Skip to main content
Log in

l-Dopa decarboxylase (DDC) constitutes an emerging biomarker in predicting patients’ survival with stomach adenocarcinomas

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Purpose

Stomach adenocarcinoma represents a major health problem and is regarded as the second commonest cause of cancer-associated mortality, universally, since it is still difficult to be perceived at a curable stage. Several lines of evidence have pointed out that the expression of l-Dopa decarboxylase (DDC) gene and/or protein becomes distinctively modulated in several human neuroendocrine neoplasms as well as adenocarcinomas.

Methods

In order to elucidate the clinical role of DDC on primary gastric adenocarcinomas, we determined qualitatively and quantitatively the mRNA levels of the gene with regular PCR and real-time PCR by using the comparative threshold cycle method, correspondingly, and detected the expression of DDC protein by immunoblotting in cancerous and normal stomach tissue specimens.

Results

A statistically significant association was disclosed between DDC expression and gastric intestinal histotype as well as tumor localization at the distal third part of the stomach (p = 0.025 and p = 0.029, respectively). Univariate and multivariate analyses highlighted the powerful prognostic importance of DDC in relation to disease-free survival and overall survival of gastric cancer patients. According to Kaplan–Meier curves, the relative risk of relapse was found to be decreased in DDC-positive (p = 0.031) patients who, also, exhibited higher overall survival rates (p = 0.016) than those with DDC-negative tumors.

Conclusions

This work is the first to shed light on the potential clinical usefulness of DDC, as an efficient tumor biomarker in gastric cancer. The provided evidence underlines the propitious predictive value of DDC expression in the survival of stomach adenocarcinoma patients.

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

Access this article

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

Similar content being viewed by others

References

  • Akoh JA, Macintyre IM (1992) Improving survival in gastric cancer: review of 5-year survival rates in English language publications from 1970. Br J Surg 79(4):293–299

    Article  PubMed  CAS  Google Scholar 

  • Avgeris M, Koutalellis G, Fragoulis EG, Scorilas A (2008) Expression analysis and clinical utility of l-Dopa decarboxylase (DDC) in prostate cancer. Clin Biochem 41(14–15):1140–1149. doi:10.1016/j.clinbiochem.2008.04.026

    Article  PubMed  CAS  Google Scholar 

  • Barranco SC, Townsend CM Jr, Casartelli C, Macik BG, Burger NL, Boerwinkle WR, Gourley WK (1983) Establishment and characterization of an in vitro model system for human adenocarcinoma of the stomach. Cancer Res 43(4):1703–1709

    PubMed  CAS  Google Scholar 

  • Batteiger B, Newhall WJT, Jones RB (1982) The use of Tween 20 as a blocking agent in the immunological detection of proteins transferred to nitrocellulose membranes. J Immunol Methods 55(3):297–307

    Article  PubMed  CAS  Google Scholar 

  • Bradford MM (1976) A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Anal Biochem 72:248–254

    Article  PubMed  CAS  Google Scholar 

  • Camp RL, Dolled-Filhart M, Rimm DL (2004) X-tile: a new bio-informatics tool for biomarker assessment and outcome-based cut-point optimization. Clin Cancer Res 10(21):7252–7259. doi:10.1158/1078-0432.CCR-04-0713

    Article  PubMed  CAS  Google Scholar 

  • Cervantes A, Rodriguez Braun E, Perez Fidalgo A, Chirivella Gonzalez I (2007) Molecular biology of gastric cancer. Clin Transl Oncol 9(4):208–215

    Article  PubMed  CAS  Google Scholar 

  • Chakroborty D, Sarkar C, Mitra RB, Banerjee S, Dasgupta PS, Basu S (2004) Depleted dopamine in gastric cancer tissues: dopamine treatment retards growth of gastric cancer by inhibiting angiogenesis. Clin Cancer Res 10(13):4349–4356. doi:10.1158/1078-0432.CCR-04-0059

    Article  PubMed  CAS  Google Scholar 

  • Chalatsa I, Nikolouzou E, Fragoulis EG, Vassilacopoulou D (2011) l-Dopa decarboxylase expression profile in human cancer cells. Mol Biol Rep 38(2):1005–1011. doi:10.1007/s11033-010-0196-x

    Article  PubMed  CAS  Google Scholar 

  • Craig SP, Thai AL, Weber M, Craig IW (1992) Localisation of the gene for human aromatic l-amino acid decarboxylase (DDC) to chromosome 7p13→p11 by in situ hybridisation. Cytogenet Cell Genet 61(2):114–116

    Article  PubMed  CAS  Google Scholar 

  • Ferlay J, Autier P, Boniol M, Heanue M, Colombet M, Boyle P (2007) Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol 18(3):581–592. doi:10.1093/annonc/mdl498

    Article  PubMed  CAS  Google Scholar 

  • Fox JG, Wang TC (2007) Inflammation, atrophy, and gastric cancer. J Clin Invest 117(1):60–69. doi:10.1172/JCI30111

    Article  PubMed  CAS  Google Scholar 

  • Gilbert J, Haber M, Bordow SB, Marshall GM, Norris MD (1999) Use of tumor-specific gene expression for the differential diagnosis of neuroblastoma from other pediatric small round-cell malignancies. Am J Pathol 155(1):17–21

    Article  PubMed  CAS  Google Scholar 

  • Hohenberger P, Gretschel S (2003) Gastric cancer. Lancet 362(9380):305–315

    Article  PubMed  Google Scholar 

  • Ichinose H, Sumi-Ichinose C, Ohye T, Hagino Y, Fujita K, Nagatsu T (1992) Tissue-specific alternative splicing of the first exon generates two types of mRNAs in human aromatic l-amino acid decarboxylase. Biochemistry 31(46):11546–11550

    Article  PubMed  CAS  Google Scholar 

  • Isobe K, Nakai T, Yukimasa N, Nanmoku T, Takekoshi K, Nomura F (1998) Expression of mRNA coding for four catecholamine-synthesizing enzymes in human adrenal pheochromocytomas. Eur J Endocrinol 138(4):383–387

    Article  PubMed  CAS  Google Scholar 

  • Jensen SM, Gazdar AF, Cuttitta F, Russell EK, Linnoila RI (1990) A comparison of synaptophysin, chromogranin, and l-dopa decarboxylase as markers for neuroendocrine differentiation in lung cancer cell lines. Cancer Res 50(18):6068–6074

    PubMed  CAS  Google Scholar 

  • Khushalani N (2008) Cancer of the esophagus and stomach. Mayo Clin Proc 83(6):712–722

    PubMed  Google Scholar 

  • Kokkinou I, Fragoulis EG, Vassilacopoulou D (2009) The U937 macrophage cell line expresses enzymatically active l-Dopa decarboxylase. J Neuroimmunol 216(1–2):51–58. doi:10.1016/j.jneuroim.2009.09.001

    Article  PubMed  CAS  Google Scholar 

  • Kontos CK, Papadopoulos IN, Fragoulis EG, Scorilas A (2010) Quantitative expression analysis and prognostic significance of l-DOPA decarboxylase in colorectal adenocarcinoma. Br J Cancer 102(9):1384–1390. doi:10.1038/sj.bjc.6605654

    Article  PubMed  CAS  Google Scholar 

  • Laemmli UK (1970) Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227(5259):680–685

    Article  PubMed  CAS  Google Scholar 

  • Lauren P (1965) The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49

    PubMed  CAS  Google Scholar 

  • Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25(4):402–408. doi:10.1006/meth.2001.1262

    Article  PubMed  CAS  Google Scholar 

  • Mappouras DG, Stiakakis J, Fragoulis EG (1990) Purification and characterization of l-dopa decarboxylase from human kidney. Mol Cell Biochem 94(2):147–156

    Article  PubMed  CAS  Google Scholar 

  • Murakami T (1971) Pathomorphological diagnosis. Definition and gross classification of early gastric cancer. Gann Monogr Cancer Res 11:53–55

    Google Scholar 

  • Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108

    Article  PubMed  Google Scholar 

  • Patsis C, Glyka V, Yiotakis I, Fragoulis EG, Scorilas A (2012) l-DOPA decarboxylase (DDC) expression status as a novel molecular tumor marker for diagnostic and prognostic purposes in laryngeal cancer. Transl Oncol 5(4):288–296

    PubMed  Google Scholar 

  • Sakakura C, Takemura M, Hagiwara A, Shimomura K, Miyagawa K, Nakashima S, Yoshikawa T, Takagi T, Kin S, Nakase Y, Fujiyama J, Hayasizaki Y, Okazaki Y, Yamagishi H (2004) Overexpression of dopa decarboxylase in peritoneal dissemination of gastric cancer and its potential as a novel marker for the detection of peritoneal micrometastases with real-time RT-PCR. Br J Cancer 90(3):665–671. doi:10.1038/sj.bjc.6601544

    Article  PubMed  CAS  Google Scholar 

  • Smith MG, Hold GL, Tahara E, El-Omar EM (2006) Cellular and molecular aspects of gastric cancer. World J Gastroenterol 12(19):2979–2990

    PubMed  CAS  Google Scholar 

  • Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T (1992) Molecular cloning of genomic DNA and chromosomal assignment of the gene for human aromatic l-amino acid decarboxylase, the enzyme for catecholamine and serotonin biosynthesis. Biochemistry 31(8):2229–2238

    Article  PubMed  CAS  Google Scholar 

  • Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG (2000) New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92(3):205–216

    Article  PubMed  CAS  Google Scholar 

  • Towbin H, Staehelin T, Gordon J (1979) Electrophoretic transfer of proteins from polyacrylamide gels to nitrocellulose sheets: procedure and some applications. Proc Natl Acad Sci USA 76(9):4350–4354

    Article  PubMed  CAS  Google Scholar 

  • Trager C, Vernby A, Kullman A, Ora I, Kogner P, Kagedal B (2008) mRNAs of tyrosine hydroxylase and dopa decarboxylase but not of GD2 synthase are specific for neuroblastoma minimal disease and predicts outcome for children with high-risk disease when measured at diagnosis. Int J Cancer 123(12):2849–2855. doi:10.1002/ijc.23846

    Article  PubMed  Google Scholar 

  • Vassilacopoulou D, Sideris DC, Vassiliou AG, Fragoulis EG (2004) Identification and characterization of a novel form of the human l-dopa decarboxylase mRNA. Neurochem Res 29(10):1817–1823

    Article  PubMed  CAS  Google Scholar 

  • Wanebo HJ, Kennedy BJ, Chmiel J, Steele G Jr, Winchester D, Osteen R (1993) Cancer of the stomach. A patient care study by the American College of Surgeons. Ann Surg 218(5):583–592

    Article  PubMed  CAS  Google Scholar 

  • Wittekind C, Greene FL, Hutter RVP, Klimpfinger M, Sobin LH (2005) TNM-Atlas, 5th edn. Springer, New York (UICC)

    Book  Google Scholar 

  • Yasui W, Sentani K, Motoshita J, Nakayama H (2006) Molecular pathobiology of gastric cancer. Scand J Surg 95(4):225–231

    PubMed  CAS  Google Scholar 

  • Zhu MY, Juorio AV (1995) Aromatic l-amino acid decarboxylase: biological characterization and functional role. Gen Pharmacol 26(4):681–696

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Bodossaki Foundation for the generous donation of the thermal cycler ABI Prism 7500.

Conflict of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Andreas Scorilas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Florou, D., Papadopoulos, I.N., Fragoulis, E.G. et al. l-Dopa decarboxylase (DDC) constitutes an emerging biomarker in predicting patients’ survival with stomach adenocarcinomas. J Cancer Res Clin Oncol 139, 297–306 (2013). https://doi.org/10.1007/s00432-012-1326-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-012-1326-8

Keywords

Navigation