RESUMEN
O(6)-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 Apc(Min) 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 Apc(Min/+) 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 Apc(Min/+) mice.
Asunto(s)
Alquilación/fisiología , Carcinoma/genética , Carcinoma/metabolismo , Neoplasias del Colon/genética , Neoplasias del Colon/metabolismo , Metilasas de Modificación del ADN/genética , Enzimas Reparadoras del ADN/genética , Proteínas de Unión al ADN/genética , Proteínas Supresoras de Tumor/genética , Alquilantes/toxicidad , Alquilación/genética , Animales , Apoptosis/efectos de los fármacos , Apoptosis/genética , Azoximetano/toxicidad , Carcinógenos/toxicidad , Carcinoma/patología , Neoplasias del Colon/inducido químicamente , Neoplasias del Colon/patología , Sulfato de Dextran/toxicidad , Genes APC/fisiología , Predisposición Genética a la Enfermedad , Ratones , Ratones Endogámicos C57BL , Ratones NoqueadosRESUMEN
In mice, the sex difference in susceptibility to hepatocarcinogenesis results from the tumor promoting activity of testosterone and from the inhibition of tumor promotion by ovarian hormones. We investigated the role of growth hormone in the sex-dependent regulation of susceptibility, because sex hormones are known to regulate the temporal pattern of growth hormone secretion and subsequent sex differences in liver gene expression. We found that in both males and females, wild-type mice developed significantly more tumors than growth hormone-deficient, C57BL/6J-lit/lit (B6-lit/lit) mutant mice following perinatal treatment with the carcinogen N,N-diethylnitrosamine (DEN). B6 wild-type males developed 36-59-fold more liver tumors per animal than age matched B6-lit/lit males and wild-type females developed 11-fold more tumors than B6-lit/lit females. We bred the little mutation onto the more susceptible C57BR/cdJ (BR) and C3H/HeJ (C3H) strains to assess the effect of growth hormone deficiency on hepatocarcinogenesis on additional genetic backgrounds. Growth hormone deficiency suppressed liver tumor development to <1% in males of each strain and in BR strain females. In B6 and C3H females, growth hormone deficiency caused 2-4-fold reductions in the volume fraction of the liver occupied by preneoplastic lesions. Furthermore, in contrast to wild-type strains, neither gonadectomy nor strain background significantly affected susceptibility in lit/lit mice, as mean liver tumor multiplicities ranged from 0 to 0.24 +/- 0.44 and the volume fraction of preneoplastic lesions ranged from 0.21 +/- 0.22 to 0.61 +/- 1.9%. These results demonstrate that both strain and sex hormonal effects on susceptibility to liver carcinogenesis are dependent on wild-type levels of growth hormone.
Asunto(s)
Carcinoma Hepatocelular/metabolismo , Predisposición Genética a la Enfermedad , Hormona del Crecimiento/fisiología , Neoplasias Hepáticas Experimentales/metabolismo , Animales , Bromodesoxiuridina , Carcinógenos , Carcinoma Hepatocelular/inducido químicamente , Carcinoma Hepatocelular/genética , Dietilnitrosamina , Femenino , Hormona del Crecimiento/deficiencia , Técnicas para Inmunoenzimas , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/genética , Masculino , Ratones , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Orquiectomía , Ovariectomía , Reacción en Cadena de la Polimerasa , Polimorfismo de Longitud del Fragmento de Restricción , Factores SexualesRESUMEN
The LT/Sv mouse strain is characterized by its abnormally high incidence of spontaneous ovarian teratomas. These tumors have been shown to originate from parthenogenetic oocytes, which are spontaneously induced to divide. Both spontaneous parthenogenesis and ovarian teratomas are extremely rare for other mouse strains, including C57BL/6J. To identify the genes responsible for this unique phenotype of female LT/Sv mice, we performed linkage analysis of female (C57BL/6J x LT/Sv)F2 mice. A locus on chromosome 6 designated Ots1 (ovarian teratoma susceptibility) was identified as the single major locus that increases the frequency of teratomas in a semidominant manner.
