胃と腸47巻11号

2012年10月発行

今月の主題 Helicobacter pylori除菌後の胃癌 主題研究

Helicobacter pylori除菌治療によって何が変わるのか?―分子生物学からみた変化

著者： 西澤俊宏¹² 鈴木秀和¹

所属機関： ¹慶應義塾大学医学部内科学（消化器） ²独立行政法人国立病院機構東京医療センター消化器科

ページ範囲：P.1678 - P.1683

要旨　H. pylori除菌治療における胃粘膜内の分子生物学的変化について，胃発癌の観点から概説した．H. pylori感染による酸化ストレスおよびDNA修復酵素の発現低下により，遺伝子変異が蓄積する可能性が指摘されている．癌抑制遺伝子RUNX3はプロモーター領域のメチル化により発現が低下するが，除菌により発現回復を認める．H. pylori感染によりShh（sonic hedgehog）の発現は低下・消失し，COX-2は過剰発現を認める．除菌によりShhやCOX-2の発現は改善するが，腸上皮化生になると不可逆性変化となる．このような不可逆性変化もあることから，除菌治療後も発癌リスクの段階に応じた対応が必要である．

参考文献

1）Higashi H, Tsutsumi R, Muto S, et al. SHP-2 tyrosine phosphatase as an intracellular target of Helicobacter pylori CagA protein. Science 295 : 683-686, 2002

2）Suzuki H, Nishizawa T, Hibi T. Helicobacter pylori eradication therapy. Future Microbiol 5 : 639-648, 2010

3）Suzuki H, Nishizawa T, Tsugawa H, et al. Roles of oxidative stress in stomach disorders. J Clin Biochem Nutr 50 : 35-39, 2012

4）Suzuki H, Hibi T, Marshall BJ. Helicobacter pylori : present status and future prospects in Japan. J Gastroenterol 42 : 1-15, 2007

5）Leung WK, Kim JJ, Kim JG, et al. Microsatellite instability in gastric intestinal metaplasia in patients with and without gastric cancer. Am J Pathol 156 : 537-543, 2000

6）Kim JJ, Tao H, Carloni E, et al. Helicobacter pylori impairs DNA mismatch repair in gastric epithelial cells. Gastroenterology 123 : 542-553, 2002

7）Buti L, Spooner E, Van der Veen AG, et al. Helicobacter pylori cytotoxin-associated gene A（CagA）subverts the apoptosis-stimulating protein of p53（ASPP2）tumor suppressor pathway of the host. Proc Natl Acad Sci USA 108 : 9238-9243, 2011

8）Yang Z, Shu X, Chen L, et al. Expression of p53-MDM2 feedback loop related proteins in different gastric pathologies in relation to Helicobacter pylori infection : Implications in gastric carcinogenesis. Clin Res Hepatol Gastroenterol 36 : 235-245, 2012

9）Kodama M, Murakami K, Okimoto T, et al. Expression of mutant type-p53 products in H pylori-associated chronic gastritis. World J Gastroenterol 13 : 1541-1546, 2007

10）Saito Y, Suzuki H, Tsugawa H, et al. Chromatin remodeling at Alu repeats by epigenetic treatment activates silenced microRNA-512-5p with downregulation of Mcl-1 in human gastric cancer cells. Oncogene 28 : 2738-2744, 2009

11）Maekita T, Nakazawa K, Mihara M, et al. High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric mucosae and its possible association with gastric cancer risk. Clin Cancer Res 12 : 989-995, 2006

12）Perri F, Cotugno R, Piepoli A, et al. Aberrant DNA methylation in non-neoplastic gastric mucosa of H. pylori infected patients and effect of eradication. Am J Gastroenterol 102 : 1361-1371, 2007

13）Chan AO, Peng JZ, Lam SK, et al. Eradication of Helicobacter pylori infection reverses E-cadherin promoter hypermethylation. Gut 55 : 463-468, 2006

14）Konturek PC, Rembiasz K, Konturek SJ, et al. Gene expression of ornithine decarboxylase, cyclooxygenase-2, and gastrin in atrophic gastric mucosa infected with Helicobacter pylori before and after eradication therapy. Dig Dis Sci 48 : 36-46, 2003

15）Sung JJ, Leung WK, Go MY, et al. Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. Am J Pathol 157 : 729-735, 2000

16）Wang WH, Huang JQ, Zheng GF, et al. Non-steroidal anti-inflammatory drug use and the risk of gastric cancer : a systematic review and meta-analysis. J Natl Cancer Inst 95 : 1784-1791, 2003

17）Steinbach G, Lynch PM, Phillips RK, et al. The effect of celecoxib, a cyclooxygenase-2 inhibitor, in familial adenomatous polyposis. N Engl J Med 342 : 1946-1952, 2000

18）Lin FC, Liu YP, Lai CH, et al. RUNX3-mediated transcriptional inhibition of Akt suppresses tumorigenesis of human gastric cancer cells. Oncogene, 2012, in press

19）Liu Z, Xu X, Chen L, et al. Helicobacter pylori CagA inhibits the expression of Runx3 via Src/MEK/ERK and p38 MAPK pathways in gastric epithelial cell. J Cell Biochem 113 : 1080-1086, 2012

20）Fan XY, Hu XL, Han TM, et al. Association between RUNX3 promoter methylation and gastric cancer : a meta-analysis. BMC Gastroenterol 11 : 92, 2011

21）Li QL, Ito K, Sakakura C, et al. Causal relationship between the loss of RUNX3 expression and gastric cancer. Cell 109 : 113-124, 2002

22）Suzuki M, Suzuki H, Minegishi Y, et al. H. pylori-Eradication Therapy Increases RUNX3 Expression in the Glandular Epithelial Cells in Enlarged-Fold Gastritis. J Clin Biochem Nutr 46 : 259-264, 2010

23）Suzuki H, Minegishi Y, Nomoto Y, et al. Down-regulation of a morphogen（sonic hedgehog）gradient in the gastric epithelium of Helicobacter pylori-infected Mongolian gerbils. J Pathol 206 : 186-197, 2005

24）Nishizawa T, Suzuki H, Nakagawa I, et al. Rebamipide-promoted restoration of gastric mucosal sonic hedgehog expression after early Helicobacter pylori eradication. Digestion 79 : 259-262, 2009

25）Nishizawa T, Suzuki H, Nakagawa I, et al. Early Helicobacter pylori eradication restores sonic hedgehog expression in the gastric mucosa of Mongolian gerbils. Digestion 79 : 99-108, 2009

26）Shiotani A, Uedo N, Iishi H, et al. Re-expression of sonic hedgehog and reduction of CDX2 after Helicobacter pylori eradication prior to incomplete intestinal metaplasia. Int J Cancer 121 : 1182-1189, 2007

27）Shiotani A, Murao T, Uedo N, et al. Eradication of H. pylori did not improve abnormal sonic hedgehog expression in the high risk group for gastric cancer. Dig Dis Sci 57 : 643-649, 2012

28）Song Z, Yue W, Wei B, et al. Sonic hedgehog pathway is essential for maintenance of cancer stem-like cells in human gastric cancer. PLoS One 6 : e17687, 2011

29）Saze Z, Terashima M, Kogure M, et al. Activation of the Sonic Hedgehog Pathway and Its Prognostic Impact in Patients with Gastric Cancer. Dig Surg 29 : 115-123, 2012

30）Yoo YA, Kang MH, Lee HJ, et al. Sonic hedgehog pathway promotes metastasis and lymphangiogenesis via activation of Akt, EMT, and MMP-9 pathway in gastric cancer. Cancer Res 71 : 7061-7070, 2011