by 100. C3HeB/FeJ, n = 10; LC22I, n = 31; LC26I, n = 22; LC28I, n = 16.

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