CDX1 is an important molecular mediator of Barrett's metaplasia

Wong, Newton A C S; Wilding, Jennifer L.; Bartlett, Simon; Liu, Y.; Warren, Bryan F.; Piris, J; Maynard, Nicholas; Marshall, Robert; Bodmer, W F

doi:10.1073/pnas.0502031102

Cited by 95 publications

(83 citation statements)

References 32 publications

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“…It seems likely that the expression of other markers of intestinal epithelial differentiation, such as villin, MUC2, and sucrase isomaltase, may also be regulated by CDX1. The overall data are consistent with the idea that CDX1 expression is a key switch for intestinal epithelial differentiation, as suggested by Wong et al (29) with respect to the development of intestinal metaplasia in Barrett's oesophagus, and presumably also in gastric mucosa (31), where intestinal metaplasia is assumed often to be a precursor to the development of gastric carcinomas. The differential expression of CDX1 appears to be controlled by promoter methylation (19,29).…”

Section: Discussionsupporting

confidence: 78%

“…CDX1 also seems to play a key role in the control of the expression of the transmembrane protein, A33, which is almost uniquely associated with intestinal epithelium (21,29,30). Other published evidence suggests that ectopic expression of CDX1 in an undifferentiated rat cell line results in differentiated phenotypes with columnar epithelial features, together with induction of differentiation markers, such as villin and aminopeptidase N (16).…”

Section: Discussionmentioning

confidence: 99%

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Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

Chan

Wong

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

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CDX1 is a transcription factor that plays a key role in intestinal development and differentiation. However, the downstream targets of CDX1 are less well defined than those of its close homologue, CDX2. We report here the identification of downstream targets of CDX1 using microarray gene-expression analysis and other approaches. Keratin 20 (KRT20), a member of the intermediate filament and a well-known marker of intestinal differentiation, was initially identified as one of the genes likely to be directly regulated by CDX1. CDX1 and KRT20 mRNA expression were significantly correlated in a panel of 38 colorectal cancer cell lines. Deletion and mutation analysis of the KRT20 promoter showed that the minimum regulatory region for the control of KRT20 expression by CDX1 is within 246 bp upstream of the KRT20 transcription start site. ChIP analysis confirmed that CDX1 binds to the predicted CDX elements in this region of the KRT20 promoter in vivo. In addition, immunohistochemistry showed expression of CDX1 parallels that of KRT20 in the normal crypt, which further supports their close relationship. In summary, our observations strongly imply that KRT20 is directly regulated by CDX1, and therefore suggest a role for CDX1 in maintaining differentiation in intestinal epithelial cells. Because a key feature of the development of a cancer is an unbalanced program of proliferation and differentiation, dysregulation of CDX1 may be an advantage for the development of a colorectal carcinoma. This could, therefore, explain the relatively frequent down regulation of CDX1 in colorectal carcinomas by hypermethylation.colorectal cancer ͉ epithelial ͉ cell lines ͉ methylation ͉ cancer stem cells M embers of the keratin family provide structural support for the cell. They are also involved in apoptosis and protect cells from stress (1). Mutations of some keratins lead to genetic diseases, for example, of the skin and the liver (2-4). Keratin 20 (KRT20), a member of the keratin family, has been cloned and classified as a type-I keratin with a highly conserved amino acid sequence (5). It is mainly expressed in the cytoplasm of epithelial cells in the small and large intestine and in Merkel cells of the skin (5). As KRT20 is expressed in the epithelial cells of the crypt, it has been widely studied as a marker of differentiation in normal epithelium and colorectal cancer (CRC) samples (6-9). Previous studies have suggested that KRT20 is phosphorylated in association with mucin secretion and filament organization (10, 11). Transgenic mice with mutations at a conserved Arg to His site (R80H) show collapse of intermediate filaments.Despite its clearly important functions in the intestine, little is known about the regulation of KRT20.CDX1 is a homeobox transcription factor that is important for intestinal development and is specifically expressed in the small and large intestine in both mice and humans (12-15). CDX1 plays a role in intestinal epithelial cell differentiation (16) and is down-regulated in a number of CRC-derived cell lines...

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 99%

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

Chan

Wong

Liu

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

101

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“…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.…”

supporting

confidence: 62%

“…This argument is further supported by the lack of miR-215 expression in the cancer stem cell-enriched fractions of differentiated cell lines. Significantly, aberrant miR-215 expression is also coincident with CDX1 activation in Barrett's esophagus (13,39), suggesting that this axis is important in intestinal metaplasia (40).…”

Section: Discussionmentioning

confidence: 99%

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

Jones

Hara²,

Francis

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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The transcription factor caudal-type homeobox 1 (CDX1) is a key regulator of differentiation in the normal colon and in colorectal cancer (CRC). CDX1 activates the expression of enterocyte genes, but it is not clear how the concomitant silencing of stem cell genes is achieved. MicroRNAs (miRNAs) are important mediators of gene repression and have been implicated in tumor suppression and carcinogenesis, but the roles of miRNAs in differentiation, particularly in CRC, remain poorly understood. Here, we identified microRNA-215 (miR-215) as a direct transcriptional target of CDX1 by using highthroughput small RNA sequencing to profile miRNA expression in two pairs of CRC cell lines: CDX1-low HCT116 and HCT116 with stable CDX1 overexpression, and CDX1-high LS174T and LS174T with stable CDX1 knockdown. Validation of candidate miRNAs identified by RNA-seq in a larger cell-line panel revealed miR-215 to be most significantly correlated with CDX1 expression. Quantitative ChIP-PCR and promoter luciferase assays confirmed that CDX1 directly activates miR-215 transcription. miR-215 expression is depleted in FACS-enriched cancer stem cells compared with unsorted samples. Overexpression of miR-215 in poorly differentiated cell lines causes a decrease in clonogenicity, whereas miR-215 knockdown increases clonogenicity and impairs differentiation in CDX1-high cell lines. We identified the genome-wide targets of miR-215 and found that miR-215 mediates the repression of cell cycle and stemness genes downstream of CDX1. In particular, the miR-215 target gene BMI1 has been shown to promote stemness and self-renewal and to vary inversely with CDX1. Our work situates miR-215 as a link between CDX1 expression and BMI1 repression that governs differentiation in CRC.T he caudal-type homeobox 1 (CDX1) transcription factor controls enterocyte differentiation in the colon, where its expression is excluded from the crypt-base stem cell compartment. CDX1 is also central to the capacity of a colorectal cancer (CRC) cell line to differentiate, and it is a negative marker of CRC stem cells (1-3). In 19% of CRC cell lines assayed in a large study, CDX1 expression was completely lost due to promoter methylation and was down-regulated in a further 13% as a result of hemimethylation of the promoter (4). Comparison of CDX1 expression in colorectal adenocarcinoma versus matched normal tissue showed downregulation of CDX1 in 73% of tumors, which was also attributable to promoter methylation (5). Expression of CDX1 also correlates inversely with that of the polycomb complex protein BMI1, which is necessary for the maintenance of quiescent injury-inducible stem cells in the normal crypt and is expressed in cancer stem cells (2, 6-8). The mechanism underlying this inverse correlation has not yet been elucidated.In addition to these correlative data, CDX1 has also been shown to promote directly the expression of structural proteins important for epithelial differentiation including cytokeratin 20 (KRT20) (1), villin (VIL) (9), and FABP1 (10). Introduction...

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“…To examine whether the aberrant expression of CDX2 in AML could be caused by gene-specific promoter hypomethylation, a pathogenetic event that has been described in several solid tumors (26)(27)(28)(29)(30), we studied DNA methylation over a 347-bp region (nucleotide positions -193 to +154 relative to the CDX2 TSS) within a previously described (31) CpG island upstream of CDX2 exon 1 by sodium bisulfite sequencing (Supplemental Figure 2A). As shown in Supplemental Figure 2B, the CDX2 promoter region was predominantly unmethylated in BMMCs from 3 CDX2-expressing patients (expression levels, 1,101, 1,288, and 2,963, respectively).…”

Section: Figurementioning

confidence: 99%

The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis

Scholl¹,

Bansal²,

Döhner³

et al. 2007

J. Clin. Invest.

124

137

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The homeobox transcription factor CDX2 plays an important role in embryonic development and regulates the proliferation and differentiation of intestinal epithelial cells in the adult. We have found that CDX2 is expressed in leukemic cells of 90% of patients with acute myeloid leukemia (AML) but not in hematopoietic stem and progenitor cells derived from normal individuals. Stable knockdown of CDX2 expression by RNA interference inhibited the proliferation of various human AML cell lines and strongly reduced their clonogenic potential in vitro. Primary murine hematopoietic progenitor cells transduced with Cdx2 acquired serial replating activity, were able to be continuously propagated in liquid culture, generated fully penetrant and transplantable AML in BM transplant recipients, and displayed dysregulated expression of Hox family members in vitro and in vivo. These results demonstrate that aberrant expression of the developmental regulatory gene CDX2 in the adult hematopoietic compartment is a frequent event in the pathogenesis of AML; suggest a role for CDX2 as part of a common effector pathway that promotes the proliferative capacity and self-renewal potential of myeloid progenitor cells; and support the hypothesis that CDX2 is responsible, in part, for the altered HOX gene expression that is observed in most cases of AML.

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CDX1 is an important molecular mediator of Barrett's metaplasia

Cited by 95 publications

References 32 publications

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

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

The homeobox gene CDX2 is aberrantly expressed in most cases of acute myeloid leukemia and promotes leukemogenesis

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