Guo Yingqiu, Chen Yongxin, Ito Hirotaka, Watanabe Akira, Ge Xijin, Kodama Tatsuhiko, Aburatani Hiroyuki
Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, Japan.
Gene. 2006 Dec 15;384:51-61. doi: 10.1016/j.gene.2006.07.011. Epub 2006 Jul 28.
Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Several studies have identified signature gene sets that may be useful as potential diagnostic tools by global microarray analysis. Here we report the cloning and characterization of a novel gene, lin-28 homolog B (LIN28B), which is overexpressed in hepatocellular carcinoma. The heterochronic gene lin-28 is a key regulator of developmental timing in the nematode Caenorhabditis elegans. Similar with lin-28 proteins, LIN28B conserves a cold shock domain and a pair of CCHC zinc finger domains. Phylogenetic analysis suggests that they might arise as a result of duplication from an ancestral gene. Overexpression of LIN28B was noted in most HCC cell lines and clinical samples. By western blot analysis using a polyclonal antibody against LIN28B, a short LIN28B isoform was also identified in non-tumor liver tissue and fetal liver. Although predominantly localized in the cytoplasm, we found that LIN28B protein shows cell cycle-dependent nuclear translocation in Huh7 cells. Induced expression of exogenous LIN28B in a tet-off cell line promoted cancer cell proliferation. Interestingly, the segment of the unusually long 3'UTR of LIN28B contains complementary sites to let-7 microRNA of mammals. And our studies provided indirect evidence that LIN28B is a possibly natural target for let-7 mediated regulation. These findings strongly implicate a critical role of LIN28B during development and tumorigenesis and suggest a possible novel mechanism.
肝细胞癌（HCC）是全球最常见的恶性肿瘤之一。多项研究通过全基因组微阵列分析鉴定出了可能作为潜在诊断工具的特征基因集。在此，我们报告了一种新基因——lin-28同源物B（LIN28B）的克隆与特性，该基因在肝细胞癌中过表达。异时性基因lin-28是线虫秀丽隐杆线虫发育时间的关键调节因子。与lin-28蛋白相似，LIN28B保留了一个冷休克结构域和一对CCHC锌指结构域。系统发育分析表明，它们可能是由一个祖先基因复制而来的。在大多数肝癌细胞系和临床样本中均发现LIN28B过表达。通过使用抗LIN28B的多克隆抗体进行蛋白质印迹分析，在非肿瘤肝组织和胎儿肝脏中也鉴定出了一种短的LIN28B异构体。尽管LIN28B主要定位于细胞质中，但我们发现在Huh7细胞中，LIN28B蛋白呈现细胞周期依赖性的核转位。在四环素调控的细胞系中诱导外源性LIN28B的表达可促进癌细胞增殖。有趣的是，LIN28B异常长的3'UTR片段包含与哺乳动物let-7微小RNA互补的位点。我们的研究提供了间接证据，表明LIN28B可能是let-7介导调控的天然靶点。这些发现强烈暗示了LIN28B在发育和肿瘤发生过程中的关键作用，并提示了一种可能的新机制。
