Underlying mechanism of sorafenib resistance in hepatocellular carcinoma: a bioinformatics study based on validated resistance-related genes.
Underlying mechanism of sorafenib resistance in hepatocellular carcinoma: a bioinformatics study based on validated resistance-related genes.
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DOI：
10.21037/jgo-21-377
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发表时间：
2021-08
影响因子：
2.1
通讯作者：
Yu Song;Peng Gao;H. Ding;Gaoqi Xu;Yan Hu;Y. Tong;W. Xin;Liwen Zhang;Miaolian Wu;L. Fan
中科院分区：
文献类型：
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作者：
Yu Song;Peng Gao;H. Ding;Gaoqi Xu;Yan Hu;Y. Tong;W. Xin;Liwen Zhang;Miaolian Wu;L. Fan
背景索拉非尼是第一个被批准的晚期肝细胞癌（HCC）靶向治疗药物，但由于耐药，其生存获益常常被报道。基于微阵列差异表达基因的生物信息学分析，提出了一种潜在的耐药机制。然而，大多数DEG在表达水平和引起抗性的作用上都是无效的。因此，我们进行了生物信息学分析的基础上，实验确定索拉非尼耐药相关基因（SRRGs），以阐明索拉非尼耐药的机制。方法从已发表的研究中收集已被实验确定促进或抑制抗性的SRRGs。使用注释、可视化和集成发现数据库（大卫）和京都基因和基因组百科全书（KEGG）分别进行基因本体（GO）和途径富集分析。利用Cytoscape软件构建了相应的蛋白质相互作用网络（PPI），并提出了网络中枢基因。结果共鉴定出145个SRRG，其中促耐药117个，抑制耐药28个。细胞增殖、迁移、发育、对氧水平的反应、上皮-间质转化（EMT）、细胞骨架、蛋白质功能和自噬都被认为是与抗性相关的关键基因功能。与细胞增殖或凋亡、免疫功能、内分泌代谢、干细胞功能和分化相关的途径被确定为关键的耐药相关途径。总共提出了81个枢纽基因，包括以下前10个基因：TP 53、AKT 1、EGFR、STAT 3、VEGFA、JUN、MAPK 1、IL 6、PTEN和CTNNB 1。结论总之，本研究收集了实验验证的决定肝癌索拉非尼耐药的基因，概述了耐药的潜在机制，并进一步验证了肝癌索拉非尼耐药。
Background Sorafenib, the first approved targeted therapy for advanced hepatocellular carcinoma (HCC), is often reported to comprised survival-benefit due to resistance. An underlying mechanism of resistance was proposed using bioinformatics analysis based on differentially expressed genes (DEGs) from microarrays. However, most DEGs were invalidated at both the expression level, and the role in causing resistance. Therefore, we conducted a bioinformatics analysis based on experimentally determined sorafenib-resistance-related genes (SRRGs) to elucidate the mechanism of sorafenib resistance. Methods The SRRGs, which have been experimentally determined to promote or inhibit resistance, were collected from published studies. The Database for Annotation, Visualization and Integrated Discovery (DAVID) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to perform Gene Ontology (GO) and pathway enrichment analysis, respectively. A corresponding protein-protein interaction network (PPI) was created using the Cytoscape software program, and network hub genes were proposed. Results A total of 145 SRRGs, with 117 promoting and 28 inhibiting resistance, were identified. Cell proliferation, migration, development, response to oxygen levels, epithelial-to-mesenchymal transition (EMT), cell skeleton, protein function, and autophagy were all proposed as crucial gene functions related to resistance. The pathways related to cell proliferation or apoptosis, immune function, endocrine metabolism, stem cell function, and differentiation were identified as key resistance-related pathways. A total of 81 hub genes were proposed, including the following top 10 genes: TP53, AKT1, EGFR, STAT3, VEGFA, JUN, MAPK1, IL6, PTEN, and CTNNB1. Conclusions In conclusion, this study gathered experimentally validated genes that determine sorafenib resistance in HCC, provided an overview of the underlying mechanisms of resistance, and further validated sorafenib resistance in HCC.