Objective: This study aimed to identify hub genes that are associated with hepatocellular carcinoma (HCC) prognosis by bioinformatics analysis. Methods: Data were collected from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) liver HCC datasets. The robust rank ag gregation algorithm was used in integrating the data on differentially ex pressed genes (DEGs). Online databases DAVID 6.8 and REACTOME were used for gene ontology and pathway enrichment analysis. R software version 3.5.1, Cytoscape, and Kaplan-Meier plotter were used to identify hub genes. Results: Six GEO datasets and the TCGA liver HCC dataset were included in this analysis. A total of 151 upregulated and 245 downregulated DEGs were iden tified. The upregulated DEGs most significantly enriched in the functional categories of cell division, chromosomes, centromeric regions, and protein binding, whereas the downregulated DEGs most significantly enriched in the epoxygenase P450 pathway, extracellular region, and heme binding, with respect to biological process, cellular component, and molecular function analysis, respectively. Upregulated DEGS most significantly enriched the cell cycle pathway, whereas downregulated DEGs most significantly enriched the metabolism pathway. Finally, 88 upregulated and 40 downregulated genes were identified as hub genes. The top 10 upregulated hub DEGs were CDK 1, CCNB 1, CCNB 2, CDC 20, CCNA 2, AURKA , MAD 2 L 1, TOP 2 A , BUB 1 B and BUB 1. The top 10 downregulated hub DEGs were ESR 1, IGF 1, FTCD , CYP 3 A 4, SPP 2, C 8 A , CYP 2 E 1, TAT , F 9 and CYP 2 C 9. Conclusions: This study identified several upregulated and downregulated hub genes that are associated with the prognosis of HCC patients. Verification of these results using in vitro and in vivo studies is warranted.
Siegel, R.L., Miller, K.D. and Jemal, A. (2017) Cancer Statistics, 2017. CA: A Cancer Journal for Clinicians, 67, 7-30. https://doi.org/10.3322/caac.21387
Forner, A., Reig, M. and Bruix, J. (2018) Hepatocellular Carcinoma. The Lancet, 391, 1301-1314. https://doi.org/10.1016/S0140-6736(18)30010-2
Huang, G., Li, P.P., Lau, W.Y., Pan, Z.Y., Zhao, L.H., Wang, Z.G., et al. (2018) Antiviral Therapy Reduces Hepatocellular Carcinoma Recurrence in Patients with Low HBV-DNA Levels: A Randomized Controlled Trial. Annals of Surgery, 268, 943-954. https://doi.org/10.1097/SLA.0000000000002727
Llovet, J.M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.F., et al. (2008) Sorafenib in Advanced Hepatocellular Carcinoma. The New England Journal of Medicine, 359, 378-390. https://doi.org/10.1056/NEJMoa0708857
Bruix, J., Takayama, T., Mazzaferro, V., Chau, G.Y., Yang, J., Kudo, M., et al. (2015) Adjuvant Sorafenib for Hepatocellular Carcinoma after Resection or Ablation (STORM): A Phase 3, Randomised, Double-Blind, Placebo-Controlled Trial. The Lancet Oncology, 16, 1344-1354. https://doi.org/10.1016/S1470-2045(15)00198-9
Lim, H.Y., Sohn, I., Deng, S., Lee, J., Jung, S.H., Mao, M., et al. (2013) Prediction of Disease-Free Survival in Hepatocellular Carcinoma by Gene Expression Profiling. Annals of Surgical Oncology, 20, 3747-3753. https://doi.org/10.1245/s10434-013-3070-y
Roessler, S., Jia, H.L., Budhu, A., Forgues, M., Ye, Q.H., Lee, J.S., et al. (2010) A Unique Metastasis Gene Signature Enables Prediction of Tumor Relapse in Early-Stage Hepatocellular Carcinoma Patients. Cancer Research, 70, 10202-10212. https://doi.org/10.1158/0008-5472.CAN-10-2607
Tung, E.K., Mak, C.K., Fatima, S., Lo, R.C., Zhao, H., Zhang, C., et al. (2011) Clinicopathological and Prognostic Significance of Serum and Tissue Dickkopf-1 Levels in Human Hepatocellular Carcinoma. Liver International, 31, 1494-1504. https://doi.org/10.1111/j.1478-3231.2011.02597.x
Chen, Z., Chen, J., Huang, X., Wu, Y., Huang, K., Xu, W., et al. (2019) Identification of Potential Key Genes for Hepatitis B Virus-Associated Hepatocellular Carcinoma by Bioinformatics Analysis. Journal of Computational Biology, 26, 485-494. https://doi.org/10.1089/cmb.2018.0244
Shen, S., Kong, J., Qiu, Y., Yang, X., Wang, W. and Yan, L. (2019) Identification of Core Genes and Outcomes in Hepatocellular Carcinoma by Bioinformatics Analysis. Journal of Cellular Biochemistry, 120, 10069-10081. https://doi.org/10.1002/jcb.28290
Kolde, R., Laur, S., Adler, P. and Vilo, J. (2012) Robust Rank Aggregation for Gene List Integration and Meta-Analysis. Bioinformatics, 28, 573-580. https://doi.org/10.1093/bioinformatics/btr709
Sun, B., Lin, G., Ji, D., Li, S., Chi, G. and Jin, X. (2018) Dysfunction of Sister Chromatids Separation Promotes Progression of Hepatocellular Carcinoma According to Analysis of Gene Expression Profiling. Frontiers in Physiology, 9, 1019. https://doi.org/10.3389/fphys.2018.01019
Gao, X., Wang, X. and Zhang, S. (2018) Bioinformatics Identification of Crucial Genes and Pathways Associated with Hepatocellular Carcinoma. Bioscience Reports, 38, BSR20181441. https://doi.org/10.1042/BSR20181441
Wu, C.X., Wang, X.Q., Chok, S.H., Man, K., Tsang, S.H.Y., Chan, A.C.Y., et al. (2018) Blocking CDK1/PDK1/beta-Catenin Signaling by CDK1 Inhibitor RO3306 Increased the Efficacy of Sorafenib Treatment by Targeting Cancer Stem Cells in a Preclinical Model of Hepatocellular Carcinoma. Theranostics, 8, 3737-3750. https://doi.org/10.7150/thno.25487
Zhang, Y., Huang, W., Ran, Y., Xiong, Y., Zhong, Z., Fan, X., et al. (2015) miR-582-5p Inhibits Proliferation of Hepatocellular Carcinoma by Targeting CDK1 and AKT3. Tumor Biology, 36, 8309-8316. https://doi.org/10.1007/s13277-015-3582-0
Zhou, J., Han, S., Qian, W., Gu, Y., Li, X. and Yang, K. (2018) Metformin Induces miR-378 to Downregulate the CDK1, Leading to Suppression of Cell Proliferation in Hepatocellular Carcinoma. OncoTargets and Therapy, 11, 4451-4459. https://doi.org/10.2147/OTT.S167614
Gu, J., Liu, X., Li, J. and He, Y. (2019) MicroRNA-144 Inhibits Cell Proliferation, Migration and Invasion in Human Hepatocellular Carcinoma by Targeting CCNB1. Cancer Cell International, 19, 15. https://doi.org/10.1186/s12935-019-0729-x
Chai, N., Xie, H.H., Yin, J.P., Sa, K.D., Guo, Y., Wang, M., et al. (2018) FOXM1 Promotes Proliferation in Human Hepatocellular Carcinoma Cells by Transcriptional Activation of CCNB1. Biochemical and Biophysical Research Communications, 500, 924-929. https://doi.org/10.1016/j.bbrc.2018.04.201
Li, R., Jiang, X., Zhang, Y., Wang, S., Chen, X., Yu, X., et al. (2019) Cyclin B2 Overexpression in Human Hepatocellular Carcinoma Is Associated with Poor Prognosis. Archives of Medical Research, 50, 10-17. https://doi.org/10.1016/j.arcmed.2019.03.003
Yue, X., Zhang, Z., Liang, X., Gao, L., Zhang, X., Zhao, D., et al. (2012) Zinc Fingers and Homeoboxes 2 Inhibits Hepatocellular Carcinoma Cell Proliferation and Represses Expression of Cyclins A and E. Gastroenterology, 142, 1559-70e2. https://doi.org/10.1053/j.gastro.2012.02.049
Li, J., Gao, J.Z., Du, J.L., Huang, Z.X. and Wei, L.X. (2014) Increased CDC20 Expression Is Associated with Development and Progression of Hepatocellular Carcinoma. International Journal of Oncology, 45, 1547-1555. https://doi.org/10.3892/ijo.2014.2559
Li, Y., Bai, W. and Zhang, J. (2017) MiR-200c-5p Suppresses Proliferation and Metastasis of Human Hepatocellular Carcinoma (HCC) via Suppressing MAD2L1. Biomedicine & Pharmacotherapy, 92, 1038-1044. https://doi.org/10.1016/j.biopha.2017.05.092
Chen, C., Song, G., Xiang, J., Zhang, H., Zhao, S. and Zhan, Y. (2017) AURKA Promotes Cancer Metastasis by Regulating Epithelial-Mesenchymal Transition and Cancer Stem Cell Properties in Hepatocellular Carcinoma. Biochemical and Biophysical Research Communications, 486, 514-520. https://doi.org/10.1016/j.bbrc.2017.03.075
Gao, P., Wang, R., Shen, J.J., Lin, F., Wang, X., Dong, K., et al. (2008) Hypoxia-Inducible Enhancer/Alpha-Fetoprotein Promoter-Driven RNA Interference Targeting STK15 Suppresses Proliferation and Induces Apoptosis in Human Hepatocellular Carcinoma Cells. Cancer Science, 99, 2209-2217. https://doi.org/10.1111/j.1349-7006.2008.00941.x
Zhang, K., Chen, J., Chen, D., Huang, J., Feng, B., Han, S., et al. (2014) Aurora-A Promotes Chemoresistance in Hepatocelluar Carcinoma by Targeting NF-kappaB/ microRNA-21/PTEN Signaling Pathway. Oncotarget, 5, 12916-12935. https://doi.org/10.18632/oncotarget.2682
Sudan, S. and Rupasinghe, H.P. (2014) Quercetin-3-O-Glucoside Induces Human DNA Topoisomerase II Inhibition, Cell Cycle Arrest and Apoptosis in Hepatocellular Carcinoma Cells. Anticancer Research, 34, 1691-1699.
Raaijmakers, J.A., van Heesbeen, R., Blomen, V.A., Janssen, L.M.E., van Diemen, F., Brummelkamp, T.R., et al. (2018) BUB1 Is Essential for the Viability of Human Cells in Which the Spindle Assembly Checkpoint Is Compromised. Cell Reports, 22, 1424-1438. https://doi.org/10.1016/j.celrep.2018.01.034
Xu, B., Xu, T., Liu, H., Min, Q., Wang, S. and Song, Q. (2017) MiR-490-5p Suppresses Cell Proliferation and Invasion by Targeting BUB1 in Hepatocellular Carcinoma Cells. Pharmacology, 100, 269-282. https://doi.org/10.1159/000477667
Tu, C.C., Kumar, V.B., Day, C.H., Kuo, W.W., Yeh, S.P., Chen, R.J., et al. (2013) Estrogen Receptor Alpha (ESR1) Over-Expression Mediated Apoptosis in Hep3B Cells by Binding with SP1 Proteins. Journal of Molecular Endocrinology, 51, 203-212. https://doi.org/10.1530/JME-13-0085
Dai, B., Geng, L., Yu, Y., Sui, C., Xie, F., Shen, W., et al. (2014) Methylation Patterns of Estrogen Receptor Alpha Promoter Correlate with Estrogen Receptor Alpha Expression and Clinicopathological Factors in Hepatocellular Carcinoma. Experimental Biology and Medicine (Maywood), 239, 883-890. https://doi.org/10.1177/1535370214536651
Shen, L., Xu, L., Zhang, J. and Jiang, D. (2018) Preoperative Serum Insulin-Like Growth Factor 1 Level as a Prognostic Factor in Patients Undergoing Hepatic Resection for Hepatocellular Carcinoma. Journal of Interferon & Cytokine Research, 38, 153-160. https://doi.org/10.1089/jir.2017.0107
Cho, E., Kim, H.C., Lee, J.H., Jeong-Ju, Y., Choi, W.M., Cho, Y.Y., et al. (2014) Serum Insulin-Like Growth Factor-1 Predicts Disease Progression and Survival in Patients with Hepatocellular Carcinoma Who Undergo Transarterial Chemoembolization. PLoS ONE, 9, e90862. https://doi.org/10.1371/journal.pone.0090862
Lei, T. and Ling, X. (2015) IGF-1 Promotes the Growth and Metastasis of Hepatocellular Carcinoma via the Inhibition of Proteasome-Mediated Cathepsin B Degradation. World Journal of Gastroenterology, 21, 10137-10149. https://doi.org/10.3748/wjg.v21.i35.10137
Kanarek, N., Keys, H.R., Cantor, J.R., Lewis, C.A., Chan, S.H., Kunchok, T., et al. (2018) Histidine Catabolism Is a Major Determinant of Methotrexate Sensitivity. Nature, 559, 632-636. https://doi.org/10.1038/s41586-018-0316-7
Ashida, R., Okamura, Y., Ohshima, K., Kakuda, Y., Uesaka, K., Sugiura, T., et al. (2017) CYP3A4 Gene Is a Novel Biomarker for Predicting a Poor Prognosis in Hepatocellular Carcinoma. Cancer Genomics Proteomics, 14, 445-453. https://doi.org/10.21873/cgp.20054
Liu, H., Lou, G., Li, C., Wang, X., Cederbaum, A.I., Gan, L., et al. (2014) HBx Inhibits CYP2E1 Gene Expression via Downregulating HNF4alpha in Human Hepatoma Cells. PLoS ONE, 9, e107913. https://doi.org/10.1371/journal.pone.0107913
Yu, D., Green, B., Marrone, A., Guo, Y., Kadlubar, S., Lin, D., et al. (2015) Suppression of CYP2C9 by microRNA hsa-miR-128-3p in Human Liver Cells and Association with Hepatocellular Carcinoma. Scientific Reports, 5, Article No. 8534. https://doi.org/10.1038/srep08534
Tsunedomi, R., Iizuka, N., Hamamoto, Y., Uchimura, S., Miyamoto, T., Tamesa, T., et al. (2005) Patterns of Expression of Cytochrome P450 Genes in Progression of hepatItis C Virus-Associated Hepatocellular Carcinoma. International Journal of Oncology, 27, 661-667
Yan, T., Lu, L., Xie, C., Chen, J., Peng, X., Zhu, L., et al. (2015) Severely Impaired and Dysregulated Cytochrome P450 Expression and Activities in Hepatocellular Carcinoma: Implications for Personalized Treatment in Patients. Molecular Cancer Therapeutics, 14, 2874-2886. https://doi.org/10.1158/1535-7163.MCT-15-0274
Lao, L., Shen, J., Tian, H., Yao, Q., Li, Y., Qian, L., et al. (2016) Secreted Phosphoprotein 24 kD Inhibits Growth of Human Prostate Cancer Cells Stimulated by BMP-2. Anticancer Research, 36, 5773-5780. https://doi.org/10.21873/anticanres.11161
Fu, L., Dong, S.S., Xie, Y.W., Tai, L.S., Chen, L., Kong, K.L., et al. (2010) Down-Regulation of Tyrosine Aminotransferase at a Frequently Deleted Region 16q22 Contributes to the Pathogenesis of Hepatocellular Carcinoma. Hepatology, 51, 1624-1634. https://doi.org/10.1002/hep.23540