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Gene Biomarkers Derived from Clinical Data of Hepatocellular Carcinoma

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Abstract

Hepatocellular carcinoma (HCC) is a common cancer of high mortality, mainly due to the difficulty in diagnosis during its clinical stage. Here we aim to find the gene biomarkers, which are of important significance for diagnosis and treatment. In this work, 3682 differentially expressed genes on HCC were firstly differentiated based on the Cancer Genome Atlas database (TCGA). Co-expression modules of these differentially expressed genes were then constructed based on the weighted correlation network algorithm. The correlation coefficient between the co-expression module and clinical data from the Broad GDAC Firehose was thereafter derived. Finally, the interactive network of genes was then constructed. Then, the hub genes were used to implement enrichment analysis and pathway analysis in the Database for Annotation, Visualization and Integrated Discovery (DAVID) database. Results revealed that the abnormally expressed genes in the module played an important role in the biological process including cell division, sister chromatid cohesion, DNA repair, and G1/S transition of mitotic cell cycle. Meanwhile, these genes also enriched in a few crucial pathways related to Cell cycle, Oocyte meiosis, and p53 signaling. Via investigating the closeness centrality of the interactive network, eight gene biomarkers including the CKAP2, TPX2, CDCA8, KIFC1, MELK, SGO1, RACGAP1, and KIAA1524 gene were discovered, whose functions had been indeed revealed to be correlated with HCC. This study, therefore, suggests that the abnormal expression of those eight genes may be taken as gene biomarkers of HCC.

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References

  1. Han LL, Lv Y, Guo H et al (2014) Implications of biomarkers in human hepatocellular carcinoma pathogenesis and therapy. World J Gastroenterol 20(30):10249–10261. https://doi.org/10.3748/wjg.v20.i30.10249

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Kim JU, Cox IJ, Taylor-Robinson SD (2017) The quest for relevant hepatocellular carcinoma biomarkers. Cell Mol Gastroenterol Hepatol 4(2):283–284. https://doi.org/10.1016/j.jcmgh.2017.06.003

    Article  PubMed  PubMed Central  Google Scholar 

  3. Miura T, Ban D, Tanaka S et al (2015) Distinct clinicopathological phenotype of hepatocellular carcinoma with ethoxybenzyl-magnetic resonance imaging hyperintensity: association with gene expression signature. Am J Surg 210(3):561–569. https://doi.org/10.1016/j.amjsurg.2015.03.027

    Article  PubMed  Google Scholar 

  4. Zhou C, Zhang W, Chen W et al (2017) Integrated analysis of copy number variations and gene expression profiling in hepatocellular carcinoma. Sci Rep 7(1):10570. https://doi.org/10.1038/s41598-017-11029-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Wei L, Lian B, Zhang Y et al (2014) Application of microRNA and mRNA expression profiling on prognostic biomarker discovery for hepatocellular carcinoma. BMC Genomics 15(1):S13. https://doi.org/10.1186/1471-2164-15-S1-S13

    Article  PubMed  PubMed Central  Google Scholar 

  6. Maher CA, Kumar-Sinha C, Cao XH et al (2009) Transcriptome sequencing to detect gene fusions in cancer. Nature 458:97–101. https://doi.org/10.1038/nature07638

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Griffith M, Griffith OL, Mwenifumbo J et al (2010) Alternative expression analysis by RNA sequencing. Nat Methods 7:843–847. https://doi.org/10.1038/nmeth.1503

    Article  CAS  PubMed  Google Scholar 

  8. Maher CA, Palanisamy N, Brenner JC et al (2009) Chimeric transcript discovery by paired-end transcriptome sequencing. Proc Natl Acad Sci 106(30):12353–12358. https://doi.org/10.1073/pnas.0904720106

    Article  PubMed  PubMed Central  Google Scholar 

  9. McCarthy DJ, Chen Y, Smyth GK et al (2012) Differential expression analysis of multifactor RNA-Seq experiments with respect to biological variation. Nucleic Acids Res 40(10):4288–4297. https://doi.org/10.1093/nar/gks042

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhao Q, Caballero OL, Levy S et al (2009) Transcriptome-guided characterization of genomic rearrangements in a breast cancer cell line. Proc Natl Acad Sci 106(6):1886–1891. https://doi.org/10.1073/pnas.0812945106

    Article  PubMed  PubMed Central  Google Scholar 

  11. Sinicropi D, Qu K, Collin F et al (2012) Whole transcriptome RNA-Seq analysis of breast cancer recurrence risk using formalin-fixed paraffin-embedded tumor tissue. PLoS ONE 7(7):e40092. https://doi.org/10.1371/journal.pone.0040092

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ren S, Peng Z, Mao JH et al (2012) RNA-seq analysis of prostate cancer in the Chinese population identifies recurrent gene fusions, cancer-associated long noncoding RNAs and aberrant alternative splicings. Cell Res 22:806–821. https://doi.org/10.1038/cr.2012.30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Shah SP, Köbel M, Senz J et al (2009) Mutation of FOXL2 in granulosa-cell tumors of the ovary. N Engl J Med 360(26):2719–2729. https://doi.org/10.1056/NEJMoa0902542

    Article  CAS  PubMed  Google Scholar 

  14. Beane J, Vick J, Schembri F et al (2011) Characterizing the impact of smoking and lung cancer on the airway transcriptome using RNA-Seq. Cancer Prev Res 4(6):803–817. https://doi.org/10.1158/1940-6207.CAPR-11-0212

    Article  CAS  Google Scholar 

  15. Liu J, Yu Z, Sun M et al (2019) Identification of cancer/testis antigen 2 gene as a potential hepatocellular carcinoma therapeutic target by hub gene screening with topological analysis. Oncol Lett 18(5):4778–4788. https://doi.org/10.3892/ol.2019.10811

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Guo Y, Bao Y, Ma M et al (2017) Identification of key candidate genes and pathways in colorectal cancer by integrated bioinformatical analysis. Int J Mol Sci 18(4):722. https://doi.org/10.3390/ijms18040722

    Article  CAS  PubMed Central  Google Scholar 

  17. Agarwal R, Narayan J, Bhattacharyya A et al (2017) Gene expression profiling, pathway analysis and subtype classification reveal molecular heterogeneity in hepatocellular carcinoma and suggest subtype specific therapeutic targets. Cancer Genetics 216:37–51. https://doi.org/10.1016/j.cancergen.2017.06.002

    Article  CAS  PubMed  Google Scholar 

  18. Chen L, Liu R, Liu ZP et al (2012) Detecting early-warning signals for sudden deterioration of complex diseases by dynamical network biomarkers. Sci Rep 2:342. https://doi.org/10.1038/srep00342

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Li Y, Vongsangnak W, Chen L et al (2014) Integrative analysis reveals disease-associated genes and biomarkers for prostate cancer progression. BMC Med Genomics 7(1):S3. https://doi.org/10.1186/1755-8794-7-S1-S3

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yuan X, Chen J, Lin Y et al (2017) Network biomarkers constructed from gene expression and protein-protein interaction data for accurate prediction of leukemia. J Cancer 8(2):278–286. https://doi.org/10.7150/jca.17302

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Solé X, Crous-Bou M, Cordero D et al (2014) Discovery and validation of new potential biomarkers for early detection of colon cancer. PLoS ONE 9(9):e106748. https://doi.org/10.1371/journal.pone.0106748

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Zhang B, Horvath S (2005) A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol. https://doi.org/10.2202/1544-6115.1128

    Article  PubMed  Google Scholar 

  23. Ravasz E, Somera AL, Mongru DA et al (2002) Hierarchical organization of modularity in metabolic networks. Science 297(5586):1551–1555. https://doi.org/10.1126/science.1073374

    Article  CAS  PubMed  Google Scholar 

  24. Langfelder P, Horvath S (2007) Eigengene networks for studying the relationships between co-expression modules. BMC Syst Biol 1(1):54. https://doi.org/10.1186/1752-0509-1-54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yoo S, Wang W, Wang Q et al (2017) A pilot systematic genomic comparison of recurrence risks of hepatitis B virus-associated hepatocellular carcinoma with low- and high-degree liver fibrosis. BMC Med 15:214. https://doi.org/10.1186/s12916-017-0973-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wang SM, Ooi LL, Hui KM (2007) Identification and validation of a novel gene signature associated with the recurrence of human hepatocellular carcinoma. Clin Cancer Res 13(21):6275–6283. https://doi.org/10.1158/1078-0432.CCR-06-2236

    Article  CAS  PubMed  Google Scholar 

  27. Jiang Y, Sun A, Zhao Y et al (2019) Proteomics identifies new therapeutic targets of early-stage hepatocellular carcinoma. Nature 567:257–261. https://doi.org/10.1038/s41586-019-0987-8

    Article  CAS  PubMed  Google Scholar 

  28. Marte B (2004) Cell division and cancer. Nature 432:293. https://doi.org/10.1038/432293a

    Article  CAS  Google Scholar 

  29. Liu C, Liu L, Chen X et al (2016) Sox9 regulates self-renewal and tumorigenicity by promoting symmetrical cell division of cancer stem cells in hepatocellular carcinoma. Hepatology 64:117–129. https://doi.org/10.1002/hep.28509

    Article  CAS  PubMed  Google Scholar 

  30. Liu Q, Yang P, Tu K et al (2014) TPX2 knockdown suppressed hepatocellular carcinoma cell invasion via inactivating AKT signaling and inhibiting MMP2 and MMP9 expression. Chin J Cancer Res 26(4):410–417. https://doi.org/10.3978/j.issn.1000-9604.2014.08.01

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wang LH, Yen CJ, Li TN et al (2015) Sgo1 is a potential therapeutic target for hepatocellular carcinoma. Oncotarget 6(4):2023–2033. https://doi.org/10.18632/oncotarget.2764

    Article  PubMed  PubMed Central  Google Scholar 

  32. Gramantieri L, Trerè D, Chieco P et al (2003) In human hepatocellular carcinoma in cirrhosis proliferating cell nuclear antigen (PCNA) is involved in cell proliferation and cooperates with P21 in DNA repair. J Hepatol 39(6):997–1003. https://doi.org/10.1016/S0168-8278(03)00458-6

    Article  CAS  PubMed  Google Scholar 

  33. Lukish JR, Muro K, DeNobile J et al (1998) Prognostic significance of DNA replication errors in young patients with colorectal cancer. Ann Surg 227(1):51–56. https://doi.org/10.1097/00000658-199801000-00008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Martin-Lluesma S, Schaeffer C, Robert EI et al (2008) Hepatitis B virus X protein affects S phase progression leading to chromosome segregation defects by binding to damaged DNA binding protein 1. Hepatology 48:1467–1476. https://doi.org/10.1002/hep.22542

    Article  CAS  PubMed  Google Scholar 

  35. Wu BK, Li CC, Chen HJ et al (2006) Blocking of G1/S transition and cell death in the regenerating liver of Hepatitis B virus X protein transgenic mice. Biochem Biophys Res Commun 340(3):916–928. https://doi.org/10.1016/j.bbrc.2005.12.089

    Article  CAS  PubMed  Google Scholar 

  36. Zhang L, Guo Y, Li B et al (2013) Identification of biomarkers for hepatocellular carcinoma using network-based bioinformatics methods. Eur J Med Res 18(1):35. https://doi.org/10.1186/2047-783X-18-35

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–166. https://doi.org/10.1038/nrc2602

    Article  CAS  PubMed  Google Scholar 

  38. ElHefnawi M, Soliman B, Abu-Shahba N et al (2013) An integrative meta-analysis of microRNAs in hepatocellular carcinoma. Genom Proteom Bioinf 11(6):354–367. https://doi.org/10.1016/j.gpb.2013.05.007

    Article  CAS  Google Scholar 

  39. Wong YH, Wu CC, Lin CL et al (2015) Applying NGS data to find evolutionary network biomarkers from the early and late stages of hepatocellular carcinoma. Biomed Res Int 2015:391475. https://doi.org/10.1155/2015/391475

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hucl T (2011) Gallmeier E (2011) DNA repair: exploiting the Fanconi anemia pathway as a potential therapeutic target. Physiol Res 60(3):453–465. https://doi.org/10.33549/physiolres.932115

    Article  CAS  PubMed  Google Scholar 

  41. Palagyi A, Neveling K, Plinninger U et al (2010) Genetic inactivation of the Fanconi anemia gene FANCC identified in the hepatocellular carcinoma cell line HuH-7 confers sensitivity towards DNA-interstrand crosslinking agents. Mol Cancer 9:127. https://doi.org/10.1186/1476-4598-9-127

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Okayama A, Maruyama T, Tachibana N et al (1995) Increased prevalence of HTLV-I infection in patients with hepatocellular carcinoma associated with Hepatitis C virus. Cancer Sci 86:1–4. https://doi.org/10.1111/j.1349-7006.1995.tb02979.x

    Article  CAS  Google Scholar 

  43. Lips EH, Mulder L, Hannemann J et al (2010) Indicators of homologous recombination deficiency in breast cancer and association with response to neoadjuvant chemotherapy. Ann Oncol 22(4):870–876. https://doi.org/10.1093/annonc/mdq468

    Article  PubMed  Google Scholar 

  44. Abkevich V, Timms KM, Hennessy BT et al (2012) Patterns of genomic loss of heterozygosity predict homologous recombination repair defects in epithelial ovarian cancer. Br J Cancer 107:1776–1782. https://doi.org/10.1038/bjc.2012.451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Helleday T (2010) Homologous recombination in cancer development, treatment and development of drug resistance. Carcinogenesis 31(6):955–960. https://doi.org/10.1093/carcin/bgq064

    Article  CAS  PubMed  Google Scholar 

  46. Kiss A, Wang NJ, Xie JP et al (1997) Analysis of transforming growth factor (TGF)-alpha/epidermal growth factor receptor, hepatocyte growth Factor/c-met, TGF-beta receptor type II, and p53 expression in human hepatocellular carcinomas. Clin Cancer Res 3(7):1059–1066

    CAS  PubMed  Google Scholar 

  47. Greer EL, Brunet A (2005) FOXO transcription factors at the interface between longevity and tumor suppression. Oncogene 24(50):7410–7425. https://doi.org/10.1038/sj.onc.1209086

    Article  CAS  PubMed  Google Scholar 

  48. Guo Q, Song Y, Hua K et al (2017) Involvement of FAK-ERK2 signaling pathway in CKAP2-induced proliferation and motility in cervical carcinoma cell lines. Sci Rep 7(1):2117. https://doi.org/10.1038/s41598-017-01832-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Hayashi T, Ohtsuka M, Okamura D et al (2014) Cytoskeleton-associated protein 2 is a potential predictive marker for risk of early and extensive recurrence of hepatocellular carcinoma after operative resection. Surgery 155(1):114–123. https://doi.org/10.1016/j.surg.2013.06.009

    Article  PubMed  Google Scholar 

  50. Jeon TW, Min JK, Seo YR et al (2017) Abstract 3113: Knockdown of cell division cycle-associated 8 (CDCA8) suppresses hepatocellular carcinoma growth via the upregulation of tumor suppressor ATF3. Can Res 77(13):3113–3113. https://doi.org/10.1158/1538-7445.AM2017-3113

    Article  Google Scholar 

  51. Fu X, Zhu Y, Zheng B et al (2018) KIFC1, a novel potential prognostic factor and therapeutic target in hepatocellular carcinoma. Int J Oncol 52(6):1912–1922. https://doi.org/10.3892/ijo.2018.4348

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Xia H, Kong SN, Chen J et al (2016) MELK is an oncogenic kinase essential for early hepatocellular carcinoma recurrence. Cancer Lett 383(1):85–93. https://doi.org/10.1016/j.canlet.2016.09.017

    Article  CAS  PubMed  Google Scholar 

  53. Li Y, Li Y, Chen Y et al (2017) MicroRNA-214-3p inhibits proliferation and cell cycle progression by targeting MELK in hepatocellular carcinoma and correlates cancer prognosis. Cancer Cell Int 17(1):102. https://doi.org/10.1186/s12935-017-0471-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li Y, Zheng J, Yao J et al (2017) Aberrant expression and prognostic value of RacGAP1 in hepatocellular carcinoma. Int J Clin Exp Pathol 10:1747–1755

    CAS  Google Scholar 

  55. Junttila MR, Puustinen P, Niemelä M et al (2007) CIP2A inhibits PP2A in human malignancies. Cell 130(1):51–62. https://doi.org/10.1016/j.cell.2007.04.044

    Article  CAS  PubMed  Google Scholar 

  56. Chen KF, Liu CY, Lin YC et al (2010) CIP2A mediates effects of bortezomib on phospho-Akt and apoptosis in hepatocellular carcinoma cells. Oncogene 29:6257–6266. https://doi.org/10.1038/onc.2010.357

    Article  CAS  PubMed  Google Scholar 

  57. Côme C, Laine A, Chanrion M et al (2009) CIP2A is associated with human breast cancer aggressivity. Clin Cancer Res 15(16):5092–5100. https://doi.org/10.1158/1078-0432.CCR-08-3283

    Article  CAS  PubMed  Google Scholar 

  58. Li W, Ge Z, Liu C et al (2008) CIP2A is overexpressed in gastric cancer and its depletion leads to impaired clonogenicity, senescence, or differentiation of tumor cells. Clin Cancer Res 14(12):3722–3728. https://doi.org/10.1158/1078-0432.CCR-07-4137

    Article  CAS  PubMed  Google Scholar 

  59. Khanna A, Böckelman C, Hemmes A et al (2009) MYC-dependent regulation and prognostic role of CIP2A in gastric cancer. J Natl Cancer Inst 101(11):793–805. https://doi.org/10.1093/jnci/djp103

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grand Nos. 11371174 and 11804123) and Postgraduate Research and Practice Innovation Program of Jiangsu Province (No. KYCX18_1866). This manuscript had been accepted for presentation in CBC2019.

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Qi, J., Zhou, J., Tang, XQ. et al. Gene Biomarkers Derived from Clinical Data of Hepatocellular Carcinoma. Interdiscip Sci Comput Life Sci 12, 226–236 (2020). https://doi.org/10.1007/s12539-020-00366-8

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