CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5.

Yumiko Fujii, Kyoko Yoshihashi, Hidekazu Suzuki, Shuichi Tsutsumi, Hiroyuki Mutoh, Shin Maeda, Yukinori Yamagata, Yasuyuki Seto, Hiroyuki Aburatani, Masanori Hatakeyama

Research output: Contribution to journalArticle

60 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)20584-20589
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number50
Publication statusPublished - 2012 Dec 11

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Stomach
Epithelial Cells
Metaplasia
Phenotype
Helicobacter pylori
Stem Cells
Neoplastic Stem Cells
Homeobox Genes
Differentiation Antigens
Intestinal Mucosa
Intestines
Adenocarcinoma
Infection
Genes

ASJC Scopus subject areas

  • General

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CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5. / Fujii, Yumiko; Yoshihashi, Kyoko; Suzuki, Hidekazu; Tsutsumi, Shuichi; Mutoh, Hiroyuki; Maeda, Shin; Yamagata, Yukinori; Seto, Yasuyuki; Aburatani, Hiroyuki; Hatakeyama, Masanori.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 50, 11.12.2012, p. 20584-20589.

Research output: Contribution to journalArticle

Fujii, Y, Yoshihashi, K, Suzuki, H, Tsutsumi, S, Mutoh, H, Maeda, S, Yamagata, Y, Seto, Y, Aburatani, H & Hatakeyama, M 2012, 'CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5.', Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 50, pp. 20584-20589.
Fujii, Yumiko ; Yoshihashi, Kyoko ; Suzuki, Hidekazu ; Tsutsumi, Shuichi ; Mutoh, Hiroyuki ; Maeda, Shin ; Yamagata, Yukinori ; Seto, Yasuyuki ; Aburatani, Hiroyuki ; Hatakeyama, Masanori. / CDX1 confers intestinal phenotype on gastric epithelial cells via induction of stemness-associated reprogramming factors SALL4 and KLF5. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 50. pp. 20584-20589.
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