RESUMEN
The authors investigated the spectrum of tumors and Trp53 mutations in genetically engineered models using the FVB/N mouse that expressed the hepatitis B virus genome and/or carried a Trp53 null and wildtype allele and/or were exposed to aflatoxin B1. Liver tumor incidence was increased when all three risk factors were present. Without aflatoxin B1 exposure, neither Trp53 haploinsufficiency nor HBV expression affected liver tumor development. Liver tumor prevalence increased with aflatoxin B1 exposure (p < .001), as thirteen of fourteen mice with liver tumors were initiated with aflatoxin B1. Liver tumors were more frequent in males (12/190) than females (2/170). Seventy-three mice developed sarcomas. Trp53 haploinsufficiency was associated with increased sarcoma incidence in males and females (p < .001). In Trp53 haploinsufficient mice, the HBV transgene increased the risk of sarcoma in males and females (p < .001). Lymphoma was significantly increased in Trp53 haploinsufficient FVB/N mice. There was no loss of heterozygosity at the wildtype Trp53 locus in twenty-five sarcomas or four hepatocellular tumors examined. No mutations were identified in the mRNA (exons 2-11) of Trp53 in six liver neoplasms or twenty-four sarcomas. In this model system, HBV expression affected only hepatocellular neoplasia in association with both aflatoxin B1 initiation and p53 haploinsufficiency.
Asunto(s)
Aflatoxina B1/genética , Modelos Animales de Enfermedad , Virus de la Hepatitis B/genética , Neoplasias Hepáticas Experimentales/genética , Animales , Femenino , Ingeniería Genética/efectos adversos , Antígenos de Superficie de la Hepatitis B/genética , Inmunohistoquímica , Estimación de Kaplan-Meier , Antígeno Ki-67/genética , Neoplasias Hepáticas Experimentales/inducido químicamente , Neoplasias Hepáticas Experimentales/patología , Neoplasias Hepáticas Experimentales/virología , Masculino , Ratones , Ratones Endogámicos , Ratones Transgénicos , Factores Sexuales , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/genéticaRESUMEN
BCL2 is best known as a multifunctional anti-apoptotic protein. However, little is known about its role in cell-adhesive and motility events. Here, we show that BCL2 may play a role in the regulation of cell adhesion, spreading, and motility. When BCL2 was overexpressed in cultured murine and human cell lines, cell spreading, adhesion, and motility were impaired. Consistent with these results, the loss of Bcl2 resulted in higher motility observed in Bcl2-null mouse embryonic fibroblast (MEF) cells compared to wild type. The mechanism of BCL2 regulation of cell adhesion and motility may involve formation of a complex containing BCL2, actin, and gelsolin, which appears to functionally decrease the severing activity of gelsolin. We have observed that the lysate from MCF-7 and NIH3T3 cells that overexpressed BCL2 enhanced actin polymerization in cell-free in vitro assays. Confocal immunofluorescent localization of BCL2 and F-actin during spreading consistently showed that increased expression of BCL2 resulted in increased F-actin polymerization. Thus, the formation of BCL2 and gelsolin complexes (which possibly contain other proteins) appears to play a critical role in the regulation of cell adhesion and migration. Given the established correlation of cell motility with cancer metastasis, this result may explain why the expression of BCL2 in some tumor cell types reduces the potential for metastasis and is associated with improved patient prognosis.