title: Intestine-specific homeobox (ISX) induces intestinal metaplasia and cell proliferation to contribute to gastric carcinogenesis.
abstract: BACKGROUND
  Helicobacter pylori induces chronic inflammation and intestinal metaplasia (IM) through genetic and epigenetic changes and activation of intracellular signaling pathways that contribute to gastric carcinogenesis. However, the precise mechanism of IM in gastric carcinogenesis has not been fully elucidated. We previously found that intestine-specific homeobox (ISX) mRNA expression increased in organoids cultured from Helicobacter-infected mouse mucosa. In this study, we elucidate the role of ISX in the development of IM and gastric carcinogenesis.
  
  
  METHODS
  ISX expression was assessed in Helicobacter-infected mouse and human gastric mucosa. MKN45 gastric cancer cells were co-cultured with H. pylori to determine whether Helicobacter infection induced ISX expression. We established stable MKN45 transfected cells expressing ISX (Stable-ISX MKN45) and performed a spheroid colony formation assay and a xenograft model. We performed ISX immunohistochemistry in cancer and adjacent gastric tissues.
  
  
  RESULTS
  ISX expression was increased in mouse and human gastric mucosa infected with Helicobacter. The presence of IM and H. pylori infection in human stomach was correlated with ISX expression. H. pylori induced ISX mRNA and protein expression. CDX1/2, cyclinD1, and MUC2 were upregulated in Stable-ISX MKN45, whereas MUC5AC was downregulated. Stable-ISX MKN45 cells formed more spheroid colonies, and had high tumorigenic ability. ISX expression in gastric cancer and adjacent mucosa were correlated.
  
  
  CONCLUSIONS
  ISX expression induced by H. pylori infection may lead to IM and hyperproliferation of gastric mucosa through CDX1/2 and cyclinD1 expression, contributing to gastric carcinogenesis.
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Soichiro
authors.initials: S
authors.lastname: Sue
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.|Advanced Medical Research Center, Yokohama City University, Yokohama, Japan.
authors.forename: Wataru
authors.initials: W
authors.lastname: Shibata
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Eri
authors.initials: E
authors.lastname: Kameta
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Sato
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Yasuaki
authors.initials: Y
authors.lastname: Ishii
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Kaneko
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Haruo
authors.initials: H
authors.lastname: Miwa
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Sasaki
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Toshihide
authors.initials: T
authors.lastname: Tamura
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Kondo
authors.affiliation: Department of Gastroenterology, Yokohama City University Graduate School of Medicine, Yokohama, 236-0004, Japan. smaeda@yokohama-cu.ac.jp.
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
mesh_terms: D000818:Animals; D000071616:CDX2 Transcription Factor / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D018920:Coculture Techniques; D019938:Cyclin D1 / Q000378:metabolism; D015536:Down-Regulation; D005753:Gastric Mucosa / Q000378:metabolism* / Q000382:microbiology / Q000473:pathology*; D055785:Gene Knockdown Techniques; D016481:Helicobacter Infections / Q000150:complications / Q000378:metabolism*; D016480:Helicobacter pylori; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008679:Metaplasia / Q000150:complications / Q000378:metabolism; D051379:Mice; D055271:Mucin 5AC / Q000378:metabolism; D055262:Mucin-2 / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism*; D018874:Spheroids, Cellular; D013274:Stomach Neoplasms / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: C491273:CDX1 protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; C579132:Isx protein, human; C527930:Isx protein, mouse; C524625:MUC2 protein, human; C524678:MUC5AC protein, human; D055271:Mucin 5AC; D055262:Mucin-2; D012333:RNA, Messenger; D014157:Transcription Factors; D019938:Cyclin D1
keywords: Gastric carcinogenesis; H. pylori; ISX; Intestinal metaplasia