DLK1-DIO3印迹区基因在肝癌干祖细胞分化过程中的作用及表观遗传调控机制研究

项目名称： DLK1-DIO3印迹区基因在肝癌干祖细胞分化过程中的作用及表观遗传调控机制研究

项目编号： No.81201690

项目类型： 青年科学基金项目

立项/批准年度： 2013

项目学科： 肿瘤学1

项目作者： 徐晓

作者单位： 上海人类基因组研究中心

项目金额： 23万元

中文摘要： 已知基因组DLK1-DIO3印迹区的基因表达状态与干细胞包括诱导的多能干细胞分化阶段有关且受复杂的表观遗传机制调节。本课题组前期研究表明，父系等位基因表达的DLK1在人和鼠肝癌样本中均升高且局限在少量细胞表达，但DLK1-DIO3印迹区未发生印迹丧失；DLK1+细胞呈高增殖性，RNA干扰DLK1则减弱其增殖；DLK1随肝癌细胞分化而降低。提示1）DLK1+细胞是潜在肝癌干/祖细胞；2）DLK1-DIO3印迹区基因表达状态可能对维持肝癌干/祖细胞特征起关键作用；3）调控DLK1或DLK1-DIO3区基因表达可能促进肝癌细胞分化。本课题拟研究基因组DLK1-DIO3印迹区基因在肝癌干/祖细胞的表达谱特征、表观遗传学机制以及对其生物学特征的影响；通过遗传学或表观遗传学手段调控DLK1或DLK1-DIO3区基因表达对肝癌干/祖细胞生物学特征尤其分化的作用，为肝癌分化治疗奠定理论基础。

中文关键词： 肝癌；DLK1；DLK1-DIO3 印迹区；肿瘤干细胞；靶向治疗

英文摘要： As known, the expression status of DLK1-DIO3 imprinted region genes are related to the status of pluripotent stem cell，iPS cells included，and regulated by complex epigenetic mechanism. Our study showed that the expression of paternally allele expressed DLK1 increased in human and mice HCC specimen, its expression was limited to only a few cells, but there is no imprinting loss of DLK1-DIO3 imprinted region. DLK1+ cells showed stronger ability of proliferation. RNAi targeting to DLK1 could suppress the ability of proliferation. The expression of DLK1 decreased along with differentiation of HCC cells. All these data suggested that: 1) DLK1+ cells are potential HCC stem/progenitor cells. 2) The expression status of genes in DLK1-DIO3 imprinted region was critical to maintain the charater of HCC stem/progenitor cells. 3) Regulation expression of DLK1 or DLK1-DIO3 imprinted region gene maybe promote differentiation of HCC cells. The aim of our research is to study the expression profile of DLK1-DIO3 imprinted region genes of HCC stem/progenitor cells, the related epigenetic mechanism and its effection to biological character of HCC stem/progenitor cells; regulate the gene expression of DLK1 or DLK1-DIO3 region through genetics and epigenetics method; and found its effection to the biological character of HCC stem/

英文关键词： HCC；DLK1；DLK1-DIO3 imprinting region；cancer stem cell；target therapy