Sustained hepatic expression of FoxM1B in transgenic mice has minimal effects on hepatocellular carcinoma development but increases cell proliferation rates in preneoplastic and early neoplastic lesions
Sustained hepatic expression of FoxM1B in transgenic mice has minimal effects on hepatocellular carcinoma development but increases cell proliferation rates in preneoplastic and early neoplastic lesions
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DOI：
10.1038/sj.onc.1206640
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发表时间：
2003-09-18
期刊：
影响因子：
8
通讯作者：
Adami, GR
中科院分区：
文献类型：
--
作者：
Kalinina, OA;Kalinin, SA;Adami, GR
成年小鼠肝脏中Forkhead转录因子FoxM1B的表达增加加速了肝部分切除后肝细胞的增殖，而在完整肝细胞中，转基因(TG)蛋白是无效的，对增殖没有影响。为了研究FoxM1B对小鼠肝肿瘤形成的影响，我们检测了FoxM1B在二乙基亚硝胺(DEN)/苯巴比妥诱导方案治疗的小鼠肝细胞中的持续富集性。FoxM1B在肝细胞中的TG丰富并没有增加正常肝组织的增殖率，即使当FoxM1B定位于细胞核时也是如此。然而，它确实导致癌前病变和早期肿瘤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。随着肿瘤进展为肝细胞癌，额外的TG FoxM1B蛋白对细胞增殖没有影响，与野生型动物相比，肿瘤负担没有增加。这表明，FoxM1B在肝脏中的人工浓缩可能不会在该器官中产生肿瘤。FoxM1B已被建议作为治疗随年龄增长的肝功能障碍的基因治疗方案。
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.