Molecular Biology Reports

, Volume 39, Issue 3, pp 2843–2849 | Cite as

Induction of cell differentiation and promotion of endocan gene expression in stomach cancer by melatonin

  • Sumei Zhang
  • Li Zuo
  • Shuyu Gui
  • Qing Zhou
  • Wei Wei
  • Yuan WangEmail author


The pineal hormone melatonin has been shown to have anticancer therapeutic properties in patients with gastric cancer, the mechanisms, however, remain largely unknown. The present study examined the effects of melatonin on cell differentiation related factors, namely, endocan, alkaline phosphatase, and lactate dehydrogenase, in gastric adenocarcinoma cell line SGC7901. Expression of endocan was significantly decreased in tissue of gastric cancer as compared to normal stomach tissue, as determined by immunohistochemical staining, and there is correlation between the degree of the decrease of endocan expression and the degree of differentiation of the cancer. Treatment of cultured gastric adenocarcinoma cells with 10−4 mol/l melatonin significantly increased the gene expression of endocan and down-regulated the activity of alkaline phosphatase and lactate dehydrogenase, two enzymes that promote de-differentiation in gastric tissue; and there was a negative correlation between the level of endocan expression and the activities of differentiation marker enzymes in the melatonin treated cancer cells. Gastric cancer cells treated with melatonin show more differentiated morphologic phenotype as compared the untreated cells. The findings indicate that melatonin may play its anticancer role in gastric adenocarcinoma by acting as a differentiation inducer.


Gastric cancer SGC7901 Differentiation Endocan 



This study was supported by Natural Science Foundation of Anhui Province (No. 090413116) and National Natural Science Foundation of China (No. 30971226).


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55:74–108PubMedCrossRefGoogle Scholar
  2. 2.
    Zhang Q, Li Y, Li X, Zhou W, Shi B, Chen H, Yuan W (2009) PARP-1 Val762Ala polymorphism, CagA + H. pylori infection and risk for gastric cancer in Han Chinese population. Mol Biol Rep 36:1461–1467PubMedCrossRefGoogle Scholar
  3. 3.
    Hou R, Cao B, Chen Z, Li Y, Ning T, Li C, Xu C, Chen Z (2010) Association of cytotoxic T lymphocyte-associated antigen-4 gene haplotype with the susceptibility to gastric cancer. Mol Biol Rep 37:515–520PubMedCrossRefGoogle Scholar
  4. 4.
    Lissoni P, Brivio F, Ardizzoia A, Tancini G, Barni S (1993) Subcutaneous therapy with low-dose interleukin-2 plus the neurohormone melatonin in metastatic gastric cancer patients with low performance status. Tumori 79:401–404PubMedGoogle Scholar
  5. 5.
    Alberti C (1958) Melatonin: the first hormone isolated from the pineal body. Farmaco Sci 13:604–605PubMedGoogle Scholar
  6. 6.
    Berra B, Rizzo AM (2009) Melatonin: circadian rhythm regulator, chronobiotic, antioxidant and beyond. Clin Dermatol 27:202–209PubMedCrossRefGoogle Scholar
  7. 7.
    Cardinali DP, Esquifino AI, Srinivasan V, Pandi-Perumal SR (2008) Melatonin and the immune system in aging. Neuroimmunomodulation 5:272–278CrossRefGoogle Scholar
  8. 8.
    Ambriz-Tututi M, Rocha-González HI, Cruz SL, Granados-Soto V (2009) Melatonin: a hormone that modulates pain. Life Sci 84:489–498PubMedCrossRefGoogle Scholar
  9. 9.
    Srinivasan V, Pandi-Perumal SR, Trahkt I, Spence DW, Poeggeler B, Hardeland R, Cardinali DP (2009) Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci 119:821–846PubMedCrossRefGoogle Scholar
  10. 10.
    Bubenik GA, Blask DE, Brown GM, Maestroni GJ, Pang SF, Reiter RJ, Viswanathan M, Zisapel N (1998) Prospects of the clinical utilization of melatonin. Biol Signals Recept 7:195–219PubMedCrossRefGoogle Scholar
  11. 11.
    Lissoni P, Barni S, Tancini G, Ardizzoia A, Rovelli F, Cazzaniga M, Brivio F, Piperno A, Aldeghi R, Fossati D (1993) Immunotherapy with subcutaneous low-dose interleukin-2 and the pineal indole melatonin as a new effective therapy in advanced cancers of the digestive tract. Br J Cancer 67:1404–1407PubMedCrossRefGoogle Scholar
  12. 12.
    Lissoni P, Brivio F, Fumagalli L, Messina G, Vigoré L, Parolini D, Colciago M, Rovelli F (2008) Neuroimmunomodulation in medical oncology: application of psychoneuroimmunology with subcutaneous low-dose IL-2 and the pineal hormone melatonin in patients with untreatable metastatic solid tumors. Anticancer Res 28:1377–1381PubMedGoogle Scholar
  13. 13.
    Martín-Renedo J, Mauriz JL, Jorquera F, Ruiz-Andrés O, González P, González-Gallego J (2008) Melatonin induces cell cycle arrest and apoptosis in hepatocarcinoma HepG2 cell line. J Pineal Res 45:532–540PubMedCrossRefGoogle Scholar
  14. 14.
    Korkmaz A, Tamura H, Manchester LC, Ogden GB, Tan DX, Reiter RJ (2009) Combination of melatonin and a peroxisome proliferator-activated receptor-gamma agonist induces apoptosis in a breast cancer cell line. J Pineal Res 46:115–116PubMedCrossRefGoogle Scholar
  15. 15.
    Bechard D, Gentina T, Delehedde M, Scherperee Al, Lyon M, Aumercier M, Vazeux R, Richet C, Degand P, Jude B, Janin A, Fernig DG, Tonnel AB, Lassalle P (2001) Endocan is a novel chondroitin sulfate/dermatan sulfate proteoglycan that promotes hepatocyte growth factor/scatter factor mitogenic activity. J Biol Chem 276:48341–48349PubMedGoogle Scholar
  16. 16.
    Béchard D, Scherperee Al, Hammad H, Gentina T, Tsicopoulos A, Aumercier M, Pestel J, Dessaint JP, Tonnel AB, Lassalle P (2001) Human endothelial-cell specific molecule-1 binds directly to the integrin CD11a/CD18 (LFA-1) and blocks binding to intercellular adhesion molecule-1. J Immunol 167:3099–3106PubMedGoogle Scholar
  17. 17.
    Chen LY, Liu X, Wang SL, Qin CY (2010) Over-expression of the Endocan gene in endothelial cells from hepatocellular carcinoma is associated with angiogenesis and tumour invasion. J Int Med Res 38:498–510PubMedGoogle Scholar
  18. 18.
    Perey L, Benhattar J, Peters R, Jaunin P, Leyvraz S (2001) High tumour contamination of leukaphereses in patients with small cell carcinoma of the lung: a comparison of immunocytochemistry and RT-PCR. Br J Cancer 85:1713–1721PubMedCrossRefGoogle Scholar
  19. 19.
    Leroy X, Aubert S, Zini L, Franquet H, Kervoaze G, Villers A, Delehedde M, Copin MC, Lassalle P (2010) Vascular endocan (ESM-1) is markedly overexpressed in clear cell renal cell carcinoma. Histopathology 56:80–187CrossRefGoogle Scholar
  20. 20.
    Maurage CA, Adam E, Minéo JF, Sarrazin S, Debunne M, Siminski RM, Baroncini M, Lassalle P, Blond S, Delehedde M (2009) Endocan expression and localization in human glioblastomas. J Neuropathol Exp Neurol 68:633–641PubMedCrossRefGoogle Scholar
  21. 21.
    Grigoriu BD, Depontieu F, Scherpereel A, Gourcerol D, Devos P, Ouatas T, Lafitte JJ, Copin MC, Tonnel AB, Lassalle P (2006) Endocan expression and relationship with survival in human non-small cell lung cancer. Clin Cancer Res 12:4575–4582PubMedCrossRefGoogle Scholar
  22. 22.
    Huang GW, Tao YM, Ding X (2009) Endocan expression correlated with poor survival in human hepatocellular carcinoma. Dig Dis Sci 54:389–394PubMedCrossRefGoogle Scholar
  23. 23.
    Zuo L, Zhang SM, Hu RL, Zhu HQ, Zhou Q, Gui SY, Wu Q, Wang Y (2008) Correlation between expression and differentiation of endocan in colorectal cancer. World J Gastroenterol 14:4562–4568PubMedCrossRefGoogle Scholar
  24. 24.
    Herz F, Halwer M (1990) Differential effects of sodium butyrate and hyperosolality on the modulation of alkaline phosphatases of LoVo cells. Exp Cell Res 188:50–54PubMedCrossRefGoogle Scholar
  25. 25.
    Honma Y, Takenaga K, Kasukabe T, Hozumi M (1980) Induction of differentiation of cultured human promyelocytic leukemia cells by retinoids. Biochem Biophys Res Commun 95:507–512PubMedCrossRefGoogle Scholar
  26. 26.
    Fishman WH (1992) Recent developments in alkaline phosphatase research. Clin Chem 38:2484PubMedGoogle Scholar
  27. 27.
    Carda-Abella P, Perez-Cuadrado S, Lara-Baruque S, Gil-Grande L, Nuñez-Puertas A (1982) LDH isoenzyme patterns in tumors, polyps, and uninvolved mucosa of human cancerous colon. Cancer 49:80–83PubMedCrossRefGoogle Scholar
  28. 28.
    Nowak G, Griffin JM, Schnellmann RG (1996) Hypoxia and proliferation are primary responsible for induction of lactate dehydrogenase activity in cultured cells. J Toxicol Environ Health 46:439–452Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2011

Authors and Affiliations

  • Sumei Zhang
    • 1
    • 2
    • 4
  • Li Zuo
    • 1
    • 2
    • 4
  • Shuyu Gui
    • 3
  • Qing Zhou
    • 2
    • 4
  • Wei Wei
    • 1
  • Yuan Wang
    • 1
    • 2
    • 4
    Email author
  1. 1.Institute of Clinical PharmacologyAnhui Medical UniversityHefeiPeople’s Republic of China
  2. 2.Laboratory of Molecular Biology and Department of BiochemistryAnhui Medical UniversityHefeiPeople’s Republic of China
  3. 3.Department of Respiratory DiseaseAnhui Medical UniversityHefeiPeople’s Republic of China
  4. 4.Key Laboratory of Anti-inflammatory and Immunological Pharmacology, Ministry of Education and Key Laboratory of Gene Resource Utilization for Severe Disease of Anhui ProvinceAnhui Medical UniversityHefeiPeople’s Republic of China

Personalised recommendations