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Characterization of Hepatocellular Carcinoma Related Genes and Metabolites in Human Nonalcoholic Fatty Liver Disease

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Abstract

Background

The worldwide prevalences of nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) are estimated to range from 30 to 40 % and 5–17 %, respectively. Hepatocellular carcinoma (HCC) is primarily caused by hepatitis B infection, but retrospective data suggest that 4–29 % of NASH cases will progress to HCC. Currently the connection between NASH and HCC is unclear.

Aims

The purpose of this study was to identify changes in expression of HCC-related genes and metabolite profiles in NAFLD progression.

Methods

Transcriptomic and metabolomic datasets from human liver tissue representing NAFLD progression (normal, steatosis, NASH) were utilized and compared to published data for HCC.

Results

Genes involved in Wnt signaling were downregulated in NASH but have been reported to be upregulated in HCC. Extracellular matrix/angiogenesis genes were upregulated in NASH, similar to reports in HCC. Iron homeostasis is known to be perturbed in HCC and we observed downregulation of genes in this pathway. In the metabolomics analysis of hepatic NAFLD samples, several changes were opposite to what has been reported in plasma of HCC patients (lysine, phenylalanine, citrulline, creatine, creatinine, glycodeoxycholic acid, inosine, and alpha-ketoglutarate). In contrast, multiple acyl-lyso-phosphatidylcholine metabolites were downregulated in NASH livers, consistent with observations in HCC patient plasma.

Conclusions

These data indicate an overlap in the pathogenesis of NAFLD and HCC where several classes of HCC related genes and metabolites are altered in NAFLD. Importantly, Wnt signaling and several metabolites are different, thus implicating these genes and metabolites as mediators in the transition from NASH to HCC.

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References

  1. Aigner E, Theurl I, Haufe H, et al. Copper availability contributes to iron perturbations in human nonalcoholic fatty liver disease. Gastroenterology. 2008;135:680–688.

    Article  CAS  PubMed  Google Scholar 

  2. Ali R, Cusi K. New diagnostic and treatment approaches in non-alcoholic fatty liver disease (NAFLD). Ann Med. 2009;41:265–278.

    Article  CAS  PubMed  Google Scholar 

  3. Baffy G, Brunt EM, Caldwell SH. Hepatocellular carcinoma in nonalcoholic fatty liver disease: an emerging menace. J Hepatol. 2012;56:1384–1391.

    Article  PubMed  Google Scholar 

  4. Benjamini Y, Hochberg Y. Controlling the false discovery rate—a practical and powerful approach to multiple testing. J Roy Stat Soc Ser B Method. 1995;57:289–300.

    Google Scholar 

  5. Boyault S, Rickman DS, de Reynies A, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42–52.

    Article  CAS  PubMed  Google Scholar 

  6. Bugianesi E. Non-alcoholic steatohepatitis and cancer. Clin Liver Dis. 2007;11:191–207.

    Google Scholar 

  7. Cadoret A, Ovejero C, Terris B, et al. New targets of beta-catenin signaling in the liver are involved in the glutamine metabolism. Oncogene. 2002;21:8293–8301.

    Article  CAS  PubMed  Google Scholar 

  8. Cavard C, Terris B, Grimber G, et al. Overexpression of regenerating islet-derived 1 alpha and 3 alpha genes in human primary liver tumors with beta-catenin mutations. Oncogene. 2006;25:599–608.

    Article  CAS  PubMed  Google Scholar 

  9. Chan DW, Chan CY, Yam JW, Ching YP, Ng IO. Prickle-1 negatively regulates Wnt/beta-catenin pathway by promoting Dishevelled ubiquitination/degradation in liver cancer. Gastroenterology. 2006;131:1218–1227.

    Article  CAS  PubMed  Google Scholar 

  10. Chen T, Xie G, Wang X, et al. Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma. Mol Cell Proteomics. 2011;10:M110.004945-1–13.

    Google Scholar 

  11. Coulon S, Heindryckx F, Geerts A, Van Steenkiste C, Colle I, Van Vlierberghe H. Angiogenesis in chronic liver disease and its complications. Liver Int. 2011;31:146–162.

    Article  CAS  PubMed  Google Scholar 

  12. Di Bisceglie AM, Lyra AC, Schwartz M, et al. Hepatitis C-related hepatocellular carcinoma in the United States: influence of ethnic status. Am J Gastroenterol. 2003;98:2060–2063.

    PubMed  Google Scholar 

  13. Fisher CD, Lickteig AJ, Augustine LM, et al. Hepatic cytochrome P450 enzyme alterations in humans with progressive stages of nonalcoholic fatty liver disease. Drug Metab Dispos. 2009;37:2087–2094.

    Article  CAS  PubMed  Google Scholar 

  14. Kim M, Lee HC, Tsedensodnom O, et al. Functional interaction between Wnt3 and Frizzled-7 leads to activation of the Wnt/beta-catenin signaling pathway in hepatocellular carcinoma cells. J Hepatol. 2008;48:780–791.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321.

    Article  PubMed  Google Scholar 

  16. Lachenmayer A, Alsinet C, Savic R, et al. Wnt-pathway activation in two molecular classes of hepatocellular carcinoma and experimental modulation by Sorafenib. Clin Cancer Res. 2012;18:4997–5007.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  17. Lake AD, Novak P, Fisher CD, et al. Analysis of global and absorption, distribution, metabolism, and elimination gene expression in the progressive stages of human nonalcoholic fatty liver disease. Drug Metab Dispos. 2011;39:1954–1960.

    Article  CAS  PubMed  Google Scholar 

  18. Leonardi GC, Candido S, Cervello M, et al. The tumor microenvironment in hepatocellular carcinoma (review). Int J Oncol. 2012;40:1733–1747.

    CAS  PubMed  Google Scholar 

  19. Luo W, Friedman MS, Shedden K, Hankenson KD, Woolf PJ. GAGE: generally applicable gene set enrichment for pathway analysis. BMC Bioinform. 2009;10:161–162.

    Article  Google Scholar 

  20. Merle P, de la Monte S, Kim M, et al. Functional consequences of frizzled-7 receptor overexpression in human hepatocellular carcinoma. Gastroenterology. 2004;127:1110–1122.

    Article  CAS  PubMed  Google Scholar 

  21. Novak P, Jensen T, Oshiro MM, Watts GS, Kim CJ, Futscher BW. Agglomerative epigenetic aberrations are a common event in human breast cancer. Cancer Res. 2008;68:8616–8625.

    Article  CAS  PubMed  Google Scholar 

  22. O’Brien J, Powell LW. Non-alcoholic fatty liver disease: is iron relevant? Hepatol Int. 2011;6:332–341.

    Article  Google Scholar 

  23. Pang R, Yuen J, Yuen MF, et al. PIN1 overexpression and beta-catenin gene mutations are distinct oncogenic events in human hepatocellular carcinoma. Oncogene. 2004;23:4182–4186.

    Article  CAS  PubMed  Google Scholar 

  24. Patterson AD, Maurhofer O, Beyoglu D, et al. Aberrant lipid metabolism in hepatocellular carcinoma revealed by plasma metabolomics and lipid profiling. Cancer Res. 2011;71:6590–6600.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Qin X, Zhang H, Zhou X, et al. Proliferation and migration mediated by Dkk-1/Wnt/beta-catenin cascade in a model of hepatocellular carcinoma cells. Transl Res. 2007;150:281–294.

    Article  CAS  PubMed  Google Scholar 

  26. Ratziu V, Bonyhay L, Di Martino V, et al. Survival, liver failure, and hepatocellular carcinoma in obesity-related cryptogenic cirrhosis. Hepatology. 2002;35:1485–1493.

    Article  PubMed  Google Scholar 

  27. Regimbeau JM, Colombat M, Mognol P, et al. Obesity and diabetes as a risk factor for hepatocellular carcinoma. Liver Transpl. 2004;10:S69–S73.

    Article  PubMed  Google Scholar 

  28. Siegel AB, Zhu AX. Metabolic syndrome and hepatocellular carcinoma: two growing epidemics with a potential link. Cancer. 2009;115:5651–5661.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Smyth GK. Bioinformatics and computational biology solutions using R and bioconductor, in Limma: Linear models for microarray data. New York: Springer; 2011.

    Google Scholar 

  30. Sorrentino P, D’Angelo S, Ferbo U, Micheli P, Bracigliano A, Vecchione R. Liver iron excess in patients with hepatocellular carcinoma developed on non-alcoholic steato-hepatitis. J Hepatol. 2009;50:351–357.

    Article  CAS  PubMed  Google Scholar 

  31. Starley BQ, Calcagno CJ, Harrison SA. Nonalcoholic fatty liver disease and hepatocellular carcinoma: a weighty connection. Hepatology. 2010;51:1820–1832.

    Article  PubMed  Google Scholar 

  32. Starmann J, Falth M, Spindelbock W, et al. Gene expression profiling unravels cancer-related hepatic molecular signatures in steatohepatitis but not in steatosis. PLoS One. 2012;7:e46584.

    Google Scholar 

  33. Takagi H, Sasaki S, Suzuki H, et al. Frequent epigenetic inactivation of SFRP genes in hepatocellular carcinoma. J Gastroenterol. 2008;43:378–389.

    Article  PubMed  Google Scholar 

  34. Tan MG, Kumarasinghe MP, Wang SM, Ooi LL, Aw SE, Hui KM. Modulation of iron-regulatory genes in human hepatocellular carcinoma and its physiological consequences. Exp Biol Med (Maywood). 2009;234:693–702.

    Article  CAS  Google Scholar 

  35. Thompson MD, Monga SP. WNT/beta-catenin signaling in liver health and disease. Hepatology. 2007;45:1298–1305.

    Article  CAS  PubMed  Google Scholar 

  36. Valenti L, Swinkels DW, Burdick L, et al. Serum ferritin levels are associated with vascular damage in patients with nonalcoholic fatty liver disease. Nutr Metab Cardiovasc Dis. 2011;21:568–575.

    Article  CAS  PubMed  Google Scholar 

  37. Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM. Genomics and signaling pathways in hepatocellular carcinoma. Semin Liver Dis. 2007;27:55–76.

    Article  CAS  PubMed  Google Scholar 

  38. Yamamoto Y, Sakamoto M, Fujii G, et al. Overexpression of orphan G-protein-coupled receptor, Gpr49, in human hepatocellular carcinomas with beta-catenin mutations. Hepatology. 2003;37:528–533.

    Article  CAS  PubMed  Google Scholar 

  39. Yau TO, Chan CY, Chan KL, et al. HDPR1, a novel inhibitor of the WNT/beta-catenin signaling, is frequently downregulated in hepatocellular carcinoma: involvement of methylation-mediated gene silencing. Oncogene. 2005;24:1607–1614.

    Article  CAS  PubMed  Google Scholar 

  40. Younossi ZM, Gorreta F, Ong JP, et al. Hepatic gene expression in patients with obesity-related non-alcoholic steatohepatitis. Liver Int. 2005;25:760–771.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank the National Institutes of Health-funded Liver Tissue Cell Distribution System liver tissue samples. In particular, we thank Marion Namenwirth (University of Minnesota), Melissa Thompson (Virginia Commonwealth University), and Dr. Stephen C. Strom and Kenneth Dorko (University of Pittsburgh). Support for this work was provided by the National Institute of Health Grant [DK068039], [ES006694], [HD062489]; the NIAID grant AI083927; the National Institute of Environmental Health Science Toxicology Training Grant [ES007091]; the Liver Tissue Cell Distribution System; National Institute of Health Contract [NO1-DK-7-00041-HHSN267200700004C]; and AVOZ50510513 from the Academy of Sciences of the Czech Republic.

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Correspondence to Nathan J. Cherrington.

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Clarke, J.D., Novak, P., Lake, A.D. et al. Characterization of Hepatocellular Carcinoma Related Genes and Metabolites in Human Nonalcoholic Fatty Liver Disease. Dig Dis Sci 59, 365–374 (2014). https://doi.org/10.1007/s10620-013-2873-9

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  • DOI: https://doi.org/10.1007/s10620-013-2873-9

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