Song Yu, Gao Peng, Ding Haiying, Xu Gaoqi, Hu Yan, Tong Yinghui, Xin Wenxiu, Zhang Liwen, Wu Miaolian, Fang Luo
Department of Pharmacy, The Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Institute of Basic Medicine and Cancer (IBMC), Chinese Academy of Sciences, Hangzhou, China.
Department of Pharmacy, The Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou, China.
J Gastrointest Oncol. 2021 Aug;12(4):1895-1904. doi: 10.21037/jgo-21-377.
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.
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.
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: and .
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.
索拉非尼是首个被批准用于晚期肝细胞癌（HCC）的靶向治疗药物，但由于耐药性，其生存获益常常受到质疑。基于微阵列差异表达基因（DEG）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在表达水平和导致耐药性的作用方面均未得到验证。因此，我们基于实验确定的索拉非尼耐药相关基因（SRRG）进行了生物信息学分析，以阐明索拉非尼耐药的机制。
从已发表的研究中收集经实验确定可促进或抑制耐药性的SRRG。分别使用注释、可视化和综合发现数据库（DAVID）和京都基因与基因组百科全书（KEGG）进行基因本体（GO）和通路富集分析。使用Cytoscape软件程序创建相应的蛋白质-蛋白质相互作用网络（PPI），并提出网络枢纽基因。
共鉴定出145个SRRG，其中117个促进耐药，28个抑制耐药。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、蛋白质功能和自噬均被认为是与耐药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通路被确定为关键的耐药相关通路。共提出了81个枢纽基因，包括以下前10个基因：和。
总之，本研究收集了经实验验证的决定HCC中索拉非尼耐药性的基因，概述了潜在的耐药机制，并进一步验证了HCC中的索拉非尼耐药性。
