文章：

二乙基亚硝胺诱导的肝细胞癌模型中MtbpHypomorphic等位基因的表征

Characterization of anMtbpHypomorphic Allele in a Diethylnitrosamine-Induced Liver Carcinogenesis Model

原文发布日期：16 September 2023

DOI: 10.3390/cancers15184596

类型: Article

开放获取: 是

英文摘要：

MTBP is implicated in cell cycle progression, DNA replication, and cancer metastasis. However, the function of MTBP remains enigmatic and is dependent on cellular contexts and its cellular localization. To understand the in vivo physiological role of MTBP, it is important to generateMtbpknockout mice. However, complete deletion of theMtbpgene in mice results in early embryonic lethality, while its heterozygous deletion shows modest biological phenotypes, including enhanced cancer metastasis. To overcome this and better characterize the in vivo physiological function of MTBP, we, for the first time, generated mice that carry anMtbphypomorphic allele (MtbpH) in which Mtbp protein is expressed at approximately 30% of that in the wild-type allele. We treated wild-type,Mtbp+/−, andMtbpH/−mice with a liver carcinogen, diethylnitrosamine (DEN), and found that theMtbpH/−mice showed worse overall survival when compared to the wild-type mice. Consistent with previous reports using human liver cancer cells, mouse embryonic fibroblasts (MEFs) from theMtbpH/−mice showed an increase in the nuclear localization of p-Erk1/2 and migratory potential. Thus,MtbpH/−mice and cells fromMtbpH/−mice are valuable to understand the in vivo physiological role of Mtbp and validate the diverse functions of MTBP that have been observed in human cells.

摘要翻译： 

MTBP蛋白参与细胞周期进程、DNA复制及癌症转移过程。然而，其功能机制仍不明确，且取决于细胞环境及其亚细胞定位。为探究MTBP在体内的生理功能，构建Mtbp基因敲除小鼠模型至关重要。但完全敲除小鼠Mtbp基因会导致早期胚胎致死，而其杂合缺失仅表现出有限的生物学表型，包括增强的癌症转移能力。为突破此局限并更精准表征MTBP的体内生理功能，本研究首次构建了携带Mtbp低效等位基因（MtbpH）的小鼠模型，该模型中Mtbp蛋白表达量约为野生型的30%。通过使用肝脏致癌物二乙基亚硝胺（DEN）处理野生型、Mtbp+/−及MtbpH/−小鼠，发现MtbpH/−小鼠总体生存率显著低于野生型。与既往人类肝癌细胞研究结果一致，源自MtbpH/−小鼠的胚胎成纤维细胞（MEFs）显示磷酸化Erk1/2核定位增强及迁移潜能上升。因此，MtbpH/−小鼠及其衍生细胞系为解析Mtbp体内生理功能、验证人类细胞中观察到的MTBP多样化功能提供了重要研究工具。

原文链接：

Characterization of anMtbpHypomorphic Allele in a Diethylnitrosamine-Induced Liver Carcinogenesis Model