最近研究表明孤儿核受体LRH-1参与多种癌症的发生。 但LRH-1是否同样影响肝癌的发生国内外未见报道。已有基因芯片数据证明LRH-1在肝癌组织中呈高表达，我们用Transcription Activator-Like Effector Nucleases (TALENs)介导的基因组编辑构建了下调LRH-1表达的HepG2细胞模型(HepG2LRH-1/-)并鉴定成功，测序结果显示在单一细胞来源的HepG2LRH-1/-细胞克隆中，至少检测到了5种不同的突变修复情况，提示LRH-1在肝癌细胞中可能存在基因组上拷贝数的扩增。另外HepG2LRH-1/-细胞的增殖速度明显低于正常HepG2细胞。我们推测LRH-1可能在肝癌组织中通过在基因组拷贝数的增加上调其表达水平并促进肝癌发生。本研究将利用HepG2LRH-1/-细胞模型为探索LRH-1作为肝癌治疗中潜在的药物靶点提供前期的科学依据。

Aim..The aim of this project is to identify the functions of the nuclear receptor LRH-1（liver receptor homolog-1）in hepatocellular carcinoma (HCC). ..Project Background..Nuclear receptors are a large superfamily transcriptional factors that function as ligand dependent or independent sensor molecules which not only regulate a broad range of physiological processes such as metabolism, development, reproduction, but also play various and significant roles in diseases, such as cancers. LRH-1 (liver receptor homolog-1), belongs to the fifth subfamily of nuclear receptor, is recently found to be involved in the development and progression of several cancers including colon cancer, breast cancer and pancreatic cancer. ..Brief Project Description..Existed gene-chip results indicate that LRH-1 shows higher expression level in HCC than that in normal tissue. Therefore, we speculate that LRH-1 may play a role in HCC. Base on this hypothesis, four HepG2LRH-1/- cell models with low LRH-1 expression are generated by genome editing mediated by Transcription Activator-Like Effector Nucleases (TALENs). According to sequencing results, at least five different mutations are detected in one HepG2LRH-1/- model which is from single cell clone. In addition, HepG2LRH-1/- cells grow significantly slower than HepG2. In this project, we will investigate the molecular mechanisms of LRH-1 in carcinogenesis of HCC. ..Significance of Project..Considering current treatment options for HCC are still limited and also mostly ineffective, the novel therapeutic targets and drugs are urgently needed. The present proposal will investigate the molecular mechanisms of LRH-1 in HCC. Given that LRH-1 specific antagonist is already developed, the outcomes from this project will provide new insights into the pathogenesis of HCC and explore a potential therapeutic target for HCC treatment.