Department of Radiology, The Second People's Hospital of Hunan Province/Brain Hospital of Hunan Province, Changsha, China.
Department of Radiology, Changsha Central Hospital, Changsha, China.
Pathol Oncol Res. 2021 Oct 19;27:1609985. doi: 10.3389/pore.2021.1609985. eCollection 2021.
Hepatocellular carcinoma (HCC), a high mortality malignancy, has become a worldwide public health concern. Acquired resistance to the multikinase inhibitor sorafenib challenges its clinical efficacy and the survival benefits it provides to patients with advanced HCC. This study aimed to identify critical genes and pathways associated with sorafenib resistance in HCC using integrated bioinformatics analysis. Differentially expressed genes (DEGs) were identified using four HCC gene expression profiles (including 34 sorafenib-resistant and 29 sorafenib-sensitive samples) based on the robust rank aggregation method and R software. Gene ontology (GO) functional annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed using the Database for Annotation, Visualization and Integrated Discovery (DAVID) online tool. A protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes (STRING), and small molecules reversing sorafenib resistance were searched for using the connectivity map (CMAP) database. Pearson correlation and survival analyses of hub genes were performed using cBioPortal and Gene Expression Profiling and Interactive Analysis (GEPIA). Finally, the expression levels of hub genes in sorafenib-resistant HCC cells were verified using quantitative polymerase chain reaction (q-PCR). A total of 165 integrated DEGs (66 upregulated and 99 downregulated in sorafenib resistant samples compared sorafenib sensitive ones) primarily enriched in negative regulation of endopeptidase activity, extracellular exosome, and protease binding were identified. Some pathways were commonly shared between the integrated DEGs. Seven promising therapeutic agents and 13 hub genes were identified. These findings provide a strategy and theoretical basis for overcoming sorafenib resistance in HCC patients.
肝细胞癌（HCC）是一种高死亡率的恶性肿瘤，已成为全球公共卫生关注的焦点。多激酶抑制剂索拉非尼获得性耐药性挑战了其临床疗效及其为晚期 HCC 患者提供的生存获益。本研究旨在通过整合生物信息学分析，确定与 HCC 索拉非尼耐药相关的关键基因和途径。使用稳健秩聚合方法和 R 软件，基于四个 HCC 基因表达谱（包括 34 个索拉非尼耐药和 29 个索拉非尼敏感样本）鉴定差异表达基因（DEGs）。使用数据库注释、可视化和综合发现（DAVID）在线工具进行基因本体（GO）功能注释和京都基因与基因组百科全书（KEGG）途径分析。使用搜索工具检索相互作用基因（STRING）构建蛋白质-蛋白质相互作用（PPI）网络，并使用连接图谱（CMAP）数据库搜索逆转索拉非尼耐药的小分子。使用 cBioPortal 和基因表达谱和交互式分析（GEPIA）进行关键基因的 Pearson 相关性和生存分析。最后，使用定量聚合酶链反应（q-PCR）验证索拉非尼耐药 HCC 细胞中关键基因的表达水平。鉴定出 165 个整合的 DEGs（与索拉非尼敏感样本相比，索拉非尼耐药样本中 66 个上调和 99 个下调），主要富集在肽酶活性、细胞外外泌体和蛋白酶结合的负调控中。一些途径在整合的 DEGs 之间共同共享。确定了 7 种有前途的治疗剂和 13 个关键基因。这些发现为克服 HCC 患者索拉非尼耐药提供了策略和理论依据。
