Nine Hub Genes Related to the Prognosis of HBV-positive Hepatocellular Carcinoma Identified by Protein Interaction Analysis

Overview

Journal Ann Transl Med

Publisher AME Publishing Company

Date 2020 May 13

PMID 32395522

Citations 13

Authors

Wenhui Xie

Bin Wang

Xiaoting Wang

Diyu Hou

Huiyan Su

Huifang Huang

Affiliations

Soon will be listed here.

Abstract

Background: Hepatocellular carcinoma (HCC) represents the second highest cause of cancer-associated deaths worldwide, and hepatitis B virus (HBV) infection is a major risk factor. Here, we aimed to identify genetic signatures of HBV-positive (HBV) HCC and uncover potential carcinogenic mechanisms.

Methods: Gene expression profiles of 124 HBV-positive samples, including tumor and non-tumor tissues were subjected to bioinformatics analysis. The expression levels of thymidylate synthase (TYMS) and CDC45 in patients' samples were validated by immunohistochemistry (IHC) and their association with patient survival was assessed by the Kaplan-Meier method.

Results: A total of 666 differentially expressed genes (DEGs) were identified. The 137 upregulated genes were mainly enriched in the cell cycle, P53 signaling pathway, and extracellular matrix-receptor interaction, whereas the 529 downregulated genes were enriched in cytochrome P450 xenobiotic and drug metabolism, and cytokine-cytokine receptor interaction. A total of 15 hub genes were identified from the protein-protein interaction (PPI) network and 10 of them were strongly associated with HBV HCC. The expression of 9 hub genes (, and ) was associated with poor overall survival. Validation of TYMS and CDC45 protein expression levels in clinical samples by IHC showed that they were higher in HBV HCC than in HBV HCC or normal tissue and were associated with poor patient survival.

Conclusions: HBV may induce HCC through regulation of host gene expression. Among the hub DEGs identified, 9 key genes could be used as new prognostic biomarkers and treatment targets for HBV HCC.

Citing Articles

LncRNA THUMPD3-AS1/microRNA-4465/KPNA2 axis impacts human hepatocellular carcinoma cell phenotypes.

Wang J, Qiao C, Luo B, Qin L Regen Ther. 2025; 28:413-420.

PMID: 39925963 PMC: 11804268. DOI: 10.1016/j.reth.2025.01.010.

BIRC5 knockdown ameliorates hepatocellular carcinoma progression via regulating PPARγ pathway and cuproptosis.

Mai Y, Ji Z, Tan Y, Feng L, Qin J Discov Oncol. 2024; 15(1):706.

PMID: 39585552 PMC: 11589110. DOI: 10.1007/s12672-024-01592-y.

Integrating bioinformatics and machine learning methods to analyze diagnostic biomarkers for HBV-induced hepatocellular carcinoma.

Yang A, Liu J, Li M, Zhang H, Zhang X, Wu L Diagn Pathol. 2024; 19(1):105.

PMID: 39095799 PMC: 11295615. DOI: 10.1186/s13000-024-01528-8.

The role of Aurora kinase A in hepatocellular carcinoma: Unveiling the intriguing functions of a key but still underexplored factor in liver cancer.

Grisetti L, Garcia C, Saponaro A, Tiribelli C, Pascut D Cell Prolif. 2024; 57(8):e13641.

PMID: 38590119 PMC: 11294426. DOI: 10.1111/cpr.13641.

Identification and validation of core genes as promising diagnostic signature in hepatocellular carcinoma based on integrated bioinformatics approach.

Kumar P, Singh A, Tiwari K, Mishra S, Rajput V, Minkina T Sci Rep. 2022; 12(1):19072.

PMID: 36351994 PMC: 9646875. DOI: 10.1038/s41598-022-22059-6.

References

Yang L, Luo Q, Lu L, Zhu W, Sun H, Wei R . Increased neutrophil extracellular traps promote metastasis potential of hepatocellular carcinoma via provoking tumorous inflammatory response. J Hematol Oncol. 2020; 13(1):3. PMC: 6945602. DOI: 10.1186/s13045-019-0836-0. View

Chin C, Chen S, Wu H, Ho C, Ko M, Lin C . cytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014; 8 Suppl 4:S11. PMC: 4290687. DOI: 10.1186/1752-0509-8-S4-S11. View

Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M . Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2014; 136(5):E359-86. DOI: 10.1002/ijc.29210. View

Liu B, Yao Z, Hu K, Huang H, Xu S, Wang Q . ShRNA-mediated silencing of the Ndc80 gene suppress cell proliferation and affected hepatitis B virus-related hepatocellular carcinoma. Clin Res Hepatol Gastroenterol. 2015; 40(3):297-303. DOI: 10.1016/j.clinre.2015.08.002. View

Vogelstein B, Papadopoulos N, Velculescu V, Zhou S, Diaz Jr L, Kinzler K . Cancer genome landscapes. Science. 2013; 339(6127):1546-58. PMC: 3749880. DOI: 10.1126/science.1235122. View

Davis S, Meltzer P . GEOquery: a bridge between the Gene Expression Omnibus (GEO) and BioConductor. Bioinformatics. 2007; 23(14):1846-7. DOI: 10.1093/bioinformatics/btm254. View

Ying H, Xu Z, Chen M, Zhou S, Liang X, Cai X . Overexpression of Zwint predicts poor prognosis and promotes the proliferation of hepatocellular carcinoma by regulating cell-cycle-related proteins. Onco Targets Ther. 2018; 11:689-702. PMC: 5800459. DOI: 10.2147/OTT.S152138. View

Xia L, Huang W, Tian D, Zhu H, Zhang Y, Hu H . Upregulated FoxM1 expression induced by hepatitis B virus X protein promotes tumor metastasis and indicates poor prognosis in hepatitis B virus-related hepatocellular carcinoma. J Hepatol. 2012; 57(3):600-12. DOI: 10.1016/j.jhep.2012.04.020. View

Li L, Hu Z, Zhou Z, Chen X, Liu F, Zhang J . Serum microRNA profiles serve as novel biomarkers for HBV infection and diagnosis of HBV-positive hepatocarcinoma. Cancer Res. 2010; 70(23):9798-807. DOI: 10.1158/0008-5472.CAN-10-1001. View

10.

Lamb J, Crawford E, Peck D, Modell J, Blat I, Wrobel M . The Connectivity Map: using gene-expression signatures to connect small molecules, genes, and disease. Science. 2006; 313(5795):1929-35. DOI: 10.1126/science.1132939. View

11.

Chan S, Wong V, Qin S, Chan H . Infection and Cancer: The Case of Hepatitis B. J Clin Oncol. 2015; 34(1):83-90. DOI: 10.1200/JCO.2015.61.5724. View

12.

Hsu C, Chen Y, Su H, Huang G, Shu C, Tong-Lin Wu T . Targeting TPX2 Suppresses the Tumorigenesis of Hepatocellular Carcinoma Cells Resulting in Arrested Mitotic Phase Progression and Increased Genomic Instability. J Cancer. 2017; 8(8):1378-1394. PMC: 5479243. DOI: 10.7150/jca.17478. View

13.

Chen C, Song G, Xiang J, Zhang H, Zhao S, Zhan Y . AURKA promotes cancer metastasis by regulating epithelial-mesenchymal transition and cancer stem cell properties in hepatocellular carcinoma. Biochem Biophys Res Commun. 2017; 486(2):514-520. DOI: 10.1016/j.bbrc.2017.03.075. View

14.

Yang Q, Zhong S, He L, Jia X, Tang H, Cheng S . PBK overexpression promotes metastasis of hepatocellular carcinoma via activating ETV4-uPAR signaling pathway. Cancer Lett. 2019; 452:90-102. DOI: 10.1016/j.canlet.2019.03.028. View

15.

Lin H, Chen Y, Hsu W, Yang C, Kao C, Tsai T . Resveratrol helps recovery from fatty liver and protects against hepatocellular carcinoma induced by hepatitis B virus X protein in a mouse model. Cancer Prev Res (Phila). 2012; 5(7):952-62. DOI: 10.1158/1940-6207.CAPR-12-0001. View

16.

Xie C, Mao X, Huang J, Ding Y, Wu J, Dong S . KOBAS 2.0: a web server for annotation and identification of enriched pathways and diseases. Nucleic Acids Res. 2011; 39(Web Server issue):W316-22. PMC: 3125809. DOI: 10.1093/nar/gkr483. View

17.

Jiang J, Huang Z, Chen X, Luo R, Cai H, Wang H . Trifluoperazine Activates FOXO1-Related Signals to Inhibit Tumor Growth in Hepatocellular Carcinoma. DNA Cell Biol. 2017; 36(10):813-821. DOI: 10.1089/dna.2017.3790. View

18.

Rhodes D, Kalyana-Sundaram S, Mahavisno V, Varambally R, Yu J, Briggs B . Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia. 2007; 9(2):166-80. PMC: 1813932. DOI: 10.1593/neo.07112. View

19.

Qin Y, Zhao D, Zhou H, Wang X, Zhong W, Chen S . Apigenin inhibits NF-κB and snail signaling, EMT and metastasis in human hepatocellular carcinoma. Oncotarget. 2016; 7(27):41421-41431. PMC: 5173069. DOI: 10.18632/oncotarget.9404. View

20.

Dennis Jr G, Sherman B, Hosack D, Yang J, Gao W, Lane H . DAVID: Database for Annotation, Visualization, and Integrated Discovery. Genome Biol. 2003; 4(5):P3. View