通过人源的原发原位肝细胞癌模型研究ARID2在肝癌发生中的作用及分子机制

Hepatocellular carcinoma (HCC) has become the fourth most common cancers and the third most common cause of cancer mortality in China. However, there is little medicine that is useful for HCC cure. Cancer genomic studies with high-throughput sequencing have identified plenty of mutant genes in HCC, but the function and mechanism of these genes in HCC development are still unknown. Based on the experience of long term study on the molecular mechanism of human disease （PNAS 2015; FASEB J 2015）, we built up the driver gene screening model for HCC via the combination of the human liver organoid culture, CRISPR/Cas9 gene editing and mouse model. In this project, the function and mechanism of high-frequent mutant ARID2 on the development of HCC will be analyzed on this model. The mutant ARID2 will be induced in organoid and mouse liver by CRISPR/Cas9 system and its influence to the liver cell proliferation and stemness maintenance will be monitored, as well as the tumor driving capability combined with other mutants. Further studies will be carried out to analyze the possible mechanism of HCC development driven by the mutation of ARID2 through SWI/SNF. Taken together, this project will promote our understanding on the pathologic mechanism of HCC

肝细胞癌（HCC）是我国发病率第四、致死率第三的恶性肿瘤，尚无有效的药物治疗手段。高通量测序等肿瘤基因组研究在HCC中发现了众多的基因突变，但这些基因在HCC发生发展中的作用和机制尚不清楚。在长期人类疾病的分子机理研究（PNAS 2015; FASEB J 2015）基础上，我们建立了基于人源肝脏类器官、CRISPR/Cas9基因组编辑和模式动物的HCC驱动基因研究平台。在此平台上本项目计划研究HCC中高频突变基因ARID2在HCC发生发展中的作用和分子机制。我们将利用CRISPR/Cas9在类器官和小鼠体内突变ARID2，检测其对正常肝细胞的生长和干性的影响，及结合其他突变的成瘤能力。我们还将进一步研究ARID2突变可能通过影响SWI/SNF促进HCC发生的分子机制。本研究将有助于对HCC发病机理的深入理解。