Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany;
Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
Cancer Genomics Proteomics. 2023 Dec;20(6suppl):646-668. doi: 10.21873/cgp.20413.
Despite availability of several treatment options for non-small cell lung cancer (NSCLC), such as surgery, chemotherapy, radiation, targeted therapy and immunotherapy, the survival rate of patients for five years is in the range of 22%. Therefore, identification of new targets and treatment modalities for this disease is an important issue. In this context, we screened the PubMed database for up-regulated circular RNAs (circRNAs) which promote growth of NSCLC in preclinical models in vitro as well as in vivo xenograft models in immuno-compromised mice. This approach led to potential targets for further validation and inhibition with small molecules or antibody-derived entities. In case of preclinical validation, the corresponding circRNAs can be inhibited with small interfering RNAs (siRNA) or short hairpin RNAs (shRNA). The identified circRNAs act by sponging microRNAs (miRs) preventing cleavage of the mRNA of the corresponding targets. We identified nine circRNAs up-regulating transmembrane receptors, five circRNAs increasing expression of secreted proteins, nine circRNAs promoting expression of components of signaling pathways, six circRNAs involved in regulation of splicing and RNA processing, six circRNAs up-regulating actin-related and RNA processing components, seven circRNAs increasing the steady-state levels of transcription factors, two circRNAs increasing high-mobility group proteins, four circRNAs increasing components of the epigenetic modification system and three circRNAs up-regulating protein components of additional systems.
尽管有多种治疗非小细胞肺癌 (NSCLC) 的方法，如手术、化疗、放疗、靶向治疗和免疫治疗，但患者五年生存率在 22%左右。因此，寻找新的治疗靶点和治疗方法对于这种疾病是一个重要的问题。在这种情况下，我们在 PubMed 数据库中筛选了体外临床前模型和免疫缺陷小鼠体内异种移植模型中促进 NSCLC 生长的上调环状 RNA (circRNA)。这种方法为进一步用小分子或抗体衍生实体进行验证和抑制提供了潜在的靶标。在临床前验证中，相应的 circRNA 可以用小干扰 RNA (siRNA) 或短发夹 RNA (shRNA) 抑制。鉴定出的 circRNA 通过海绵 microRNA (miR) 起作用，防止相应靶标 mRNA 的切割。我们鉴定出了 9 个上调跨膜受体的 circRNA、5 个上调分泌蛋白表达的 circRNA、9 个上调信号通路组成成分表达的 circRNA、6 个参与调控剪接和 RNA 加工的 circRNA、6 个上调肌动蛋白相关和 RNA 加工成分的 circRNA、7 个上调转录因子稳态水平的 circRNA、2 个上调高迁移率族蛋白的 circRNA、4 个上调表观遗传修饰系统成分的 circRNA 和 3 个上调其他系统蛋白成分的 circRNA。
