Department of Oncology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200025, P. R. China.
Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan University, Wuhan, 430071, P. R. China.
Mol Cancer. 2024 Oct 24;23(1):239. doi: 10.1186/s12943-024-02155-z.
The quest to understand the molecular mechanisms of tumour metastasis and identify pivotal biomarkers for cancer therapy is increasing in importance. Single-omics analyses, constrained by their focus on a single biological layer, cannot fully elucidate the complexities of tumour molecular profiles and can thus overlook crucial molecular targets. In response to this limitation, we developed a multiobjective recommendation system (RJH-Metastasis 1.0) anchored in a multiomics knowledge graph to integrate genome, transcriptome, and proteome data and corroborative literature evidence and then conducted comprehensive analyses of colorectal cancer with liver metastasis (CRCLM). A total of 25 key genes significantly associated with CRCLM were recommended by our system, and GNB1, GATAD2A, GBP2, MACROD1, and EIF5B were further highlighted. Specifically, GNB1 presented fewer mutations but elevated RNA transcription and protein expression in CRCLM patients. The role of GNB1 in promoting the malignant behaviours of colon cancer cells was demonstrated via in vitro and in vivo studies. Aberrant expression of GNB1 could be regulated by METTL1-driven m7G modification. METTL1 knockdown decreased m7G modification in the 3' UTR of GNB1, increasing its mRNA transcription and translation during liver metastasis. Furthermore, GNB1 induced the formation of an immunosuppressive microenvironment by promoting the CLEC2C-KLRB1 interaction between memory B cells and KLRB1PD-1CD8 cells. GNB1 expression and the efficacy of PD-1 antibody-based treatment in CRCLM patients were significantly correlated. In summary, our recommendation system can be used for effective exploration of key molecules in colorectal cancer, among which GNB1 was identified as a critical CRCLM promoter and immunotherapy biomarker in colorectal cancer patients.
研究肿瘤转移的分子机制并确定癌症治疗的关键生物标志物的重要性日益增加。由于单组学分析侧重于单一的生物学层面,因此无法完全阐明肿瘤分子谱的复杂性,从而可能忽略了关键的分子靶标。针对这一局限性,我们开发了一个基于多组学知识图的多目标推荐系统(RJH-Metastasis 1.0),该系统整合了基因组、转录组和蛋白质组数据以及相关文献证据,然后对结直肠癌肝转移(CRCLM)进行了全面分析。我们的系统推荐了 25 个与 CRCLM 显著相关的关键基因,其中 GNB1、GATAD2A、GBP2、MACROD1 和 EIF5B 得到了进一步的强调。具体而言,GNB1 在 CRCLM 患者中表现出较少的突变,但 RNA 转录和蛋白表达水平升高。通过体外和体内研究证实了 GNB1 在促进结肠癌癌细胞恶性行为中的作用。GNB1 的异常表达可通过 METTL1 驱动的 m7G 修饰进行调节。METTL1 敲低降低了 GNB1 3'UTR 中的 m7G 修饰,增加了其在肝转移过程中的 mRNA 转录和翻译。此外,GNB1 通过促进记忆 B 细胞和 KLRB1PD-1CD8 细胞之间的 CLEC2C-KLRB1 相互作用,诱导形成免疫抑制微环境。GNB1 表达与 CRCLM 患者基于 PD-1 抗体的治疗效果显著相关。总之,我们的推荐系统可用于有效探索结直肠癌中的关键分子,其中 GNB1 被确定为结直肠癌患者中 CRCLM 的关键促进因子和免疫治疗生物标志物。