A multidimensional recommendation framework for identifying biological targets to aid the diagnosis and treatment of liver metastasis in patients with colorectal cancer

IF 27.7 1区 医学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY
Feng Qi, Na Gao, Jia Li, Chenfei Zhou, Jinling Jiang, Bin Zhou, Liting Guo, Xiaohui Feng, Jun Ji, Qu Cai, Liu Yang, Rongjia Zhu, Xinyi Que, Junwei Wu, Wenqi Xi, Wenxing Qin, Jun Zhang
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Abstract

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 KLRB1+PD-1+CD8+ 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.
确定生物靶点的多维推荐框架,帮助诊断和治疗结直肠癌患者的肝转移
了解肿瘤转移的分子机制和确定癌症治疗的关键生物标志物的研究越来越重要。单个组学分析受限于其对单个生物层的关注,无法完全阐明复杂的肿瘤分子特征,因此可能会忽略关键的分子靶点。针对这一局限性,我们开发了一个多目标推荐系统(RJH-Metastasis 1.0),该系统以多组学知识图谱为基础,整合了基因组、转录组和蛋白质组数据以及确凿的文献证据,然后对伴有肝转移的结直肠癌(CRCLM)进行了全面分析。我们的系统共推荐了 25 个与 CRCLM 显著相关的关键基因,并进一步突出了 GNB1、GATAD2A、GBP2、MACROD1 和 EIF5B。具体来说,GNB1在CRCLM患者中的突变较少,但其RNA转录和蛋白表达均有所升高。体外和体内研究证实了 GNB1 在促进结肠癌细胞恶性行为中的作用。GNB1的异常表达可由METTL1驱动的m7G修饰调节。敲除 METTL1 会减少 GNB1 3' UTR 中的 m7G 修饰,从而在肝转移过程中增加其 mRNA 的转录和翻译。此外,GNB1 通过促进记忆 B 细胞与 KLRB1+PD-1+CD8+ 细胞之间的 CLEC2C-KLRB1 相互作用,诱导形成免疫抑制微环境。GNB1的表达与基于PD-1抗体治疗CRCLM患者的疗效有显著相关性。总之,我们的推荐系统可用于有效探索结直肠癌的关键分子,其中 GNB1 被确定为结直肠癌患者中关键的 CRCLM 启动子和免疫治疗生物标志物。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Molecular Cancer
Molecular Cancer 医学-生化与分子生物学
CiteScore
54.90
自引率
2.70%
发文量
224
审稿时长
2 months
期刊介绍: Molecular Cancer is a platform that encourages the exchange of ideas and discoveries in the field of cancer research, particularly focusing on the molecular aspects. Our goal is to facilitate discussions and provide insights into various areas of cancer and related biomedical science. We welcome articles from basic, translational, and clinical research that contribute to the advancement of understanding, prevention, diagnosis, and treatment of cancer. The scope of topics covered in Molecular Cancer is diverse and inclusive. These include, but are not limited to, cell and tumor biology, angiogenesis, utilizing animal models, understanding metastasis, exploring cancer antigens and the immune response, investigating cellular signaling and molecular biology, examining epidemiology, genetic and molecular profiling of cancer, identifying molecular targets, studying cancer stem cells, exploring DNA damage and repair mechanisms, analyzing cell cycle regulation, investigating apoptosis, exploring molecular virology, and evaluating vaccine and antibody-based cancer therapies. Molecular Cancer serves as an important platform for sharing exciting discoveries in cancer-related research. It offers an unparalleled opportunity to communicate information to both specialists and the general public. The online presence of Molecular Cancer enables immediate publication of accepted articles and facilitates the presentation of large datasets and supplementary information. This ensures that new research is efficiently and rapidly disseminated to the scientific community.
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