Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA.
Laboratory of Gene Regulation and Signal Transduction, Department of Pharmacology, University of California San Diego, School of Medicine, 9500 Gilman Drive, San Diego, CA 92093, USA; Department of Gastroenterology, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan.
Cancer Cell. 2018 Jun 11;33(6):1061-1077.e6. doi: 10.1016/j.ccell.2018.05.003.
How fully differentiated cells that experience carcinogenic insults become proliferative cancer progenitors that acquire multiple initiating mutations is not clear. This question is of particular relevance to hepatocellular carcinoma (HCC), which arises from differentiated hepatocytes. Here we show that one solution to this problem is provided by CD44, a hyaluronic acid receptor whose expression is rapidly induced in carcinogen-exposed hepatocytes in a STAT3-dependent manner. Once expressed, CD44 potentiates AKT activation to induce the phosphorylation and nuclear translocation of Mdm2, which terminates the p53 genomic surveillance response. This allows DNA-damaged hepatocytes to escape p53-induced death and senescence and respond to proliferative signals that promote fixation of mutations and their transmission to daughter cells that go on to become HCC progenitors.
细胞在经历致癌因素后是如何完全分化成为具有增殖能力的肿瘤祖细胞，并获得多个起始突变的，目前尚不清楚。这个问题对于肝癌（HCC）尤为重要，因为 HCC 起源于分化的肝细胞。本文中，我们发现 CD44 提供了一种解决方案，CD44 是透明质酸受体，其表达可被 STAT3 依赖性方式快速诱导至暴露于致癌剂的肝细胞中。一旦表达，CD44 就会增强 AKT 的激活，从而诱导 Mdm2 的磷酸化和核转位，从而终止 p53 基因组监测反应。这使得受损的肝细胞能够逃避 p53 诱导的死亡和衰老，并对促进突变固定及其传递给继续成为 HCC 祖细胞的子细胞的增殖信号做出反应。
