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.CagA | Wnt | β-catenin

The CDX1–microRNA-215 axis regulates colorectal cancer stem cell differentiation

“…Introduction of CDX1 into poorly differentiated, non-lumen-forming cell lines that do not express endogenous CDX1 induces lumen formation in three-dimensional (3D) cell culture (2). Transgenic expression of Cdx1 in mouse gastric epithelium causes intestinal transdifferentiation (11,12), which supports the observation that CDX1 is up-regulated in Barrett's metaplasia of the esophagus (13). Although several transcriptional targets and functional effects of CDX1 have been identified, there remains much to learn about the mechanisms by which it promotes differentiation and, in particular, those by which it inhibits stemness.…”

Two Novel Variants on 13q22.1 Are Associated with Risk of Esophageal Squamous Cell Carcinoma

“…In colon cancer, KLF5 acts as an important mediator of KRAS during intestinal carcinogenesis process (33)(34)(35)(36). A similar oncogenic function of KLF5 has also been observed in the severity of premalignant lesions in human gastric carcinogenesis induced by H. pylori (37)(38)(39)(40). Considering ESCC, however, KLF5 might play a tumor suppressor role.…”

Gastric-to-intestinal transdifferentiation and cancer

“…1). Of interest in that study, the authors noted that CagAderegulated β-catenin transactivated the intestinal specific transcription factor CDX1, which was followed by up-regulation of the intestinal differentiation marker Muc2 (12), findings that provided the framework for the work of Fujii et al (2).…”

“…Importantly, the authors extend these findings into the gastric niche by demonstrating that levels of SALL4 and KLF5 were significantly increased within gastric mucosa of CDX1-overexpressing vs. WT mice, and within human gastric tissue harvested from patients with intestinal metaplasia, compared with patients without this lesion. Returning to mechanistic studies, Fujii et al (2) subsequently determine that other markers of intestinal cell stemness, including GATA binding protein 6 (GATA6), follistatin (FST), leucine-rich repeat containing G protein-coupled receptor 5 (LGR5), and BMI1 polycomb ring finger oncogene (BMI1), were up-regulated in CDX1-overexpressing cells. CDX1-dependent up-regulation of stemness factors was followed by an increase in expression of a subset of intestinal differentiation markers, including sucrase-isomaltase (SI) and membrane metallo-endopeptidase (MME), which characterize absorptive enterocytes, but no increase in markers of Paneth cells or enteroendocrine cells.…”