Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers.
Sal-like protein 4 (SALL4), a stem cell biomarker in liver cancers.
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DOI：
10.1002/hep.26159
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发表时间：
2013-04
期刊：
影响因子：
--
通讯作者：
Nakauchi H
中科院分区：
文献类型：
--
作者：
Oikawa T;Kamiya A;Zeniya M;Chikada H;Hyuck AD;Yamazaki Y;Wauthier E;Tajiri H;Miller LD;Wang XW;Reid LM;Nakauchi H
肝癌、肝细胞癌（hcc）、胆管癌（CCs）和纤维层状hcc （fl - hcc）是世界上最常见的癌症之一，预后较差。对肝癌中重要基因的研究主要集中在锌指转录因子家族成员盐样蛋白4 （SALL4）。它是胚胎发生、器官发生、多能性的调节剂，可引起体细胞重编程，是干细胞的标记物。我们发现它在正常小鼠肝母细胞、正常人肝干细胞、肝母细胞和胆道树干细胞中表达，但在成熟的肝实质细胞和胆道树细胞中不表达。它在人类hcc、hcc、肝细胞和胆管合并癌、FL-HCC以及免疫受损宿主的衍生可移植肿瘤系的手术标本中强烈表达。生物信息学分析表明，肿瘤中SALL4表达升高与HCC患者生存不良相关。实验操作SALL4的表达导致人肝癌细胞系在体外和体内免疫受损宿主中增殖与分化的变化。利用病毒介导的SALL4基因转移对细胞系进行了功能的获得和丧失分析。在体外和体内均出现显著的生长抑制，并伴随着SALL4的下调而出现分化增加。SALL4的过表达导致体外细胞增殖增加，与细胞角化蛋白19 （CK19）、EpCAM和atp结合casset - g2 （ABCG2）的表达增加相关。SALL4的表达是干细胞的指标，是肝癌的预后标志物，与细胞和肿瘤生长相关，对5-FU具有抗性，抑制SALL4可导致肿瘤分化，减缓肿瘤生长。SALL4是一种新的肝癌治疗靶点。
Liver cancers, hepatocellular carcinomas (HCCs), cholangiocarcinomas (CCs) and fibrolamellar HCCs (FL-HCCs), are among the most common cancers worldwide and are associated with a poor prognosis. Investigations of genes important in liver cancers have focused on Sal-like protein 4, SALL4, a member of a family of zinc finger transcription factors. It is a regulator of embryogenesis, organogenesis, pluripotency, can elicit reprogramming of somatic cells, and is a marker of stem cells. We found it expressed in normal murine hepatoblasts, normal human hepatic stem cells, hepatoblasts and biliary tree stem cells, but not in mature parenchymal cells of liver or biliary tree. It was strongly expressed in surgical specimens of human HCCs, CCs, a combined hepatocellular and cholangiocarcinoma, a FL-HCC and in derivative, transplantable tumor lines in immune-compromised hosts. Bioinformatics analyses indicated that elevated expression of SALL4 in tumors is associated with poor survival of HCC patients. Experimental manipulation of SALL4’s expression results in changes in proliferation versus differentiation in human HCC cell lines in vitro and in vivo in immune-compromised hosts. Virus-mediated gene transfer of SALL4 was used to do gain and loss of function analyses in the cell lines. Significant growth inhibition in vitro and in vivo, accompanied by an increase in differentiation occurred with down-regulation of SALL4. Over-expression of SALL4 resulted in increased cell proliferation in vitro, correlating with an increase in expression of cytokeratin19 (CK19), EpCAM, and ATP-binding cassette-G2 (ABCG2). SALL4’s expression is an indicator of stem cells, a prognostic marker in liver cancers, correlates with cell and tumor growth, with resistance to 5-FU, and its suppression results in differentiation and slowed tumor growth. SALL4 is a novel therapeutic target for liver cancers.
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