Skip to main content
SpringerLink
Log in

TCGA whole-transcriptome sequencing data reveals significantly dysregulated genes and signaling pathways in hepatocellular carcinoma

  • Research Article
  • Published:
Frontiers of Medicine Aims and scope Submit manuscript

Abstract

This study systematically evaluates the TCGA whole-transcriptome sequencing data of hepatocellular carcinoma (HCC) by comparing the global gene expression profiles between tumors and their corresponding nontumorous liver tissue. Based on the differential gene expression analysis, we identified a number of novel dysregulated genes, in addition to those previously reported. Top-listing upregulated (CENPF and FOXM1) and downregulated (CLEC4G, CRHBP, and CLEC1B) genes were successfully validated using qPCR on our cohort of 65 pairs of human HCCs. Further examination for the mechanistic overview by subjecting significantly upregulated and downregulated genes to gene set enrichment analysis showed that different cellular pathways were involved. This study provides useful information on the transcriptomic landscape and molecular mechanism of hepatocarcinogenesis for development of new biomarkers and further in-depth characterization.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. El-Serag HB. Hepatocellular carcinoma. N Engl J Med 2011; 365 (12): 1118–1127

    Article  CAS  PubMed  Google Scholar 

  2. Villanueva A, Llovet JM. Liver cancer in 2013: mutational landscape of HCC—the end of the beginning. Nat Rev Clin Oncol 2014; 11(2): 73–74

    Article  CAS  PubMed  Google Scholar 

  3. Jia HL, Ye QH, Qin LX, Budhu A, Forgues M, Chen Y, Liu YK, Sun HC, Wang L, Lu HZ, Shen F, Tang ZY, Wang XW. Gene expression profiling reveals potential biomarkers of human hepatocellular carcinoma. Clin Cancer Res 2007; 13(4): 1133–1139

    Article  CAS  PubMed  Google Scholar 

  4. Lee JS, Thorgeirsson SS. Comparative and integrative functional genomics of HCC. Oncogene 2006; 25(27): 3801–3809

    Article  CAS  PubMed  Google Scholar 

  5. Marshall A, Lukk M, Kutter C, Davies S, Alexander G, Odom DT. Global gene expression profiling reveals SPINK1 as a potential hepatocellular carcinoma marker. PLoS ONE 2013; 8(3): e59459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Patil MA, Chua MS, Pan KH, Lin R, Lih CJ, Cheung ST, Ho C, Li R, Fan ST, Cohen SN, Chen X, So S. An integrated data analysis approach to characterize genes highly expressed in hepatocellular carcinoma. Oncogene 2005; 24(23): 3737–3747

    Article  CAS  PubMed  Google Scholar 

  7. Skawran B, Steinemann D, Weigmann A, Flemming P, Becker T, Flik J, Kreipe H, Schlegelberger B, Wilkens L. Gene expression profiling in hepatocellular carcinoma: upregulation of genes in amplified chromosome regions. Mod Pathol 2008; 21(5): 505–516

    Article  CAS  PubMed  Google Scholar 

  8. Huang Q, Lin B, Liu H, Ma X, Mo F, Yu W, Li L, Li H, Tian T, Wu D, Shen F, Xing J, Chen ZN. RNA-Seq analyses generate comprehensive transcriptomic landscape and reveal complex transcript patterns in hepatocellular carcinoma. PLoS ONE 2011; 6(10): e26168

  9. Lin KT, Shann YJ, Chau GY, Hsu CN, Huang CY. Identification of latent biomarkers in hepatocellular carcinoma by ultra-deep whole-transcriptome sequencing. Oncogene 2014; 33(39): 4786–4794

    Article  CAS  PubMed  Google Scholar 

  10. Ho DW, Yang ZF, Yi K, Lam CT, Ng MN, Yu WC, Lau J, Wan T, Wang X, Yan Z, Liu H, Zhang Y, Fan ST. Gene expression profiling of liver cancer stem cells by RNA-sequencing. PLoS ONE 2012; 7(5): e37159

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics 2010; 26(1): 139–140

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Ho DW, Ng IO. uGPA: unified Gene Pathway Analyzer package for high-throughput genome-wide screening data provides mechanistic overview on human diseases. Clin Chim Acta 2015; 441: 105–108

    Article  CAS  PubMed  Google Scholar 

  13. Hong G, Zhang W, Li H, Shen X, Guo Z. Separate enrichment analysis of pathways for up- and downregulated genes. J R Soc Interface 2014; 11(92): 20130950

  14. Aytes A, Mitrofanova A, Lefebvre C, Alvarez MJ, Castillo-Martin M, Zheng T, Eastham JA, Gopalan A, Pienta KJ, Shen MM, Califano A, Abate-Shen C. Cross-species regulatory network analysis identifies a synergistic interaction between FOXM1 and CENPF that drives prostate cancer malignancy. Cancer Cell 2014; 25(5): 638–651

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Cummings RD, McEver RP. C-type lectins. In: Varki A, Cummings RD, Esko JD, Freeze HH, Stanley P, Bertozzi CR, Hart GW, Eltzler ME. Essentials of Glycobiology. Cold Spring Harbor (NY): Cold Spring Harbor Laboratory Press, 2009

    Google Scholar 

  16. Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S, Wernerus H, Björling L, Ponten F. Towards a knowledge-based Human Protein Atlas. Nat Biotechnol 2010; 28(12): 1248–1250

    Article  CAS  PubMed  Google Scholar 

  17. Bale TL, Giordano FJ, Hickey RP, Huang Y, Nath AK, Peterson KL, Vale WW, Lee KF. Corticotropin-releasing factor receptor 2 is a tonic suppressor of vascularization. Proc Natl Acad Sci USA 2002; 99(11): 7734–7739

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Graziani G, Tentori L, Portarena I, Barbarino M, Tringali G, Pozzoli G, Navarra P. CRH inhibits cell growth of human endometrial adenocarcinoma cells via CRH-receptor 1-mediated activation of cAMP-PKA pathway. Endocrinology 2002; 143(3): 807–813

    Article  CAS  PubMed  Google Scholar 

  19. Hao Z, Huang Y, Cleman J, Jovin IS, Vale WW, Bale TL, Giordano FJ. Urocortin2 inhibits tumor growth via effects on vascularization and cell proliferation. Proc Natl Acad Sci USA 2008; 105(10): 3939–3944

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang J, Xu Y, Xu Y, Zhu H, Zhang R, Zhang G, Li S. Urocortin’s inhibition of tumor growth and angiogenesis in hepatocellular carcinoma via corticotrophin-releasing factor receptor 2. Cancer Invest 2008; 26(4): 359–368

    Article  PubMed  Google Scholar 

  21. Tezval H, Atschekzei F, Peters I, Waalkes S, Hennenlotter J, Stenzl A, Becker JU, Merseburger AS, Kuczyk MA, Serth J. Reduced mRNA expression level of corticotropin-releasing hormone-binding protein is associated with aggressive human kidney cancer. BMC Cancer 2013; 13(1): 199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Graña X, Reddy EP. Cell cycle control in mammalian cells: role of cyclins, cyclin dependent kinases (CDKs), growth suppressor genes and cyclin-dependent kinase inhibitors (CKIs). Oncogene 1995; 11(2): 211–219

    PubMed  Google Scholar 

  23. Lew DJ, Kornbluth S. Regulatory roles of cyclin dependent kinase phosphorylation in cell cycle control. Curr Opin Cell Biol 1996; 8(6): 795–804

    Article  CAS  PubMed  Google Scholar 

  24. Nebert DW, Russell DW. Clinical importance of the cytochromes P450. Lancet 2002; 360(9340): 1155–1162

    Article  CAS  PubMed  Google Scholar 

  25. Denison MS, Whitlock JP Jr. Xenobiotic-inducible transcription of cytochrome P450 genes. J Biol Chem 1995; 270(31): 18175–18178

    Article  CAS  PubMed  Google Scholar 

  26. Guengerich FP. Common and uncommon cytochrome P450 reactions related to metabolism and chemical toxicity. Chem Res Toxicol 2001; 14(6): 611–650

    Article  CAS  PubMed  Google Scholar 

  27. Burkholder B, Huang RY, Burgess R, Luo S, Jones VS, Zhang W, Lv ZQ, Gao CY, Wang BL, Zhang YM, Huang RP. Tumor-induced perturbations of cytokines and immune cell networks. Biochim Biophys Acta 2014; 1845(2): 182–201

    CAS  PubMed  Google Scholar 

  28. Lacy P, Stow JL. Cytokine release from innate immune cells: association with diverse membrane trafficking pathways. Blood 2011; 118(1): 9–18

    Article  CAS  PubMed  Google Scholar 

  29. Lippitz BE. Cytokine patterns in patients with cancer: a systematic review. Lancet Oncol 2013; 14(6): e218–e228

Download references

Author information

Authors and Affiliations

  1. Department of Pathology and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong SAR, China

    Daniel Wai-Hung Ho, Alan Ka-Lun Kai & Irene Oi-Lin Ng

Authors
  1. Daniel Wai-Hung Ho
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Alan Ka-Lun Kai
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Irene Oi-Lin Ng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Irene Oi-Lin Ng.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ho, D.WH., Kai, A.KL. & Ng, I.OL. TCGA whole-transcriptome sequencing data reveals significantly dysregulated genes and signaling pathways in hepatocellular carcinoma. Front. Med. 9, 322–330 (2015). https://doi.org/10.1007/s11684-015-0408-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11684-015-0408-9

Keywords

Search

Navigation