Nie Junjie, Liu Xinwei, Xu Mu, Chen Xiaoxiang, Hu Shangshang, Gu Xinliang, Sun Huiling, Gao Tianyi, Pan Yuqin, Wang Shukui
General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu, China.
General Clinical Research Center, Nanjing First Hospital, Nanjing Medical University, Nanjing 210000, Jiangsu, China.
Transl Oncol. 2024 Nov;49:102097. doi: 10.1016/j.tranon.2024.102097. Epub 2024 Aug 21.
Synthetic lethality (SL) emerges as a novel concept being explored to combat cancer progression and resistance to conventional therapy. Despite the efficacy of chemotherapy in select cases of colorectal cancer (CRC), a substantial proportion of patients encounter challenges, leading to an adverse prognosis of CRC patients. CRC-related SL genes offer a potential avenue for identifying therapeutic targets.
CRC-related SL genes were obtained from the SynLethDB database. The bulk RNA sequencing data, mutation data, and clinical information for treated and untreated CRC patients were enrolled from the UCSC and GEO databases. The Tumor Immunology Single Cell Center database served as the repository for collecting and analyzing single-cell RNA sequencing data. The synergistic killing effect of SL genes and chemotherapeutic drugs on resistant cells was experimentally verified.
In the present study, pivotal SL genes associated with chemoresistance identified by using WGCNA and CRC patients categorized into two groups based on these genes. Variations between the groups were most pronounced in pathways associated with extracellular matrix remodeling. Further by integrating mutation data, five potential SL genes were discerned, which were highly expressed in the presence of TP53 or KRAS mutations, leading to a severely poor prognosis. Subsequent time series analysis revealed that the expression of GTF2H5 was gradually elevated at different stages of the transition from sensitive to resistant in CRC cells. Finally, it was preliminarily verified by experiments that GTF2H5 may play a key role in driving the drug-resistant transition within CRC cells.
The identification of SL genes that collaboratively interact with chemotherapeutic agents could provide new insights into solving the issue of chemotherapy resistance in CRC patients. And GTF2H5 wields a fundamental influence in inducing chemoresistance in CRC, which provided a potential therapeutic target for CRC.
合成致死（SL）作为一种新的概念正在被探索用于对抗癌症进展和对传统疗法的耐药性。尽管化疗在某些结直肠癌（CRC）病例中有效，但相当一部分患者面临挑战，导致CRC患者预后不良。与CRC相关的SL基因提供了识别治疗靶点的潜在途径。
从SynLethDB数据库中获取与CRC相关的SL基因。从UCSC和GEO数据库中收集经治疗和未经治疗的CRC患者的批量RNA测序数据、突变数据和临床信息。肿瘤免疫单细胞中心数据库用作收集和分析单细胞RNA测序数据的储存库。通过实验验证了SL基因和化疗药物对耐药细胞的协同杀伤作用。
在本研究中，使用加权基因共表达网络分析（WGCNA）鉴定出与化疗耐药相关的关键SL基因，并根据这些基因将CRC患者分为两组。两组之间的差异在与细胞外基质重塑相关的通路中最为明显。进一步整合突变数据，识别出五个潜在的SL基因，它们在存在TP53或KRAS突变时高表达，导致预后极差。随后的时间序列分析表明，在CRC细胞从敏感转变为耐药的不同阶段，GTF2H5的表达逐渐升高。最后，通过实验初步验证了GTF2H5可能在驱动CRC细胞内耐药转变中起关键作用。
鉴定与化疗药物协同相互作用的SL基因可为解决CRC患者化疗耐药问题提供新的见解。并且GTF2H5在诱导CRC化疗耐药中发挥着重要作用，为CRC提供了一个潜在的治疗靶点。
