Original Article
 

Association of Nucleotide-binding Oligomerization Domain Receptors with Peptic Ulcer and Gastric Cancer

Abstract

Host innate immunity can affect the clinical outcomes of Helicobacter pylori infection, including gastritis, gastric ulcer, gastric adenocarcinoma, and MALT lymphoma. Nucleotide binding oligomerization domain (NOD)-1 and -2 are two molecules of innate immunity which are involved in the host defense against H. pylori. This study aimed to evaluate the effect of the expression level of NOD1 and NOD2 on the susceptibility to gastric cancer as well as peptic ulcer in individuals with H. pylori infection. The gene expression levels of these molecules were compared in three groups of non-ulcer dyspepsia (NUD) as a control group (n=52); peptic ulcer disease (PUD), (n=53); and gastric cancer (GC), (n=39). Relative expression levels of NOD1 in patients with GC were higher than those of NUD and PUD (p<0.001 and P<0.001, respectively). Similarly in case of NOD1, PUD group showed higher level of expression than NUD group (p<0.01). However, there was no significant difference between H. pylori -positive and -negative patients in NUD, PUD, or GC groups. Moreover, the expression levels of NOD2 showed no significant difference among NUD, PUD, or GC groups, while among H. pylori-positive patients, it was higher in GC group than NUD  and PUD groups (p<0.05 and p<0.01, respectively). In addition, positive correlation coefficients were attained between NOD1 and NOD2 expressions in patients with NUD (R2 Linear=0.349, p<0.001), PUD (R2 Linear=0.695, p<0.001), and GC (R2 Linear=0.385, p<0.001). Collectively, the results suggest that the chronic activation of NOD1 and NOD2 receptors might play a role in the development of gastric cancer.

1. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52(24):6735-40.

2. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420(6917):860-7.

3. Fox JG, Wang TC. Inflammation, atrophy, and gastric cancer. J Clin Invest 2007; 117(1):60-9.

4. Shacter E, Weitzman SA. Chronic inflammation and cancer. Oncology 2002; 16(2):217-26.

5. Vieth M, Stolte M. Elevated risk for gastric adenocarcinoma can be predicted from histomorphology. World J Gastroenterol 2006; 12(38):6109-14.

6. Wang P, Zhang L, Jiang JM, Ma D, Tao HX, Yuan SL, et al. Association of NOD1 and NOD2 genes polymorphisms with Helicobacter pylori related gastric cancer in a Chinese population. World J Gastroenterol 2012; 18(17):2112-20.
7. Crabtree JE. Gastric mucosal inflammatory responses to Helicobacter pylori. Aliment Pharmacol Ther 1996; 10 (Suppl 1):29–37.

8. Inohara, Chamaillard, McDonald C, Nuñez G. NOD-LRR proteins: role in host-microbial interactions and inflammatory disease. Annu Rev Biochem 2005; 74:355-83.

9. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem 2001; 276(7):4812-8.

10. Inohara N, Nuñez G. NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 2003; 3(5):371-82.

11. Strober W, Murray PJ, Kitani A, Watanabe T. Signalling pathways and molecular interactions of NOD1 and NOD2. Nat Rev Immunol 2006; 6(1):9-20.

12. Hirata Y, Ohmae T, Shibata W, Maeda S, Ogura K, Yoshida H, et al. MyD88 and TNF receptor-associated factor 6 are critical signal transducers in Helicobacter pylori-infected human epithelial cells. J Immunol 2006; 176(6):3796-803.

13. Kobayashi KS, Chamaillard M, Ogura Y, Henegariu O, Inohara N, Nuñez G, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science 2005; 307(5710):731-4.

14. Girardin SE, Tournebize R, Mavris M, Page AL, Li X, Stark GR, et al. CARD4/Nod1 mediates NF-kappaB and JNK activation by invasive Shigella flexneri. EMBO Rep 2001; 2(8):736-42.

15. Rosai J, Ackerman LV. The pathology of tumors, part III: grading, staging & classification. CA Cancer J Clin 1979; 29(2):66-77.

16. Kang MJ, Heo SK, Song EJ, Kim DJ, Han SY, Han JH, et al. Activation of Nod1 and Nod2 induces innate immune responses of prostate epithelial cells. Prostate 2012; 72(12):1351-8.

17. Chen GY, Shaw MH, Redondo G, Núñez G. The innate immune receptor Nod1 protects the intestine from inflammation-induced tumorigenesis. Cancer Res 2008; 68(24):10060-7.

18. da Silva Correia J, Miranda Y, Austin-Brown N, Hsu J, Mathison J, Xiang R, et al. Nod1-dependent control of tumor growth. Proc Natl Acad Sci U S A 2006; 103(6):1840-5.

19. Kent A, Blander JM. Nod-like receptors: key molecular switches in the conundrum of cancer. Front Immunol 2014; 5:185.
20. Rosenstiel P, Hellmig S, Hampe J, Ott S, Till A, Fischbach W, et al. Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on theclinical outcome of Helicobacter pylori infection. Cell Microbiol 2006; 8(7):1188-98.
21. Grubman A, Kaparakis M, Viala J, Allison C, Badea L, Karrar A, et al. The innate immune molecule, NOD1, regulates direct killing of Helicobacter pylori by antimicrobial peptides. Cell Microbiol 2010; 12(5):626-39.

Files
IssueVol 15, No 5 (2016) QRcode
SectionOriginal Article(s)
Keywords
Gastric cancer NOD1 protein NOD2 protein Nucleotide-binding oligomerization domain Peptic ulcer

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
1.
Mohammadian Amiri R, Tehrani M, Taghizadeh S, Shokri-Shirvani J, Fakheri H, Ajami A. Association of Nucleotide-binding Oligomerization Domain Receptors with Peptic Ulcer and Gastric Cancer. Iran J Allergy Asthma Immunol. 2016;15(5):355-362.