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Exp Ther Med. 2018 Sep;16(3):1850-1858. doi: 10.3892/etm.2018.6427. Epub 2018 Jul 9.

Identification of key pathways and biomarkers in sorafenib-resistant hepatocellular carcinoma using bioinformatics analysis.

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Guangdong Key Laboratory of Liver Disease Research, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510000, P.R. China.
Acupuncture Department, The Fourth Clinical Medical College of Guangzhou University Chinese Medicine, Shenzhen, Guangdong 518000, P.R. China.
Hepatopathy Institution, Affiliated Hospital Hubei University Chinese Medicine, Wuhan, Hubei 430061, P.R. China.
Pharmaceutical Analysis Department, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, Guangdong 510006, P.R. China.


Hepatocellular carcinoma (HCC) is one of the most common malignant types of cancer, with a high mortality rate. Sorafenib is the sole approved oral clinical therapy against advanced HCC. However, individual patients exhibit varying responses to sorafenib and the development of sorafenib resistance has been a new challenge for its clinical efficacy. The current study identified gene biomarkers and key pathways in sorafenib-resistant HCC using bioinformatics analysis. Gene dataset GSE73571 was obtained from the Gene Expression Omnibus (GEO) database, including four sorafenib-acquired resistant and three sorafenib-sensitive HCC phenotypes. Differentially expressed genes (DEGs) were identified using the web tool GEO2R. Functional and pathway enrichment of DEGs were analyzed using the Database for Annotation, Visualization and Integrated Discovery and the protein-protein interaction (PPI) network was constructed using the Search Tool for the Retrieval of Interacting Genes/Proteins and Cytoscape. A total of 1,319 DEGs were selected, which included 593 upregulated and 726 downregulated genes. Functional and pathway enrichment analysis revealed DEGs enriched in negative regulation of endopeptidase activity, cholesterol homeostasis, DNA replication and repair, coagulation cascades, insulin resistance, RNA transport, cell cycle and others. Eight hub genes, including kininogen 1, vascular cell adhesion molecule 1, apolipoprotein C3, alpha 2-HS glycoprotein, erb-b2 receptor tyrosine kinase 2, secreted protein acidic and cysteine rich, vitronectin and vimentin were identified from the PPI network. In conclusion, the present study identified DEGs and key genes in sorafenib-resistant HCC, which further the knowledge of potential mechanisms in the development of sorafenib resistance and may provide potential targets for early diagnosis and new treatments for sorafenib-resistant HCC.


Kyoto Encyclopedia of Genes and Genomes analysis; bioinformatics analysis; differentially expressed gene; protein-protein interaction; sorafenib-resistant hepatocellular carcinoma

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