Skip to main content

Advertisement

SpringerLink
Log in

Basic amino acids and dimethylarginines targeted metabolomics discriminates primary hepatocarcinoma from hepatic colorectal metastases

  • Original Article
  • Published:
Metabolomics Aims and scope Submit manuscript

Abstract

Hepatocellular carcinoma (HCC) is a very aggressive neoplasia requiring early and accurate diagnosis to improve patient outcomes with timely treatment. The liver is also very frequently colonized by metastases, and the most frequent differential diagnosis is HCC against intrahepatic cholangiocarcinoma or metastatic adenocarcinoma. Metabolomics is a powerful tool for identification of altered biomarkers in cancer, and to evaluate the efficacy of drug treatments. Here we analyzed by HILIC-MS/MS methylated arginines, basic amino acids (Arg, Cit, Orn), and their ratios in the extracts of primary HCC tissues, liver metastases from colorectal carcinoma (MET), cirrhotic related hepatitis-C-virus (CIR), and non-cirrhotic normal liver (NT) adjacent tissues. We found high levels of Arg (p < 0.0001) and Arg/Orn (p < 0.01) in MET compared to other tissues. In MET, compared to NT and CIR, Arg concentration was fivefold higher, while in HCC it was twofold higher. ADMA increased twofold compared to NT and CIR, while in HCC it was 50 % higher. Arg/Cit and ADMA/SDMA ratios were significantly higher in MET compared to NT and CIR (p < 0.005). Arg/Orn, Arg/Cit, and ADMA/SDMA ratios increased progressively from NT, CIR, HCC, to MET tissues. Arg/Cit correlated significantly with Arg/Orn ratios (r = 0.77; p < 0.0001), and discriminates tumor from non-tumor samples. In addition, the discriminant lactate/glucose ratio we previously found by NMR, also correlated significantly with the Arg levels (r = 0.64; p < 0.0001), and discriminated MET from all other tissues. The results indicated that Arg in MET is higher than other tissue classes, suggesting that, together with the lactate/glucose ratio, it can be considered a further biomarker for HCC-metastases differentiation.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  • Abdelmagid, S. A., Rickard, J. A., McDonald, W. J., Thomas, L. N., & Too, C. K. L. (2011). CAT-1-mediated arginine uptake and regulation of nitric oxide synthases for the survival of human breast cancer cell lines. Journal of Cellular Biochemistry, 112, 1084–1092.

    Article  CAS  PubMed  Google Scholar 

  • Abdelmagid, S. A., & Too, C. K. L. (2008). Prolactin and estrogen up-regulate carboxypeptidase-d to promote nitric oxide production and survival of MCF-7 breast cancer cells. Endocrinology, 149, 4821–4828.

    Article  CAS  PubMed  Google Scholar 

  • Atalay, G., Biganzoli, L., Renard, F., et al. (2003). Clinical outcome of breast cancer patients with liver metastases alone in the anthracycline-taxane era: A retrospective analysis of two prospective, randomised metastatic breast cancer trials. European Journal of Cancer, 39, 2439–2449.

    Article  CAS  PubMed  Google Scholar 

  • Beger, R. D. (2013). A review of applications of metabolomics in cancer. Metabolites, 3, 552–574.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Butler, E. B., Zhao, Y., Munoz-Pinedo, C., Lu, J., & Tan, M. (2013). Stalling the engine of resistance: Targeting cancer metabolism to overcome therapeutic resistance. Cancer Research, 73, 2709–2717.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Caso, G., McNurlan, M. A., McMillan, N. D., Eremin, O., & Garlick, P. J. (2004). Tumour cell growth in culture: Dependence on arginine. Clinical Science (Lond), 107, 371–379.

    Article  CAS  Google Scholar 

  • Chaerkady, R., Harsha, H. C., Nalli, A., et al. (2008). A quantitative proteomic approach for identification of potential biomarkers in hepatocellular carcinoma. Journal of Proteome Research, 7, 4289–4298.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chan, E. C., Koh, P. K., Mal, M., et al. (2009). Metabolic profiling of human colorectal cancer using high-resolution magic angle spinning nuclear magnetic resonance (HR-MAS NMR) spectroscopy and gas chromatography mass spectrometry (GC/MS). Journal of Proteome Research, 8, 352–361.

    Article  CAS  PubMed  Google Scholar 

  • Chen, T., Xie, G., Wang, X., et al. (2011). Serum and urine metabolite profiling reveals potential biomarkers of human hepatocellular carcinoma. Molecular and Cellular Proteomics,. doi:10.1074/mcp.M110.004945.

    Google Scholar 

  • Cheng, P. N., Lam, T. L., Lam, W. M., et al. (2007). Pegylated recombinant human arginase (rhArg-peg5,000mw) inhibits the in vitro and in vivo proliferation of human hepatocellular carcinoma through arginine depletion. Cancer Research, 67, 309–317.

    Article  CAS  PubMed  Google Scholar 

  • Colli, A., Fraquelli, M., Casazza, G., et al. (2006). Accuracy of ultrasonography, spiral CT, magnetic resonance, and alpha-fetoprotein in diagnosing hepatocellular carcinoma: A systematic review. The American Journal of Gastroenterology, 101, 513–523.

    Article  CAS  PubMed  Google Scholar 

  • Curado, M. P., Edwards, B., Shin, H. R., et al. (2007). Cancer incidence in five continents (Vol. IX, p. 160). Lyon: International Agency for Research on Cancer (IARC) Scientific Publications.

    Google Scholar 

  • D’Apolito, O., Paglia, G., Tricarico, F., et al. (2008). Development and validation of a fast quantitative method for plasma dimethylarginines analysis using liquid chromatography-tandem mass spectrometry. Clinical Biochemistry, 41, 1391–1395.

    Article  PubMed  Google Scholar 

  • Dhanasekaran, R., Limaye, A., & Cabrera, L. (2012). Hepatocellular carcinoma: current trends in worldwide epidemiology, risk factors, diagnosis, and therapeutics. Hepatic Medicine Evidence and Research, 4, 19–37.

    PubMed  PubMed Central  Google Scholar 

  • Dillon, B. J., Prieto, V. G., Curley, S. A., et al. (2004). Incidence and distribution of argininosuccinate synthetase deficiency in human cancers: a method for identifying cancers sensitive to arginine deprivation. Cancer, 100, 826–833.

    Article  CAS  PubMed  Google Scholar 

  • El-Serag, H. B., & Rudolph, K. L. (2007). Hepatocellular carcinoma: Epidemiology and molecular carcinogenesis. Gastroenterology, 132, 2557–2576.

    Article  CAS  PubMed  Google Scholar 

  • Ferlay, J., Shin, H. R., Bray, F., Forman, D., Mathers, C., & Parkin, D. M. (2010). Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. International Journal of Cancer, 127, 2893–2917.

    Article  CAS  PubMed  Google Scholar 

  • Forner, A., Llovet, J. M., & Bruix, J. (2012). Hepatocellular carcinoma. Lancet, 379, 1245–1255.

    Article  PubMed  Google Scholar 

  • Gardini, G., Cravanzola, C., Autelli, R., et al. (2003). Agmatine inhibits the proliferation of rat hepatoma cells by modulation of polyamine metabolism. Journal of Hepatology, 39, 793–799.

    Article  CAS  PubMed  Google Scholar 

  • Glazer, E. S., Piccirillo, M., Albino, V., et al. (2010). Phase II study of pegylated arginine deiminase for nonresectable and metastatic hepatocellular carcinoma. Journal of Clinical Oncology, 28, 2220–2226.

    Article  CAS  PubMed  Google Scholar 

  • Gonzalez, G. G., & Byus, C. V. (1991). Effect of dietary arginine restriction upon ornithine and polyamine metabolism during two-stage epidermal carcinogenesis in the mouse. Cancer Research, 51, 2932–2939.

    CAS  PubMed  Google Scholar 

  • Griffin, J. L., & Shockcor, J. P. (2004). Metabolic profiles of cancer cells. Nature Reviews Cancer, 4, 551–561.

    Article  CAS  PubMed  Google Scholar 

  • Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144, 646–674.

    Article  CAS  PubMed  Google Scholar 

  • Jemal, A., Bray, F., Center, M. M., Ferlay, J., Ward, E., & Forman, D. (2011). Global cancer statistics. CA: A Cancer Journal for Clinicians, 61, 69–90.

    Google Scholar 

  • Kassahun, W. T., Fangmann, J., Harms, J., Hauss, J., & Bartels, M. (2006). Liver resection and transplantation in the management of hepatocellular carcinoma: A review. Experimental and Clinical Transplantation, 4, 549–558.

    PubMed  Google Scholar 

  • Kenific, C. M., Thorburn, A., & Debnath, J. (2010). Autophagy and metastasis: another double-edged sword. Current Opinion in Cell Biology, 22, 241–245.

    Article  CAS  PubMed  Google Scholar 

  • Kim, Y. S., Maruvada, P., & Milner, J. A. (2008). Metabolomics in biomarker discovery: Future uses for cancer prevention. Future Oncology, 4, 93–102.

    Article  CAS  PubMed  Google Scholar 

  • Koppenol, W. H., Bounds, P. L., & Dang, C. V. (2011). Otto Warburg’s contributions to current concepts of cancer metabolism. Nature, 11, 325–337.

    CAS  Google Scholar 

  • Lam, T. L., Wonga, G. K. Y., Chong, H. C., et al. (2009). Recombinant human arginase inhibits proliferation of human hepatocellular carcinoma by inducing cell cycle arrest. Cancer Letters, 277, 91–100.

    Article  CAS  PubMed  Google Scholar 

  • Li, H., Zhou, Y., Zhao, A., et al. (2013). Asymmetric dimethylarginine attenuates serum starvation-induced apoptosis via suppression of the Fas (APO-1/CD95)/JNK (SAPK) pathway. Cell Death and Disease, 4, e830. doi:10.1038/cddis.2013.345.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lind, D. S. (2004). Arginine and cancer. The Journal of Nutrition, 134, 2837S–2841S.

    CAS  PubMed  Google Scholar 

  • Liu, S. Y., Zhang, R. L., Kang, H., Fan, Z. J., & Du, Z. (2013). Human liver tissue metabolic profiling research on hepatitis B virus-related hepatocellular carcinoma. World Journal of Gastroenterology, 19, 3423–3432.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Moinard, C., Cynober, L., & de Bandt, J. P. (2005). Polyamines: Metabolism and implications in human diseases. Clinical Nutrition, 24, 184–197.

    Article  CAS  PubMed  Google Scholar 

  • Morris, S. M, Jr. (2002). Regulation of the enzymes of the urea cycle and arginine metabolism. Annual Review of Nutrition, 22, 87–105.

    Article  CAS  PubMed  Google Scholar 

  • O’Connell, T. M. (2012). Recent advances in metabolomics in oncology. Bioanalysis, 4, 431–451.

    Article  PubMed  Google Scholar 

  • Paris, D., Melck, D., Stocchero, M., et al. (2010). Monitoring liver alterations during hepatic tumorigenesis by NMR profiling and pattern recognition. Metabolomics, 6, 405–416.

    Article  CAS  Google Scholar 

  • Pavlides, S., Tsirigos, A., Migneco, G., et al. (2010). The autophagic tumor stroma model of cancer. Role of oxidative stress and ketone production in fueling tumor cell metabolism. Cell Cycle, 9, 3485–3505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Satriano, J., Matsufuji, S., Murakami, Y., et al. (1998). Agmatine suppresses proliferation by frameshift induction of antizyme and attenuation of cellular polyamine levels. Journal of Biological Chemistry, 273, 15313–15316.

    Article  CAS  PubMed  Google Scholar 

  • Slebos, R. J., Jehmlich, N., Brown, B., et al. (2013). Proteomic analysis of oropharyngeal carcinomas reveals novel HPV-associated biological pathways. International Journal of Cancer, 132, 568–579.

    Article  CAS  PubMed  Google Scholar 

  • Syed, N., Langer, J., Janczar, K., et al. (2013). Epigenetic status of argininosuccinate synthetase and argininosuccinate lyase modulates autophagy and cell death in glioblastoma. Cell Death and Disease, 4, e458. doi:10.1038/cddis.2012.197.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Szlosarek, P. W., Klabatsa, A., Pallaska, A., et al. (2006). In vivo loss of expression of argininosuccinate synthetase in malignant pleural mesothelioma is a biomarker for susceptibility to arginine depletion. Clinical Cancer Research, 12, 7126–7131.

    Article  CAS  PubMed  Google Scholar 

  • Szuba, A., Chachaj, A., Wrobel, T., et al. (2008). Asymmetric dimethylarginine in hematological malignancies: a preliminary study. Leukemia & Lymphoma, 49, 2316–2320.

    Article  CAS  Google Scholar 

  • Teerlink, T. (2007). HPLC analysis of ADMA and other methylated l-arginine analogs in biological fluids. Journal of Chromatography B, 851, 21–29.

    Article  CAS  Google Scholar 

  • Vander Heiden, M. G. (2011). Targeting cancer metabolism: a therapeutic window opens. Nature Reviews Drug Discovery, 10, 671–684.

    Article  CAS  PubMed  Google Scholar 

  • Vermeersch, K. A., & Styczynski, M. P. (2013). Applications of metabolomics in cancer research. Journal of Carcinogenesis, 12, 9. doi:10.4103/1477-3163.113622.

    Article  PubMed  PubMed Central  Google Scholar 

  • World Health Organization. (2008). Mortality Database, WHO Statistical Information System. Retrieved from http://www.who.int/whosis/en/index1.html.

  • Wu, L., Li, L., Meng, S., Qi, R., Mao, Z., & Lin, M. (2013). Expression of argininosuccinate synthetase in patients with hepatocellular carcinoma. Journal of Gastroenterology and Hepatology, 28, 365–368.

    Article  CAS  PubMed  Google Scholar 

  • Yang, Y., Li, C., Nie, X., et al. (2007). Metabonomic studies of human hepatocellular carcinoma using high-resolution magic-angle spinning 1H NMR spectroscopy in conjunction with multivariate data analysis. Journal of Proteome Research, 6, 2605–2614.

    Article  CAS  PubMed  Google Scholar 

  • Yorimitsu, T., & Klionsky, D. J. (2005). Autophagy: Molecular machinery for self-eating. Cell Death and Differentiation, 12, 1542–1552.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yoshimatsu, M., Toyokawa, G., Hayami, S., et al. (2011). Dysregulationof PRMT1 and PRMT6, Type I arginine methyltransferases, is involved in various types of human cancers. International Journal of Cancer, 128, 562–573.

    Article  CAS  PubMed  Google Scholar 

  • Zhao, Y., Butler, E. B., & Tan, M. (2013). Targeting cellular metabolism to improve cancer therapeutics. Cell Death and Disease, 4, e532. doi:10.1038/cddis.2013.60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

We are grateful to patients for their important contribution to this study. Financial support was received from the University of Foggia (Premialità PRIN 2008).

Author information

Authors and Affiliations

  1. Dipartimento di Medicina Clinica e Sperimentale, Università degli Studi di Foggia, Foggia, Italy

    Oceania D’Apolito, Daniela Garofalo & Gaetano Corso

  2. Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, Naples, Italy

    Monica Gelzo

  3. Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Pozzuoli, NA, Italy

    Debora Paris, Dominique Melck & Andrea Motta

  4. Istituto di Chimica Biomolecolare, Consiglio Nazionale delle Ricerche, Sassari, SS, Italy

    Giuseppe Palmieri

  5. Istituto Nazionale per lo Studio e la Cura dei Tumori, Fondazione G. Pascale, Naples, Italy

    Rosa Calemma, Francesco Izzo & Giuseppe Castello

  6. Centro Ricerche Oncologiche di Mercogliano, Mercogliano, Italy

    Giuseppe Castello

Authors
  1. Oceania D’Apolito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniela Garofalo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Monica Gelzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Debora Paris
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Dominique Melck
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Rosa Calemma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Francesco Izzo
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Giuseppe Palmieri
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giuseppe Castello
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Andrea Motta
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Gaetano Corso
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Gaetano Corso.

Additional information

Oceania D’Apolito, Daniela Garofalo and Monica Gelzo contributed equally to this work.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (PDF 291 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

D’Apolito, O., Garofalo, D., Gelzo, M. et al. Basic amino acids and dimethylarginines targeted metabolomics discriminates primary hepatocarcinoma from hepatic colorectal metastases. Metabolomics 10, 1026–1035 (2014). https://doi.org/10.1007/s11306-014-0641-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11306-014-0641-2

Keywords

Search

Navigation