Expression of Cdx1 and Cdx2 mRNAs and relevance of this expression to differentiation in human gastrointestinal mucosa - With special emphasis on participation in intestinal metaplasia of the human stomach

Gastric Cancer (Impact Factor: 3.72). 11/2001; 4(4):185-191. DOI: 10.1007/PL00011741

ABSTRACT Background. The caudal-type homeobox genes, Cdx1 and Cdx2, are candidates for directing intestinal development, differentiation, and maintenance of the intestinal phenotype. The aims
of this study were: (1) to assess the normal tissue expression patterns of Cdx1 and Cdx2 in the human gastrointestinal tract and (2) to ascertain levels in intestinal metaplasia (IM) of the stomach associated with

Methods. Fresh human tissues were collected by surgical resection from 39 patients after informed consent had been received. RNAs
were extracted from 11 distinct sites in the gastrointestinal mucosa (gastric body, gastric antrum, duodenum, jejunum, ileum,
cecum, ascending colon, transverse colon, descending colon, sigmoid colon, and rectum), and Northern hybridization was performed
for Cdx1 and Cdx2 mRNAs. In addition, RNAs were also extracted from normal gastric mucosa, and gastric mucosa with mild to severe IM, confirmed
histopathologically. Reverse-transcriptase polymerase chain reaction (RT-PCR) was then carried out for Cdx1 and Cdx2.

Results. The expression of Cdx1 mRNA increased gradually from the duodenum to the distal colon, with no expression detected in the stomach. Compared with
the distribution of Cdx1 mRNA in the mouse gastrointestinal tract, the expression of Cdx1 mRNA in the human gastrointestinal tract showed greater predominance in the jejunum and ileum. The expression of Cdx2 mRNA increased gradually from the duodenum to the proximal colon and decreased from the ascending colon to the rectum. Compared
with the expression pattern of Cdx2 mRNA in the mouse gastrointestinal tract, the expression of Cdx2 mRNA in the human gastrointestinal tract showed greater predominance in the ileum. By RT-PCR, both Cdx1 and Cdx2 mRNAs were detected in the mild and severe types of IM. However, neither of these mRNAs was identified in normal gastric
mucosa without IM.

Cdx1 and Cdx2 mRNAs are widely present in the human intestinal and colonic mucosae, but not in the gastric mucosa, suggesting that their
expression may contribute to the intestinal phenotype. The high levels of these mRNAs in IM mucosa associated with chronic
atrophic gastritis point to an association with this phenotypic shift in the gastric mucosa.

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Available from: Yasuhiro Kodera, Sep 27, 2015
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    • "CDX2 was found to be intensively involved in intestinal metaplastic differentiation [23]. CDX2 may stimulate intestinal proliferation and differentiation by transcriptional activation of intestine-specific proteins (MUC2, sucrase-isomaltase, and carbonic anhydraseI). "
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    ABSTRACT: Aim. To investigate the expressions of glutathione peroxidase 1 (GPX1) and caudal-related homeodomain transcription factor (CDX2) in GAC and their correlation with clinicopathological features and tumor cell proliferation. Methods. The expressions of GPX1, CDX2, and Ki67 were immunohistochemically evaluated in 172 GAC specimens. The association of GPX1 and CDX2 with patient's clinicopathological features and Ki67 positive rate was analyzed statistically. Results. In 172 cases of GAC, the expression of GPX1 was weaker than that in adjacent normal mucosa, and the expression of CDX2 was higher than that in adjacent normal mucosa. High expression GPX1 strong-expression was associated with differentiation, Lauren type, WHO type and extensive lymph node metastasis of GAC. High expression of CDX2 was associated with differentiation, Lauren type, WHO type, extensive lymph node metastasis, and TNM of GAC. Survival curves showed that expressions of GPX1 and CDX2 were factors of good outcome (P = .03 and .02, resp.). According to multivariate analysis, only lymph node metastasis, TNM stage, and CDX2 expression were independently associated with survival. In addition, a strong association of GPX1 expression was noted with Ki67 and CDX2. Conclusions. The expression of GPX1 and CDX2 may play a role in the carcinogenesis, differentiation, and progression of GAC, and CDX2 may be an independent prognostic factor.
    Gastroenterology Research and Practice 10/2013; 2013:380193. DOI:10.1155/2013/380193 · 1.75 Impact Factor
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    • "Moreover, both sides of the colon differ significantly in their gene expression profiles [114]. For example, CDX2 is expressed at higher levels in the proximal colon [115]. Interestingly, Aoki et al. have shown that a 50% reduction in Cdx2 levels results in a strong shift from mainly small intestinal tumours towards a large intestinal tumour phenotype in ApcΔ716 mice [106]. "
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    ABSTRACT: In contrast to the majority of sporadic colorectal cancer which predominantly occur in the distal colon, most mismatch repair deficient tumours arise at the proximal side. At present, these regional preferences have not been explained properly. Recently, we have screened colorectal tumours for mutations in Wnt-related genes focusing specifically on colorectal location. Combining this analysis with published data, we propose a mechanism underlying the side-related preferences of colorectal cancers, based on the specific acquired genetic defects in β-catenin signalling.
    Biochimica et Biophysica Acta 08/2011; 1816(2):219-31. DOI:10.1016/j.bbcan.2011.07.005 · 4.66 Impact Factor
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    • "Caudal-type homeobox 2 (Cdx2), a mammalian member of the caudal-related homeobox gene family, plays an important role in the differentiation of intestinal cells and in maintaining the intestinal phenotype by binding to the promoters of several intestine-specific genes including gobletspecific gene mucin 2 (MUC2) [4] [5]. Mizoshita et al. [6] reported that Cdx2 mRNA was widely present in human intestinal and colonic mucosa, but not in normal gastric mucosa. However, the nuclear expression of Cdx2 has been reported in gastric mucosa associated with intestinal metaplasia , as well as in relation to intestinal-type gastric carcinomas [7, 8]. "
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    ABSTRACT: Clinical and experimental studies showed that the reflux of bile into the stomach contributes to the induction of intestinal metaplasia of the stomach and gastric carcinogenesis. Caudal-type homeobox 2 (Cdx2) plays a key role in the exhibition of intestinal phenotypes by regulating the expression of intestine-specific genes such as goblet-specific gene mucin 2 (MUC2). We investigated the involvement of the farnesoid X receptor (FXR), a nuclear receptor for bile acids, in the chenodeoxycholic acid (CDCA)-induced expression of Cdx2 and MUC2 in normal rat gastric epithelial cells (RGM-1 cells). RGM-1 cells were treated with CDCA or GW4064, an FXR agonist, in the presence or absence of guggulsterone, an FXR antagonist. CDCA induced dose-dependent expression of Cdx2 and MUC2 at both the mRNA and protein levels. The maximum stimulation of Cdx2 and MUC2 mRNA induced by CDCA was observed at 3 h and by 6 h, respectively. GW4064 also induced expression of these molecules. The effects of CDCA and GW4064 on expression of Cdx2 and MUC2 were abolished by guggulsterone. These findings suggest that bile acids may induce gastric intestinal metaplasia and carcinogenesis through the FXR.
    Journal of Clinical Biochemistry and Nutrition 01/2010; 46(1):81-6. DOI:10.3164/jcbn.09-71 · 2.19 Impact Factor
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