Keng Vincent W, Chiu Amy P, To Jeffrey C, Li Xiao-Xiao, Linden Michael A, Amin Khalid, Moriarity Branden S, Yusa Kosuke
The Hong Kong Polytechnic University Shenzhen Research Institute, Shenzhen 518057, China.
Department of Applied Biology and Chemical Technology, State Key Laboratory of Chemical Biology and Drug Discovery, The Hong Kong Polytechnic University, Kowloon, Hong Kong, China.
Heliyon. 2023 Jul 28;9(8):e18774. doi: 10.1016/j.heliyon.2023.e18774. eCollection 2023 Aug.
Various molecular subclasses of hepatocellular carcinoma (HCC) exists, with many novel cooperating oncogenes and tumor suppressor genes involved in its tumorigenesis. The emerging importance of WNT signaling in HCC has been established. However, the intricate genetic mechanisms involved in this complex signaling pathway remains to be elucidated. Importantly, while some cooperating genes have been identified, there are still many unknown genes associated with catenin beta 1 ()-induced HCC. Mutations in both oncogenes and tumor suppressor genes are required for HCC tumorigenesis. The emergence of the CRISPR/Cas9 system has allowed researchers now to target both alleles efficiently. In this novel study, the Sleeping Beauty transposon system was used as a gene delivery system to stably integrate an expression cassette that carry pools of gRNAs and overexpress a mutant version of into the hepatocyte genome. We identified 206 candidate genes that drive HCC tumorigenesis in the context of WNT signaling activation and, neurofibromin 2 () gene, a known tumor suppressor gene with clinical relevance was validated in this proof-of-principle study.
肝细胞癌（HCC）存在多种分子亚类，其肿瘤发生涉及许多新的协同致癌基因和肿瘤抑制基因。WNT信号在HCC中的重要性已逐渐显现。然而，这一复杂信号通路中涉及的复杂遗传机制仍有待阐明。重要的是，虽然已经鉴定出一些协同基因，但仍有许多与β-连环蛋白1（）诱导的HCC相关的未知基因。HCC肿瘤发生需要致癌基因和肿瘤抑制基因的突变。CRISPR/Cas9系统的出现使研究人员现在能够有效地靶向两个等位基因。在这项新研究中，Sleeping Beauty转座子系统被用作基因传递系统，以稳定整合一个携带gRNA池的表达盒，并在肝细胞基因组中过表达的突变版本。我们鉴定出206个在WNT信号激活背景下驱动HCC肿瘤发生的候选基因，并且在这项原理验证研究中验证了神经纤维瘤蛋白2（）基因，这是一个具有临床相关性的已知肿瘤抑制基因。
