Peroxisome proliferator-activated receptor (PPAR ) is a nuclear receptor that is important in many physiological and pathological processes, such as lipid metabolism, insulin sensitivity, inflammation, cell proliferation, and carcinogenesis. Several studies have shown that PPAR plays an important role in gastric mucosal injury due to Helicobacter pylori (H. pylori). As H. pylori infection is the main etiologic factor in chronic gastritis and gastric cancer, understanding of the potential roles of PPAR in H. pylori infection may lead to the development of a therapeutic target. In this paper, the authors discuss the current knowledge on the role of PPAR in H. pylori infection and its related gastric carcinogenesis. 1. Introduction Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors and members of the nuclear hormone receptor superfamily. To date, three isoforms of PPARs (PPARα, PPARδ/β, and PPARγ) have been identified in mammals. PPAR forms a heterodimer with its preferential binding partner—retinoid X receptor (RXR). The function of PPAR/RXR heterodimer depends on its interactions with cofactor complexes (coactivators or corepressors). After activation by ligand, the PPAR/RXR heterodimer binds to specific DNA response elements called peroxisome proliferator response elements (PPREs) of the target genes. This results in transcription regulation of these genes (Figure 1) [1]. PPARs play a significant role in regulation of fatty acid oxidation and glucose utilization [2]. PPARγ was originally identified as a differentiation transcription factor for adipose tissue [3]. In addition, PPARγ is involved in the control of inflammation and glucose metabolism and participates in the processes of cellular proliferation, differentiation, and apoptosis [4]. Natural ligands for PPARγ are 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) and various polyunsaturated fatty acids [5, 6]. The insulin sensitizing thiazolinediones, which are selective ligands of the nuclear transcription factor PPARγ, were the first drugs used to treat insulin resistance in patients with type II diabetes [7]. Figure 1: A basic mechanism of PPAR signaling. Following ligand binding, PPAR forms a heterodimer with RXR, which binds to the PPRE of target genes and regulates the transcription of these genes. Helicobacter pylori (H. pylori) infection is the main etiologic agent in gastric inflammation, and longstanding infection with this organism is linked to gastric cancer [8]. Based on epidemiological studies, the risk of gastric cancer conferred by H. pylori
References
[1]
L. Michalik, B. Desvergne, and W. Wahli, “Peroxisome-proliferator-activated receptors and cancers: complex stories,” Nature Reviews Cancer, vol. 4, no. 1, pp. 61–70, 2004.
[2]
S. Kersten, B. Desvergne, and W. Wahli, “Roles of PPARS in health and disease,” Nature, vol. 405, no. 6785, pp. 421–424, 2000.
[3]
P. Tontonoz, E. Hu, and B. M. Spiegelman, “Stimulation of adipogenesis in fibroblasts by PPARγ2, a lipid-activated transcription factor,” Cell, vol. 79, no. 7, pp. 1147–1156, 1994.
[4]
P. Delerive, J. C. Fruchart, and B. Staels, “Peroxisome proliferator-activated receptors in inflammation control,” Journal of Endocrinology, vol. 169, no. 3, pp. 453–459, 2001.
[5]
B. M. Forman, P. Tontonoz, J. Chen, R. P. Brun, B. M. Spiegelman, and R. M. Evans, “15-Deoxy-Δ12, 14-prostaglandin J2 is a ligand for the adipocyte determination factor PPARγ,” Cell, vol. 83, no. 5, pp. 803–812, 1995.
[6]
S. A. Kliewer, J. M. Lenhard, T. M. Willson, I. Patel, D. C. Morris, and J. M. Lehmann, “A prostaglandin J2 metabolite binds peroxisome proliferator-activated receptor γ and promotes adipocyte differentiation,” Cell, vol. 83, no. 5, pp. 813–819, 1995.
[7]
J. M. Lehmann, L. B. Moore, T. A. Smith-Oliver, W. O. Wilkison, T. M. Willson, and S. A. Kliewer, “An antidiabetic thiazolidinedione is a high affinity ligand for peroxisome proliferator-activated receptor γ (PPARγ),” The Journal of Biological Chemistry, vol. 270, no. 22, pp. 12953–12956, 1995.
[8]
R. M. Peek Jr. and M. J. Blaser, “Helicobacter pylori and gastrointestinal tract adenocarcinomas,” Nature Reviews Cancer, vol. 2, no. 1, pp. 28–37, 2002.
[9]
V. Herrera and J. Parsonnet, “Helicobacter pylori and gastric adenocarcinoma,” Clinical Microbiology and Infection, vol. 15, no. 11, pp. 971–976, 2009.
[10]
D. B. Polk and R. M. Peek Jr., “Helicobacter pylori: gastric cancer and beyond,” Nature Reviews Cancer, vol. 10, no. 6, pp. 403–414, 2010.
[11]
O. Braissant, F. Foufelle, C. Scotto, M. Dau？a, and W. Wahli, “Differential expression of peroxisome proliferator-activated receptors (PPARs): tissue distribution of PPAR-α, -β, and -γ in the adult rat,” Endocrinology, vol. 137, no. 1, pp. 354–366, 1996.
[12]
P. C. Konturek, J. Kania, V. Kukharsky et al., “Implication of peroxisome proliferator-activated receptor γ and proinflammatory cytokines in gastric carcinogenesis: link to Helicobacter pylori-infection,” Journal of Pharmacological Sciences, vol. 96, no. 2, pp. 134–143, 2004.
[13]
S. H. Son, H. K. Kim, J. S. Ji et al., “Expression of peroxisome proliferator-activated receptor (PPAR) gamma in Helicobacter pylori-infected gastric epithelium,” The Korean Journal of Gastroenterology, vol. 49, no. 2, pp. 72–78, 2007, in Korean.
[14]
H. Haruna, T. Shimizu, Y. Ohtsuka et al., “Expression of COX-1, COX-2, and PPAR-γ in the gastric mucosa of children with Helicobacter pylori infection,” Pediatrics International, vol. 50, no. 1, pp. 1–6, 2008.
[15]
H. Inoue, T. Tanabe, and K. Umesono, “Feedback control of cyclooxygenase-2 expression through PPARγ,” The Journal of Biological Chemistry, vol. 275, no. 36, pp. 28028–28032, 2000.
[16]
P. C. Konturek, J. Kania, J. W. Konturek, A. Nikiforuk, S. J. Konturek, and E. G. Hahn, “H. pylori infection, atrophic gastritis, cytokines, gastrin, COX-2, PPARγ and impaired apoptosis in gastric carcinogenesis,” Medical Science Monitor, vol. 9, no. 7, pp. SR53–SR66, 2003.
[17]
L. Dubuquoy, S. Dharancy, S. Nutten, S. Pettersson, J. Auwerx, and P. Desreumaux, “Role of peroxisome proliferator-activated receptor γ and retinoid X receptor heterodimer in hepatogastroenterological diseases,” The Lancet, vol. 360, no. 9343, pp. 1410–1418, 2002.
[18]
R. A. Gupta, D. B. Polk, U. Krishna et al., “Activation of peroxisome proliferator-activated receptor γ suppresses nuclear factor κB-mediated apoptosis induced by Helicobacter pylori in gastric epithelial cells,” The Journal of Biological Chemistry, vol. 276, no. 33, pp. 31059–31066, 2001.
[19]
J. Piotrowski, H. Piotrowski, D. Skrodzka, A. Slomiany, and B. L. Slomiany, “Induction of acute gastritis and epithelial apoptosis by Helicobacter pylori lipopolysaccharide,” Scandinavian Journal of Gastroenterology, vol. 32, no. 3, pp. 203–211, 1997.
[20]
B. L. Slomiany and A. Slomiany, “Suppression of gastric mucosal inflammatory responses to Helicobacter pylori lipopolysaccharide by peroxisome proliferator-activated receptor γ activation,” IUBMB Life, vol. 53, no. 6, pp. 303–308, 2002.
[21]
B. L. Slomiany and A. Slomiany, “Impedance of Helicobacter pylori lipopolysaccharide interference with gastric mucin synthesis by peroxisome proliferator-activated receptor γ activation involves phosphatidylinositol 3-kinase/ERK pathway,” IUBMB Life, vol. 55, no. 2, pp. 97–102, 2003.
[22]
S. Basu, S. K. Pathak, G. Chatterjee, S. Pathak, J. Basu, and M. Kundu, “Helicobacter pylori protein HP0175 transactivates epidermal growth factor receptor through TLR4 in gastric epithelial cells,” The Journal of Biological Chemistry, vol. 283, no. 47, pp. 32369–32376, 2008.
[23]
O. S. Gardner, B. J. Dewar, H. S. Earp, J. M. Samet, and L. M. Graves, “Dependence of peroxisome proliferator-activated receptor ligand-induced mitogen-activated protein kinase signaling on epidermal growth factor receptor transactivation,” The Journal of Biological Chemistry, vol. 278, no. 47, pp. 46261–46269, 2003.
[24]
B. L. Slomiany and A. Slomiany, “Role of epidermal growth factor receptor transactivation in PPARγ-dependent suppression of Helicobacter pylori interference with gastric mucin synthesis,” Inflammopharmacology, vol. 12, no. 2, pp. 177–188, 2004.
[25]
K. D. Crew and A. I. Neugut, “Epidemiology of gastric cancer,” World Journal of Gastroenterology, vol. 12, no. 3, pp. 354–362, 2006.
[26]
A. Jemal, R. Siegel, J. Xu, and E. Ward, “Cancer statistics, 2010,” CA: A Cancer Journal for Clinicians, vol. 60, no. 5, pp. 277–300, 2010.
[27]
J. S. Macdonald, S. R. Smalley, J. Benedetti et al., “Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction,” The New England Journal of Medicine, vol. 345, no. 10, pp. 725–730, 2001.
[28]
N. Takahashi, T. Okumura, W. Motomura, Y. Fujimoto, I. Kawabata, and Y. Kohgo, “Activation of PPARγ inhibits cell growth and induces apoptosis in human gastric cancer cells,” FEBS Letters, vol. 455, no. 1-2, pp. 135–139, 1999.
[29]
H. Sato, S. Ishihara, K. Kawashima et al., “Expression of peroxisome proliferator-activated receptor (PPAR)γ in gastric cancer and inhibitory effects of PPARγ agonists,” British Journal of Cancer, vol. 83, no. 10, pp. 1394–1400, 2000.
[30]
Y.-X. Chen, X.-Y. Zhong, Y.-F. Qin, W. Bing, and L.-Z. He, “15d-PGJ2 inhibits cell growth and induces apoptosis of MCG-803 human gastric cancer cell line,” World Journal of Gastroenterology, vol. 9, no. 10, pp. 2149–2153, 2003.
[31]
W. K. Leung, A. H. C. Bai, V. Y. W. Chan et al., “Effect of peroxisome proliferator activated receptor γ ligands on growth and gene expression profiles of gastric cancer cells,” Gut, vol. 53, no. 3, pp. 331–338, 2004.
[32]
C. W. Cheon, D. H. Kim, D. H. Kim, Y. H. Cho, and J. H. Kim, “Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells,” World Journal of Gastroenterology, vol. 15, no. 3, pp. 310–320, 2009.
[33]
S. Nomura, A. Nakajima, S. Ishimine, N. Matsuhashi, T. Kadowaki, and M. Kaminishi, “Differential expression of peroxisome proliferator-activated receptor in histologically different human gastric cancer tissues,” Journal of Experimental and Clinical Cancer Research, vol. 25, no. 3, pp. 443–448, 2006.
[34]
Q. He, J. Chen, H.-L. Lin, P.-J. Hu, and M.-H. Chen, “Expression of peroxisome proliferator-activated receptor γ, E-cadherin and matrix metalloproteinases-2 in gastric carcinoma and lymph node metastases,” Chinese Medical Journal, vol. 120, no. 17, pp. 1498–1504, 2007.
[35]
E. Burgermeister, T. Friedrich, I. Hitkova et al., “The Ras inhibitors caveolin-1 and docking protein 1 activate peroxisome proliferator-activated receptor γ through spatial relocalization at helix 7 of its ligand-binding domain,” Molecular and Cellular Biology, vol. 31, no. 16, pp. 3497–3510, 2011.
[36]
S. Kitamura, Y. Miyazaki, S. Hiraoka et al., “PPARγ inhibits the expression of c-MET in human gastric cancer cells through the suppression of Ets,” Biochemical and Biophysical Research Communications, vol. 265, no. 2, pp. 453–456, 1999.
[37]
K. Yoshida, K. Tanabe, D. Fujii, N. Oue, W. Yasui, and T. Toge, “Induction mechanism of apoptosis by troglitazone through peroxisome proliferator-activated receptor-γ in gastric carcinoma cells,” Anticancer Research, vol. 23, no. 1, pp. 267–273, 2003.
[38]
S. Takeuchi, T. Okumura, W. Motomura, M. Nagamine, N. Takahashi, and Y. Kohgo, “Troglitazone induces G1 arrest by p27Kip1 induction that is mediated by inhibition of proteasome in human gastric cancer cells,” Japanese Journal of Cancer Research, vol. 93, no. 7, pp. 774–782, 2002.
[39]
M. Nagamine, T. Okumura, S. Tanno et al., “PPARγ ligand-induced apoptosis through a p53-dependent mechanism in human gastric cancer cells,” Cancer Science, vol. 94, no. 4, pp. 338–343, 2003.
[40]
P. C. Konturek, J. Kania, V. Kukharsky, S. Ocker, E. G. Hahn, and S. J. Konturek, “Influence of gastrin on the expression of cyclooxygenase-2, hepatocyte growth factor and apoptosis-related proteins in gastric epithelial cells,” Journal of Physiology and Pharmacology, vol. 54, no. 1, pp. 17–32, 2003.
[41]
J. Lu, K. Imamura, S. Nomura et al., “Chemopreventive effect of peroxisome proliferator-activated receptor γ on gastric carcinogenesis in mice,” Cancer Research, vol. 65, no. 11, pp. 4769–4774, 2005.
[42]
H. Shirin, E. M. Sordillo, T. K. Kolevska et al., “Chronic Helicobacter pylori infection induces an apoptosis-resistant phenotype associated with decreased expression of p27kip1,” Infection and Immunity, vol. 68, no. 9, pp. 5321–5328, 2000.
[43]
J. Yu, W. K. Leung, E. K. W. Ng et al., “Effect of Helicobacter pylori eradication on expression of cyclin D2 and p27 in gastric intestinal metaplasia,” Alimentary Pharmacology and Therapeutics, vol. 15, no. 9, pp. 1505–1511, 2001.
[44]
S. S. Kim, P. Meitner, T. A. Konkin, Y. S. Cho, M. B. Resnick, and S. F. Moss, “Altered expression of Skp2, c-Myc and p27 proteins but not mRNA after H. pylori eradication in chronic gastritis,” Modern Pathology, vol. 19, no. 1, pp. 49–58, 2006.
[45]
S. S. Kim, Y. S. Cho, H. K. Kim et al., “The effect of rosiglitazone on the cell proliferation and the expressions of p27 and skp2 in Helicobacter pylori infected human gastric epithelial cells,” The Korean Journal of Gastroenterology, vol. 55, no. 4, pp. 225–231, 2010, in Korean.
[46]
Y. Chung-Jen, B. A. Beamer, C. Negri et al., “Molecular scanning of the human peroxisome proliferator activated receptor γ (hPPARγ) gene in diabetic Caucasians: identification of a Pro12Ala PPARγ2 missense mutation,” Biochemical and Biophysical Research Communications, vol. 241, no. 2, pp. 270–274, 1997.
[47]
S. S. Deeb, L. Fajas, M. Nemoto et al., “A Pro12Ala substitution in PPARγ2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity,” Nature Genetics, vol. 20, no. 3, pp. 284–287, 1998.
[48]
W. Xu, Y. Li, X. Wang et al., “PPARγ polymorphisms and cancer risk: a meta-analysis involving 32,138 subjects,” Oncology Reports, vol. 24, no. 2, pp. 579–585, 2010.
[49]
W.-P. Koh, J. M. Yuan, D. Van Den Berg, S. A. Ingles, and M. C. Yu, “Peroxisome proliferator-activated receptor (PPAR) γ gene polymorphisms and colorectal cancer risk among Chinese in Singapore,” Carcinogenesis, vol. 27, no. 9, pp. 1797–1802, 2006.
[50]
S.-Y. Liao, Z.-R. Zeng, W. K. Leung et al., “Peroxisome proliferator-activated receptor-gamma Pro12Ala polymorphism, Helicobacter pylori infection and non-cardia gastric carcinoma in Chinese,” Alimentary Pharmacology and Therapeutics, vol. 23, no. 2, pp. 289–294, 2006.
[51]
T. Tahara, T. Arisawa, T. Shibata et al., “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,” Digestive Diseases and Sciences, vol. 53, no. 3, pp. 614–621, 2008.
[52]
K. N. Prasad, A. Saxena, U. C. Ghoshal, M. R. Bhagat, and N. Krishnani, “Analysis of Pro12Ala PPAR gamma polymorphism and Helicobacter pylori infection in gastric adenocarcinoma and peptic ulcer disease,” Annals of Oncology, vol. 19, no. 7, pp. 1299–1303, 2008.
[53]
A. Bazargani, S. S. Khoramrooz, E. Kamali-Sarvestani, S. A. Taghavi, and M. Saberifiroozi, “Association between peroxisome proliferator-activated receptor-γ gene polymorphism (Pro12Ala) and Helicobacter pylori infection in gastric carcinogenesis,” Scandinavian Journal of Gastroenterology, vol. 45, no. 10, pp. 1162–1167, 2010.
