https://doi.org/10.4081/itjm.2023.1626

Identification of hub genes associated with hepatitis B virus-related hepatocellular cancer using weighted gene co-expression network analysis and protein-protein interaction network analysis

Vol. 17 No. 2 (2023)
Published: 6 September 2023
GEO, TCGA-LIHC, HBV-related HCC, bioinformatics
Abstract Views: 679
PDF: 322
HTML: 46
Publisher's note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Authors

Wenze Wu
The Third Affiliated Hospital of Soochow University, China.
Fang Lin
Children’s Hospital of Nanjing Medical University, Nanjing, China.
Zifan Chen
The Third Affiliated Hospital of Soochow University, China.
Kejia Wu
The Third Affiliated Hospital of Soochow University, China.
Changhuan Ma
Changzhou Maternal and Child Health Care Hospital, China.
Jing Zhuang
Changzhou Maternal and Child Health Care Hospital, China.
Donglin Sun
czdyrmyysdl@163.com
The Third Affiliated Hospital of Soochow University, China.
Qiang Zhu
Children’s Hospital of Nanjing Medical University, Nanjing, China.
Longqing Shi
The Third Affiliated Hospital of Soochow University, China.

Background. Chronic hepatitis B virus (HBV) infection is the main pathogen of hepatocellular carcinoma. However, the mechanisms of HBV-related hepatocellular carcinoma (HCC) progression are practically unknown. Materials and Methods. The results of RNA-sequence and clinical data for GSE121248 and GSE17548 were accessed from the Gene Expression Omnibus data library. We screened Sangerbox 3.0 for differentially expressed genes (DEGs). The weighted gene co-expression network analysis (WGCNA) was employed to select core modules and hub genes, and protein-protein interaction network module analysis also played a significant part in it. Validation was performed using RNA-sequence data of cancer and normal tissues of HBV-related HCC patients in the cancer genome atlas-liver hepatocellular cancer database (TCGA-LIHC). Results. 787 DEGs were identified from GSE121248 and 772 DEGs were identified from GSE17548. WGCNA analysis indicated that black modules (99 genes) and grey modules (105 genes) were significantly associated with HBV-related HCC. Gene ontology analysis found that there is a direct correlation between DEGs and the regulation of cell movement and adhesion; the internal components and external packaging structure of plasma membrane; signaling receptor binding, calcium ion binding, etc. Kyoto Encyclopedia of Genes and Genomes pathway analysis found out the association between cytokine receptors, cytokine-cytokine receptor interactions, and viral protein interactions with cytokines were important and HBV-related HCC. Finally, we further validated 6 key genes including C7, EGR1, EGR3, FOS, FOSB, and prostaglandin-endoperoxide synthase 2 by using the TCGALIHC. Conclusions. We identified 6 hub genes as candidate biomarkers for HBV-related HCC. These hub genes may act as an essential part of HBV-related HCC progression.

Dimensions

Altmetric

PlumX Metrics

Downloads

Download data is not yet available.

PlumX Metrics

PlumX Metrics  provide insights into the ways people interact with individual pieces of research output (articles, conference proceedings, book chapters, and many more) in the online environment. Examples include, when research is mentioned in the news or is tweeted about. Collectively known as PlumX Metrics, these metrics are divided into five categories to help make sense of the huge amounts of data involved and to enable analysis by comparing like with like.

Citations

Crossref
Scopus
Google Scholar
Europe PMC
Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2018;68:394-424. DOI: https://doi.org/10.3322/caac.21492
McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of Hepatocellular Carcinoma. Hepatology 2021;73:4-13. DOI: https://doi.org/10.1002/hep.31288
D’Souza S, Lau KC, Coffin CS, et al. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol 2020;26:5759-83. DOI: https://doi.org/10.3748/wjg.v26.i38.5759
Heimbach JK, Kulik LM, Finn RS, et al. AASLD guidelines for the treatment of hepatocellular carcinoma. Hepatology 2018;67:358-80. DOI: https://doi.org/10.1002/hep.29086
Papatheodoridis GV, Sypsa V, Dalekos G, et al. Eightyear survival in chronic hepatitis B patients under longterm entecavir or tenofovir therapy is similar to the general population. J Hepatol 2018;68:1129-36. DOI: https://doi.org/10.1016/j.jhep.2018.01.031
Papatheodoridi M, Tampaki M, Lok AS, et al. Risk of HBV reactivation during therapies for HCC: A systematic review. Hepatology 2021. DOI: https://doi.org/10.1002/hep.32241
Bouvard V, Baan R, Straif K, et al. A review of human carcinogens-Part B: biological agents. Lancet Oncol 2009;10:321-2. DOI: https://doi.org/10.1016/S1470-2045(09)70096-8
Sherman M. Hepatocellular carcinoma: epidemiology, surveillance, and diagnosis. Semin Liver Dis 2010;30:3-16. DOI: https://doi.org/10.1055/s-0030-1247128
Yang JD, Ray Kim W, Coelho R, et al. Cirrhosis is present in most patients with hepatitis B and hepatocellular carcinoma. Clin Gastroenterol Hepatol 2011;9:64-70. DOI: https://doi.org/10.1016/j.cgh.2010.08.019
Xie Y. Hepatitis B Virus-Associated Hepatocellular Carcinoma. Adv Exp Med Biol 2017;1018:11-21. DOI: https://doi.org/10.1007/978-981-10-5765-6_2
Wang SM, Ooi LL, Hui KM. Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin Cancer Res 2007;13:6275-83. DOI: https://doi.org/10.1158/1078-0432.CCR-06-2236
Yildiz G, Arslan-Ergul A, Bagislar S, et al., Genome-wide transcriptional reorganization associated with senescence to-immortality switch during human hepatocellular carcinogenesis. PLoS One 2013;8:e64016. DOI: https://doi.org/10.1371/journal.pone.0064016
Clough E, Barrett T. The Gene Expression Omnibus Database. Methods Mol Biol, 2016;1418:93-110. DOI: https://doi.org/10.1007/978-1-4939-3578-9_5
Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics 2008;9:559. DOI: https://doi.org/10.1186/1471-2105-9-559
Wang Z, Jensen MA, Zenklusen JC. A Practical Guide to The Cancer Genome Atlas (TCGA). Methods Mol Biol 2016;1418:111-41. DOI: https://doi.org/10.1007/978-1-4939-3578-9_6
Yang JD, Hainaut P, Gores GJ, et al. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol 2019;16:589-604. DOI: https://doi.org/10.1038/s41575-019-0186-y
Tang A, Hallouch O, Chernyak V, et al. Epidemiology of hepatocellular carcinoma: target population for surveillance and diagnosis. Abdom Radiol (NY) 2018;43:13-25. DOI: https://doi.org/10.1007/s00261-017-1209-1
Chen Y, Tian Z. HBV-Induced Immune Imbalance in the Development of HCC. Front Immunol 2019;10:2048. DOI: https://doi.org/10.3389/fimmu.2019.02048
Levrero M, Zucman-Rossi J. Mechanisms of HBV-induced hepatocellular carcinoma. J Hepatol 2016;64:S84-s101. DOI: https://doi.org/10.1016/j.jhep.2016.02.021
Venook AP, Papandreou C, Furuse J, et al. The incidence and epidemiology of hepatocellular carcinoma: a global and regional perspective. Oncologist 2010;15:5-13. DOI: https://doi.org/10.1634/theoncologist.2010-S4-05
Levrero M, Pollicino T, Petersen J, et al. Control of cccDNA function in hepatitis B virus infection. J Hepatol 2009;51:581-92. DOI: https://doi.org/10.1016/j.jhep.2009.05.022
Guerrieri F, Belloni L, Pediconi N, Levrero M. Molecular mechanisms of HBV-associated hepatocarcinogenesis. Semin Liver Dis 2013;33:147-56. DOI: https://doi.org/10.1055/s-0033-1345721
Merle NS, Noe R, Halbwachs-Mecarelli L, et al. Complement System Part II: Role in Immunity. Front Immunol 2015;6:257. DOI: https://doi.org/10.3389/fimmu.2015.00257
Seol HS, Lee SE, Song JS, et al. Complement proteins C7 and CFH control the stemness of liver cancer cells via LSF-1. Cancer Lett 2016;372:24-35. DOI: https://doi.org/10.1016/j.canlet.2015.12.005
Christy B, Nathans D. DNA binding site of the growth factor-inducible protein Zif268. Proc Natl Acad Sci USA 1989;86:8737-41. DOI: https://doi.org/10.1073/pnas.86.22.8737
Peng WX, Xiong E-M, Ge L, et al. Egr-1 promotes hypoxia-induced autophagy to enhance chemo-resistance of hepatocellular carcinoma cells. Exp Cell Res 2016;340: 62-70. DOI: https://doi.org/10.1016/j.yexcr.2015.12.006
Zhang Q, Song G, Yao L, et al. miR-3928v is induced by HBx via NF-κB/EGR1 and contributes to hepatocellular carcinoma malignancy by down-regulating VDAC3. J Exp Clin Cancer Res 2018;37:14. DOI: https://doi.org/10.1186/s13046-018-0681-y
Tian H, Ge C, Li H, et al. Ribonucleotide reductase M2B inhibits cell migration and spreading by early growth response protein 1-mediated phosphatase and tensin homolog/Akt1 pathway in hepatocellular carcinoma. Hepatology 2014;59:1459-70. DOI: https://doi.org/10.1002/hep.26929
Wang L, Sun H, Wang X, et al. EGR1 mediates miR- 203a suppress the hepatocellular carcinoma cells progression by targeting HOXD3 through EGFR signaling pathway. Oncotarget 2016;7:45302-45316. DOI: https://doi.org/10.18632/oncotarget.9605
Zhang S, Xia C, Xu C, et al. Early growth response 3 inhibits growth of hepatocellular carcinoma cells via upregulation of Fas ligand. Int J Oncol 2017;50:805-14. DOI: https://doi.org/10.3892/ijo.2017.3855
Wang ZD, Qu FY, Chen YY, et al. Involvement of microRNA- 718, a new regulator of EGR3, in regulation of malignant phenotype of HCC cells. J Zhejiang Univ Sci B 2017;18:27-36. DOI: https://doi.org/10.1631/jzus.B1600205
Fan Q, He M, Deng X, et al. Derepression of c-Fos caused by microRNA-139 down-regulation contributes to the metastasis of human hepatocellular carcinoma. Cell Biochem Funct 2013;31:319-24. DOI: https://doi.org/10.1002/cbf.2902
Güller M, Toualbi-Abed K, Legrand A, et al. c-Fos overexpression increases the proliferation of human hepatocytes by stabilizing nuclear Cyclin D1. World J Gastroenterol 2008;14:6339-46. DOI: https://doi.org/10.3748/wjg.14.6339
Bakiri L, Hamacher R, Graña O, et al. Liver carcinogenesis by FOS-dependent inflammation and cholesterol dysregulation. J Exp Med 2017;214:1387-409. DOI: https://doi.org/10.1084/jem.20160935
Sitalaksmi RM, Ito K, Ogasawara K, et al. COX-2 induces T cell accumulation and IFN-gamma production during the development of chromium allergy. Autoimmunity 2019;52:228-34. DOI: https://doi.org/10.1080/08916934.2019.1662404
Xia Y, Zhuo H, Lu Y, et al. Glycogen synthase kinase 3beta inhibition promotes human iTreg differentiation and suppressive function. Immunol Res 2015;62:60-70. DOI: https://doi.org/10.1007/s12026-015-8635-3
Hussain SP, Hofseth LJ, Harris CC. Radical causes of cancer. Nat Rev Cancer 2003;3:276-85. DOI: https://doi.org/10.1038/nrc1046

How to Cite

Wu, W., Lin, F., Chen, Z., Wu, K., Ma, C., Zhuang, J., Sun, D., Zhu, Q., & Shi, L. (2023). Identification of hub genes associated with hepatitis B virus-related hepatocellular cancer using weighted gene co-expression network analysis and protein-protein interaction network analysis. Italian Journal of Medicine, 17(2). https://doi.org/10.4081/itjm.2023.1626
Copyright (c) 2023 the Author(s) Creative Commons License

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

PAGEPress has chosen to apply the Creative Commons Attribution NonCommercial 4.0 International License (CC BY-NC 4.0) to all manuscripts to be published.