胃と腸51巻1号

2016年01月発行

今月の主題 慢性胃炎を見直す 主題研究

分離腺管を用いた腸上皮化生，非腸上皮化生および胃癌の分子病理学的解析

著者： 杉本亮¹ 上杉憲幸¹ 荒川典之¹ 永塚真¹ 肥田圭介² 石田和之¹ 佐々木章² 松本主之³ 菅井有¹

所属機関： ¹岩手医科大学医学部病理診断学講座 ²岩手医科大学医学部外科学講座 ³岩手医科大学医学部内科学講座消化器内科消化管分野

ページ範囲：P.95 - P.104

要旨●腸上皮化生の分子異常を明らかにするために，分離腸上皮化生腺管，分離非腸上皮化生腺管，癌分離腺管を用いてDNAメチル化解析を行った．対象は胃癌27例から得られた腸上皮化生腺管と同一粘膜から得られた非腸上皮化生腺管，胃体部大彎から採取された非腸上皮化生腺管と分離胃癌腺管13例を用いた．メチル化解析は2パネル法を用い，HME（high methylation epigenome），IME（intermediate methylation epigenome），LME（low methylation epigenome）に分類した．さらに，分離腺管を採取した粘膜の腸上皮化生粘膜を，粘液形質の観点から完全型（CD10陽性）優位，不完全型（MUC5AC陽性）優位に分類した．腸上皮化生腺管のIMEの頻度は，同一粘膜内の非腸上皮化生腺管のそれより高かった．癌腺管のメチル化はHMEもみられたが，多くはIMEであった．MiR-34b/cのメチル化は腸上皮化生腺管（癌非腸上皮化生腺管）＞同一粘膜内の非腸上皮化生腺管＞胃体部非腸上皮化生腺管の順に高かった．加えて，不完全腸上皮化生優位粘膜のほうが完全腸上皮化生優位型よりIMEの頻度が高かった．メチル化の蓄積が腸上皮化生腺管の発生に重要な役割を担っている可能性が示唆された．

参考文献

1）Meining A, Morgner A, Miehlke S, et al. Atrophy-metaplasia-dysplasia-carcinoma sequence in the stomach：a reality or merely an hypothesis? Best Pract Res Clin Gastroenterol 15：983-998, 2001

2）Conteduca V, Sansonno D, Lauletta G, et al. Helicobacter pylori infection and gastric cancer：state of the art. Int J Oncol 42：5-18, 2013

3）Konturek PC, Konturek SJ, Brzozowski T. Helicobacter pylori infection in gastric cancerogenesis. J Physiol Pharmacol 60：3-21, 2009

4）Walker MM. Is intestinal metaplasia of the stomach reversible? Gut 52：1-4, 2003

5）Correa P, Piazuelo MB. The gastric precancerous cascade. J Dig Dis 13：2-9, 2012

6）Correa P, Piazuelo MB, Wilson KT. Pathology of gastric intestinal metaplasia：clinical implications. Am J Gastroenterol 105：493-498, 2010

7）Tatematsu M, Tsukamoto T, Toyoda T. Effects of eradication of Helicobacter pylori on gastric carcinogenesis in experimental models. J Gastroenterol 42（Suppl 17）：7-9, 2007

8）Tatematsu M, Tsukamoto T, Mizoshita T. Role of Helicobacter pylori in gastric carcinogenesis：the origin of gastric cancers and heterotopic proliferative glands in Mongolian gerbils. Helicobacter 10：97-106, 2005

9）Lengauer C, Kinzler KW, Vogelstein B. Genetic instability in colorectal cancers. Nature 386：623-627, 1997

10）Jass JR, Whitehall VL, Young J, et al. Emerging concepts in colorectal neoplasia. Gastroenterology 123：862-876, 2002

11）Pino MS, Chung DC. The chromosomal instability pathway in colon cancer. Gastroenterology 138：2059-2072, 2010

12）Sugai T, Habano W, Endoh M, et al. Molecular analysis in gastric differentiated-type intramucosal and submucosal cancers. Int J Cancer 127：2500-2509, 2010

13）Leggett B, Whitehall V. Role of the serrated pathway in colorectal cancer pathogenesis. Gastroenterology 138：2088-2100, 2010

14）Boland CR, Goel A. Microsatellite instability in colorectal cancer. Gastroenterology 138：2073-2087, 2010

15）Shin CM, Kim N, Jung Y, et al. Role of Helicobacter pylori infection in aberrant DNA methylation along multistep gastric carcinogenesis. Cancer Sci 101：1337-1346, 2010

16）Park SY, Yoo EJ, Cho NY, et al. Comparison of CpG island hypermethylation and repetitive DNA hypomethylation in premalignant stages of gastric cancer, stratified for Helicobacter pylori infection. J Pathol 219：410-416, 2009

17）Dong CX, Deng DJ, Pan KF, et al. Promoter methylation of p16 associated with Helicobacter pylori infection in precancerous gastric lesions：a population-based study. Int J Cancer 124：434-439, 2009

18）日本胃癌学会（編）．胃癌取扱い規約，14版．金原出版，pp 8-57, 2010

19）Arai T, Kino I. Morphometrical and cell kinetic studies of normal human colorectal mucosa．Comparison between the proximal and the distal large intestine．Acta Pathol Jpn 39：725-730, 1989

20）Arai T, Sakurai U, Sawabe M, et al. Frequent microsatellite instability in papillary and solid-type, poorly differentiated adenocarcinomas of the stomach. Gastric Cancer 16：505-512, 2013

21）Kimura T, Yamamoto E, Yamano H, et al. A novel pit pattern identifies the precursor of colorectal cancer derived from sessile serrated adenoma. Am J Gastroenterol 107：460-469, 2012

22）Kaneda A, Yagi K. Two groups of DNA methylation markers to classify colorectal cancer into three epigenotypes. Cancer Sci 102：18-24, 2011

23）Nakamura S, Kino I. Morphogenesis of minute adenomas in familial polyposis coli. J Natl Cancer Inst 73：41-49, 1984

24）Sugai T, Habano W, Jiao Y-F, et al. Molecular analysis of single isolated glands in gastric cancers and their surrounding gastric intestinal metaplastic mucosa. Oncol Rep 23：25-33, 2009

25）Toyota M, Ahuja N, Ohe-Toyota M, et al. CpG island methylator phenotype in colorectal cancer. Proc Natl Acad Sci U S A 96：8681-8686, 1999

26）Sugimoto R, Sugai T, Habano W, et al. Clinicopathological and molecular alterations in early gastric cancers with the microsatellite instability-high phenotype. Int J Cancer 2015 Nov 4

27）Park HJ, Kim HS, Kim JW, et al. Is microsatellite instability（MSI）associated with multiplicity in early stage gastric neoplasias? Clin Res Hepatol Gastroenterol 37：400-405, 2013

28）Wang L, Yu J, Xu J, et al. The analysis of microRNA-34 family expression in human cancer studies comparing cancer tissues with corresponding pericarcinous tissues. Gene 554：1-8, 2015

29）Zhang DG, Zheng JN, Pei DS. P53/microRNA-34-induced metabolic regulation：new opportunities in anticancer therapy. Mol Cancer 13：115-121, 2014

30）Suzuki R, Yamamoto E, Nojima M, et al. Aberrant methylation of microRNA-34b/c is a predictive marker of metachronous gastric cancer risk. J Gastroenterol 49：1135-1144, 2014

31）杉本亮，織笠俊介，菅井有，他．胃癌分離腺管および周囲粘膜における分離腸上皮化生腺管，分離非腸上皮化生腺管の分子病理学的解析．岩手医誌 65：271-283, 2013

32）Beck F, Stringer EJ. The role of Cdx genes in the gut and in axial development. Biochem Soc Trans 38：353-357, 2010