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Digestive Diseases and Sciences

, Volume 53, Issue 3, pp 614–621 | Cite as

Influence of Peroxisome Proliferator-activated Receptor (PPAR)γ Plo12Ala Polymorphism as a Shared Risk Marker for Both Gastric Cancer and Impaired Fasting Glucose (IFG) in Japanese

  • Tomomitsu TaharaEmail author
  • Tomiyasu Arisawa
  • Tomoyuki Shibata
  • Masakatsu Nakamura
  • Fangyu Wang
  • Naoko Maruyama
  • Yoshio Kamiya
  • Masahiko Nakamura
  • Hiroshi Fujita
  • Mitsuo Nagasaka
  • Masami Iwata
  • Kazuya Takahama
  • Makoto Watanabe
  • Ichiro Hirata
  • Hiroshi Nakano
Original Paper

Abstract

Activation of peroxisome proliferator-activated receptor γ (PPARγ) has been shown to inhibit the proliferation of gastric cancer cells. A common polymorphism at codon 12 of this gene (Pro12Ala) has been shown to confer protection against diabetes and colorectal cancer. We investigated the influence of PPARγ gene Plo12Ala polymorphism on the risk of gastric cancer and on the severity of Helicobacter pylori-induced gastritis as well as impaired fasting glucose (IFG) in Japanese. About 215 patients with gastric cancer (GC) and 201 patients without GC enrolled in this study. Plo12Ala polymorphism of PPARγ was investigated by PCR-RFLP in all of the subjects. The gastritis score of noncancerous antral mucosa was calculated by the updated Sydney system. The diagnosis of IFG was based on repeated evidence of serum fasting glucose (SFG) concentration of greater than or equal to 110 mg/dl. The Plo12Ala genotype of PPARγ showed a significantly higher frequency in GC patients than in controls (OR = 2.43; 95%CI = 1.04–5.67). In contrast, the Plo12Ala genotype held a lower risk of IFG (OR = 0.33; 95%CI = 0.13–0.83). The same genotype was associated with an increased risk of non-cardiac gastric cancer (OR = 2.39; 95%CI = 1.02–5.65), lower third gastric cancer (OR = 3.56; 95%CI = 1.31–9.71), advanced cancer (OR = 2.93; 95%CI = 1.13–7.58), and Lauren’s intestinal cancer (OR = 2.94; 95%CI = 1.13–7.66). Among 151 gastric cancer subjects, the atrophy and metaplasia scores of the antral mucosa adjacent to cancer showed a tendency to be higher in those with the12Ala allele. Our study suggests that the PPARγ Pro12Ala polymorphism may be a shared risk marker of both IFG and gastric cancer in Japanese.

Keywords

Gastric cancer Peroxisome proliferator-activated receptor (PPAR)γ Polymorphism Impaired fasting glucose (IFG) 

References

  1. 1.
    Murray CJ, Lopez AD (1997) Mortality by cause for eight regions of the world: global burden of disease study. Lancet 349:1269–1976PubMedCrossRefGoogle Scholar
  2. 2.
    Parkin DM, Bray F, Ferlay J, Pisani P (2001) Estimating the world cancer burden: Globocan 2000. Int J Cancer 94:153–156PubMedCrossRefGoogle Scholar
  3. 3.
    IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, Lyon (1994) Schistosomes, liver flukes, Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 61:1–241Google Scholar
  4. 4.
    Mangelsdorf DJ, Thummel C, Beato M, Herrlich P, Schutz G, Umesono K, Blumberg B, Kastner P, Mark M, Chambon P, Evans RM (1995) The nuclear receptor superfamily: the second decade. Cell 83:835–839PubMedCrossRefGoogle Scholar
  5. 5.
    Kliewer SA, Willson TM (1998) The nuclear receptor PPARgamma—bigger than fat. Curr Opin Genet Dev 8:576–581PubMedCrossRefGoogle Scholar
  6. 6.
    Corton JC, Anderson SP, Stauber A (2000) Central role of peroxisome proliferator-activated receptors in the actions of peroxisome proliferators. Annu Rev Pharmacol Toxicol 40:491–518PubMedCrossRefGoogle Scholar
  7. 7.
    Kliewer SA, Lehmann JM, Willson TM (1999) Orphan nuclear receptors: shifting endocrinology into reverse. Science 284:757–760PubMedCrossRefGoogle Scholar
  8. 8.
    Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W (1992) Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68:879–887PubMedCrossRefGoogle Scholar
  9. 9.
    Auwerx J (2002) Nuclear receptors. I. PPAR gamma in the gastrointestinal tract: gain or pain? Am J Physiol Gastrointest Liver Physiol 282:G581–585PubMedGoogle Scholar
  10. 10.
    Takahashi N, Okumura T, Motomura W, Fujimoto Y, Kawabata I, Kohgo Y (1999) Activation of PPARgamma inhibits cell growth and induces apoptosis in human gastric cancer cells. FEBS Lett 455:135–139PubMedCrossRefGoogle Scholar
  11. 11.
    Gupta RA, Polk DB, Krishna U, Israel DA, Yan F, DuBois RN, Peek RM Jr (2001) Activation of peroxisome proliferator-activated receptor gamma suppresses nuclear factor kappa B-mediated apoptosis induced by Helicobacter pylori in gastric epithelial cells. J Biol Chem 276:31059–31066PubMedCrossRefGoogle Scholar
  12. 12.
    Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J Shuldiner AR (1997) Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun 241:270–274PubMedCrossRefGoogle Scholar
  13. 13.
    Deeb SS, Fajas L, Nemoto M, Pihlajamaki J, Mykkanen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J (1998) A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet 20:284–287PubMedCrossRefGoogle Scholar
  14. 14.
    Mori H, Ikegami H, Kawaguchi Y, Seino S, Yokoi N, Takeda J, Inoue I, Seino Y, Yasuda K, Hanafusa T, Yamagata K, Awata T, Kadowaki T, Hara K, Yamada N, Gotoda T, Iwasaki N, Iwamoto Y, Sanke T, Nanjo K, Oka Y, Matsutani A, Maeda E, Kasuga M (2000) The Pro12 → Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. Diabetes 50:891–894CrossRefGoogle Scholar
  15. 15.
    Hara K, Okada T, Tobe K, Yasuda K, Mori Y, Kadowaki H, Hagura R, Akanuma Y, Kimura S, Ito C, Kadowaki T (2000) The Pro12Ala polymorphism in PPAR gamma2 may confer resistance to type 2 diabetes. Biochem Biophys Res Commun 271:212–216PubMedCrossRefGoogle Scholar
  16. 16.
    Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES (2000) The common PPARγ Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet 26:76–80PubMedCrossRefGoogle Scholar
  17. 17.
    Landi S, Moreno V, Gioia-Patricola L (2003) Association of common polymorphisms in inflammatory genes interleukin (IL)6, IL8, tumor necrosis factor α, NFKB1, and peroxisome proliferator-activated receptor γ with colorectal cancer. Cancer Res 63:3560–3566PubMedGoogle Scholar
  18. 18.
    Murtaugh MA, Ma KN, Caan BJ, Sweeney C, Wolff R, Samowitz WS, Potter JD, Slattery ML (2005) Interactions of peroxisome proliferator-activated receptor {gamma} and diet in etiology of colorectal cancer. Cancer Epidemiol Biomarkers Prev 14:1224–1229PubMedCrossRefGoogle Scholar
  19. 19.
    Liao SY, Zeng ZR, Leung WK, Zhou SZ, Chen B, Sung JJ, Hu PJ (2006) Peroxisome proliferator-activated receptor-gamma Pro12Ala polymorphism, Helicobacter pylori infection and non-cardia gastric carcinoma in Chinese. Aliment Pharmacol Ther 23:289–294PubMedCrossRefGoogle Scholar
  20. 20.
    Lauren P (1965) The two histrogical main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49PubMedGoogle Scholar
  21. 21.
    Dixon MF, Genta RM, Yardley JH, Correa P (1996) Classification and grading of gastritis. The updated Sydney System. International Workshop on the Histopathology of Gastritis, Houston 1994. Am J Surg Pathol 20:1161–1181PubMedCrossRefGoogle Scholar
  22. 22.
    Hara M, Alcoser SY, Qaadir A, Beiswenger KK, Cox NJ, Ehrmann DA (2002) Insulin resistance is attenuated in women with polycystic ovary syndrome with the Pro(12)Ala polymorphism in the PPARgamma gene. J Clin Endocrinol Metab 87:772–775PubMedCrossRefGoogle Scholar
  23. 23.
    Mori Y, Kim-Motoyama H, Katakura T, Yasuda K, Kadowaki H, Beamer BA, Shuldiner AR, Akanuma Y, Yazaki Y, Kadowaki T (1998) Effect of the Pro12Ala variant of the human peroxisome proliferator-activated receptor γ2 gene on adipocity, fat distribution, and insulin sensitivity in Japanese men. Biochem Biophys Res Commun 252:195–198CrossRefGoogle Scholar
  24. 24.
    Lu J, Imamura K, Nomura S, Mafune K, Nakajima A, Kadowaki T, Kubota N, Terauchi Y, Ishii G, Ochiai A, Esumi H, Kaminishi M (2005) Chemopreventive effect of peroxisome proliferator-activated receptor gamma on gastric carcinogenesis in mice. Cancer Res 65:4769–4774PubMedCrossRefGoogle Scholar
  25. 25.
    Jiang C, Ting AT, Seed B (1998) PPAR-gamma agonists inhibit production of monocyte inflammatory cytokines. Nature 391:82–86PubMedCrossRefGoogle Scholar
  26. 26.
    Ricote M, Li AC, Willson TM, Kelly CJ, Glass CK (1998) The peroxisome proliferator-activated receptor-gamma is a negative regulator of macrophage activation. ature 391:79–82Google Scholar
  27. 27.
    Slomiany BL, Slomiany A (2002) Suppression of gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide by peroxisome proliferator-activated receptor gamma activation. IUBMB Life 53:303–308PubMedCrossRefGoogle Scholar
  28. 28.
    Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M (1975) A model for gastric cancer epidemiology. Lancet 12:58–60CrossRefGoogle Scholar
  29. 29.
    Correa P (1995) Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol Suppl 1:S37–43Google Scholar
  30. 30.
    Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345:784–789PubMedCrossRefGoogle Scholar
  31. 31.
    Gralinski MR, Rowse PE, Breider MA (1998) Effects of troglitazone and pioglitazone on cytokine-mediated endothelial cell proliferation in vitro. J Cardiovasc Pharmacol 31:909–913PubMedCrossRefGoogle Scholar
  32. 32.
    Xin X, Yang S, Kowalski J, Gerritsen ME (1999) Peroxisome proliferator-activated receptor gamma ligands are potent inhibitors of angiogenesis in vitro and in vivo. J Biol Chem 13:9116–9121CrossRefGoogle Scholar
  33. 33.
    Sasaki T, Fujii K, Yoshida K, Shimura H, Sasahira T, Ohmori H, Kuniyasu H (2006) Peritoneal metastasis inhibition by linoleic acid with activation of PPARgamma in human gastrointestinal cancer cells. Virchows Arch 448:422–427PubMedCrossRefGoogle Scholar
  34. 34.
    Badawi AF, Eldeen MB, Liu Y, Ross EA, Badr MZ (2004) Inhibition of rat mammary gland carcinogenesis by simultaneous targeting of cyclooxygenase-2 and peroxisome proliferator-activated receptor gamma. Cancer Res 64:1181–1189PubMedCrossRefGoogle Scholar
  35. 35.
    Terashita Y, Sasaki H, Haruki N, Nishiwaki T, Ishiguro H, Shibata Y, Kudo J,Konishi S, Kato J, Koyama H, Kimura M, Sato A, Shinoda N, Kuwabara Y, Fujii Y (2002) Decreased peroxisome proliferator-activated receptor gamma gene expression is correlated with poor prognosis in patients with esophageal cancer. Jpn J Clin Oncol 32:238–243PubMedCrossRefGoogle Scholar
  36. 36.
    El-Omar EM, Penman ID, Ardill JE, Chittajallu RS, Howie C, McColl KE (1995) Helicobacter pylori infection and abnormalities of acid secretion in patients with duodenal ulcer disease. Gastroenterology 109:681–691PubMedCrossRefGoogle Scholar
  37. 37.
    Lee S, Iida M, Yao T, Shindo S, Nose Y, Akazawa K, Okabe H, Fujishima M (1990) Risk of gastric cancer in patients with non-surgically treated peptic ulcer. Scand J Gastroenterol 25:1223–1226PubMedCrossRefGoogle Scholar
  38. 38.
    Kekki M, Samloff IM, Varis K, Ihamaki T (1991) Serum pepsinogen I and serum gastrin in the screening of severe atrophic corpus gastritis. Scand J Gastroenterol 186 Suppl:109–116CrossRefGoogle Scholar
  39. 39.
    Yen CJ, Beamer BA, Negri C, Silver K, Brown KA, Yarnall DP, Burns DK, Roth J, Shuldiner AR (1997) Molecular scanning of the human peroxisome proliferator activated receptor gamma (hPPAR gamma) gene in diabetic Caucasians: identification of a Pro12Ala PPAR gamma 2 missense mutation. Biochem Biophys Res Commun 241:270–274PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Tomomitsu Tahara
    • 1
    Email author
  • Tomiyasu Arisawa
    • 1
  • Tomoyuki Shibata
    • 1
  • Masakatsu Nakamura
    • 1
  • Fangyu Wang
    • 1
  • Naoko Maruyama
    • 1
  • Yoshio Kamiya
    • 1
  • Masahiko Nakamura
    • 1
  • Hiroshi Fujita
    • 1
  • Mitsuo Nagasaka
    • 1
  • Masami Iwata
    • 1
  • Kazuya Takahama
    • 1
  • Makoto Watanabe
    • 1
  • Ichiro Hirata
    • 1
  • Hiroshi Nakano
    • 2
  1. 1.Department of GastroenterologyFujita Health University School of MedicineToyoakeJapan
  2. 2.Fujita Health UniversityToyoakeJapan

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