Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
Cancer Genomics Proteomics. 2023 Nov-Dec;20(6):500-521. doi: 10.21873/cgp.20401.
Hepatocellular carcinoma (HCC) ranges as number two with respect to the incidence of tumors and is associated with a dismal prognosis. The therapeutic efficacy of approved multi-tyrosine kinase inhibitors and checkpoint inhibitors is modest. Therefore, the identification of new therapeutic targets and entities is of paramount importance. We searched the literature for up-regulated circular RNAs (circRNAs) which mediate efficacy in preclinical in vivo models of HCC. Our search resulted in 14 circRNAs which up-regulate plasma membrane transmembrane receptors, while 5 circRNAs induced secreted proteins. Two circRNAs facilitated replication of Hepatitis B or C viruses. Three circRNAs up-regulated high mobility group proteins. Six circRNAs regulated components of the ubiquitin system. Seven circRNAs induced GTPases of the family of ras-associated binding proteins (RABs). Three circRNAs induced redox-related proteins, eight of them up-regulated metabolic enzymes and nine circRNAs induced signaling-related proteins. The identified circRNAs up-regulate the corresponding targets by sponging microRNAs. Identified circRNAs and their targets have to be validated by standard criteria of preclinical drug development. Identified targets can potentially be inhibited by small molecules or antibody-based moieties and circRNAs can be inhibited by small-interfering RNAs (siRNAs) or short hairpin RNAs (shRNAs) for therapeutic purposes.
肝细胞癌（HCC）在肿瘤发病率方面位居第二，且预后不良。已批准的多酪氨酸激酶抑制剂和检查点抑制剂的治疗效果并不理想。因此，寻找新的治疗靶点和药物实体至关重要。我们在文献中搜索了介导 HCC 临床前动物模型疗效的上调环状 RNA（circRNA）。我们的搜索结果发现了 14 个上调质膜跨膜受体的 circRNA，而 5 个 circRNA 诱导分泌蛋白。两种 circRNA 促进乙型或丙型肝炎病毒的复制。三种 circRNA 上调高迁移率族蛋白。六种 circRNA 调节泛素系统的组成部分。七种 circRNA 诱导 Ras 相关结合蛋白家族的 GTPase。三种 circRNA 诱导与氧化还原相关的蛋白，其中八种上调代谢酶，九种 circRNA 诱导信号相关蛋白。鉴定出的 circRNA 通过海绵 microRNA 上调相应的靶基因。鉴定出的 circRNA 及其靶基因需要通过临床前药物开发的标准标准进行验证。鉴定出的靶基因可以通过小分子或基于抗体的部分进行抑制，circRNA 可以通过小干扰 RNA（siRNA）或短发夹 RNA（shRNA）进行治疗性抑制。
