title: CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5.
abstract: Intestinal metaplasia of the stomach, a mucosal change characterized by the conversion of gastric epithelium into an intestinal phenotype, is a precancerous lesion from which intestinal-type gastric adenocarcinoma arises. Chronic infection with Helicobacter pylori is a major cause of gastric intestinal metaplasia, and aberrant induction by H. pylori of the intestine-specific caudal-related homeobox (CDX) transcription factors, CDX1 and CDX2, plays a key role in this metaplastic change. As such, a critical issue arises as to how these factors govern the cell- and tissue-type switching. In this study, we explored genes directly activated by CDX1 in gastric epithelial cells and identified stemness-associated reprogramming factors SALL4 and KLF5. Indeed, SALL4 and KLF5 were aberrantly expressed in the CDX1(+) intestinal metaplasia of the stomach in both humans and mice. In cultured gastric epithelial cells, sustained expression of CDX1 gave rise to the induction of early intestinal-stemness markers, followed by the expression of intestinal-differentiation markers. Furthermore, the induction of these markers was suppressed by inhibiting either SALL4 or KLF5 expression, indicating that CDX1-induced SALL4 and KLF5 converted gastric epithelial cells into tissue stem-like progenitor cells, which then transdifferentiated into intestinal epithelial cells. Our study places the stemness-related reprogramming factors as critical components of CDX1-directed transcriptional circuitries that promote intestinal metaplasia. Requirement of a transit through dedifferentiated stem/progenitor-like cells, which share properties in common with cancer stem cells, may underlie predisposition of intestinal metaplasia to neoplastic transformation.
authors.affiliation: Division of Microbiology, Graduate School of Medicine, The  University of Tokyo, Tokyo 113-0033,  Japan.
authors.forename: Yumiko
authors.initials: Y
authors.lastname: Fujii
authors.forename: Kyoko
authors.initials: K
authors.lastname: Yoshihashi
authors.forename: Hidekazu
authors.initials: H
authors.lastname: Suzuki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Tsutsumi
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Mutoh
authors.forename: Shin
authors.initials: S
authors.lastname: Maeda
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Yamagata
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Seto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
mesh_terms: D053687:Adult Stem Cells / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D054338:Cell Transdifferentiation / Q000235:genetics / Q000502:physiology; D018076:DNA, Complementary / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D005753:Gastric Mucosa / Q000378:metabolism* / Q000473:pathology*; D005819:Genetic Markers; D016480:Helicobacter pylori / Q000472:pathogenicity; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007413:Intestinal Mucosa / Q000378:metabolism* / Q000473:pathology; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D008297:Male; D008679:Metaplasia; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010641:Phenotype; D012689:Sequence Homology, Nucleic Acid; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C491273:CDX1 protein, human; C491272:Cdx1 protein, mouse; D018076:DNA, Complementary; D004268:DNA-Binding Proteins; D005819:Genetic Markers; D018398:Homeodomain Proteins; C492214:KLF5 protein, human; C118391:Klf5 protein, mouse; D051741:Kruppel-Like Transcription Factors; C472575:SALL4 protein, human; C509167:Sall4 protein, mouse; D014157:Transcription Factors