Kalinina Olga A, Kalinin Sergey A, Polack Evelyne W, Mikaelian Igor, Panda Suchismita, Costa Robert H, Adami Guy R
Department of Oral Medicine and Diagnostic Sciences and the Center for Molecular Biology of Oral Diseases, College of Dentistry, University of Illinois at Chicago, Chicago, IL 60612, USA.
Oncogene. 2003 Sep 18;22(40):6266-76. doi: 10.1038/sj.onc.1206640.
Increased hepatic expression of the Forkhead transcription factor FoxM1B in adult mice accelerates hepatocyte proliferation after partial hepatectomy, while in hepatocytes in intact liver the transgenic (Tg) protein is inactive and has no effect on proliferation. To investigate the influence of FoxM1B on liver tumor formation, we examined the effect of sustained enrichment of FoxM1B in the hepatocytes of mice treated with a diethylnitrosamine (DEN)/phenobarbital tumor induction protocol. Tg enrichment of FoxM1B in hepatocytes did not increase the proliferation rate in normal liver tissue even when the protein was localized to the nucleus. However, it did cause an increase in the proliferation rate and size of preneoplastic and early neoplastic lesions, although having no effects on the total numbers of these lesions. As tumors progressed to hepatocellular carcinomas, the additional Tg FoxM1B protein had no effect on cell proliferation, and there was no increase in tumor burden compared to wild-type animals. This suggests that the artificial enrichment of FoxM1B in the liver, which has been suggested as a gene therapy protocol for liver dysfunction with aging, may not be tumorigenic in that organ.
成年小鼠肝脏中叉头转录因子FoxM1B的表达增加会加速部分肝切除术后的肝细胞增殖，而在完整肝脏的肝细胞中，转基因（Tg）蛋白无活性，对增殖没有影响。为了研究FoxM1B对肝脏肿瘤形成的影响，我们检测了在用二乙基亚硝胺（DEN）/苯巴比妥肿瘤诱导方案处理的小鼠肝细胞中持续富集FoxM1B的效果。即使蛋白定位于细胞核，肝细胞中FoxM1B的Tg富集也不会增加正常肝组织中的增殖率。然而，它确实导致了癌前和早期肿瘤性病变的增殖率和大小增加，尽管对这些病变的总数没有影响。随着肿瘤发展为肝细胞癌，额外的Tg FoxM1B蛋白对细胞增殖没有影响，与野生型动物相比，肿瘤负担也没有增加。这表明，已被提议作为衰老性肝功能障碍基因治疗方案的肝脏中FoxM1B的人工富集，在该器官中可能不会致癌。
