Immunohistochemical assessment for Cdx2 expression in the Barrett metaplasia–dysplasia–adenocarcinoma sequence

Hayes, Stephen; Ahmed, Sajad; Clark, Peter

doi:10.1136/jcp.2010.075945

Cited by 23 publications

(19 citation statements)

References 20 publications

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“…For instance, chronic inflammation of the oesophagus leads to intestinal metaplasia (Barrett's oesophagus) associated with expression of the intestinal transcription factor Cdx2, suggesting that Cdx2 may drive metaplasia 39. The cell type origin of carcinoma often does not correlate with its histological characteristics.…”

Section: Discussionmentioning

confidence: 99%

Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia

Prévôt

Simion

Grimont

et al. 2012

Gut

111

103

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Objective Growing evidence suggests that a phenotypic switch converting pancreatic acinar cells to duct-like cells can lead to pancreatic intraepithelial neoplasia (PanIN) and eventually to invasive pancreatic ductal adenocarcinoma. Histologically, the onset of this switch is characterised by the co-expression of acinar and ductal markers in acini, a lesion called acinar-to-ductal metaplasia (ADM). Transcriptional regulators required to initiate ADM still remain unknown, yet need to be identified to characterise the regulatory networks that drive ADM. Here we investigate the role of the ductal transcription factors Hepatocyte Nuclear Factor 6 (HNF6, also known as Onecut1)and SRY-related HMG box factor 9 (Sox9) in ADM. Design Expression of HNF6 and Sox9 is measured by immunostaining in normal and diseased human pancreas. The function of the factors is tested in cultured cells and in mouse models of ADM by a combination of gain- and loss-of-function experiments. Results Expression of HNF6 and Sox9 is ectopically induced in acinar cells in human ADM, as well as in mouse models of ADM. We show that these factors are required for repression of acinar genes, for modulation of ADM-associated changes in cell polarity, and for activation of ductal genes in metaplastic acinar cells. Conclusions HNF6 and Sox9 are new biomarkers of ADM and constitute candidate targets for preventive therapy in cases when ADM may lead to cancer. Our work also highlights that ectopic activation of transcription factors may underlie metaplastic processes occurring in other organs.

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Section: Discussionmentioning

confidence: 99%

Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia

Prévôt

Simion

Grimont

et al. 2012

Gut

111

103

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“…The CDX1 and CDX2 complexes are indicated by black arrowheads (lanes 1,7,13,20,26,32). The specificity of the complexes was confirmed by incubation with an anti-CDX1 (lanes 2,8,14,20,26,32) or anti-CDX2 (lanes 3,9,15,21,27,33) antibody. To further confirm the specificity of the anti-CDX antibodies used in supershifts, anti-PPAR␣ (lanes 4,10,16,22,28,34) and anti-RXR␣ (lanes 5,11,17,23,29,35) antibodies were tested in parallel.…”

Section: G127mentioning

confidence: 91%

“…However, their levels have been reported to be aberrantly elevated in esophageal metaplasia, such as BE, compared with the adjacent normal tissue (36,41). Similarly to the bile acid transporters, CDX2 expression has been reported to be decreased upon progression of esophageal metaplasia into high-grade adenocarcinoma (21,42). A number of CDX1 and CDX2 transcriptional target genes have been identified so far.…”

mentioning

confidence: 99%

Regulation of the gene encoding the intestinal bile acid transporter ASBT by the caudal-type homeobox proteins CDX1 and CDX2

Jüttner

Kullak‐Ublick

et al. 2012

American Journal of Physiology-Gastrointestinal and Liver Physi

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Ma L, Jüttner M, Kullak-Ublick GA, Eloranta JJ. Regulation of the gene encoding the intestinal bile acid transporter ASBT by the caudal-type homeobox proteins CDX1 and CDX2. Am J Physiol Gastrointest Liver Physiol 302: G123-G133, 2012. First published October 20, 2011 doi:10.1152/ajpgi.00102.2011The apical sodium-dependent bile acid transporter (ASBT) is expressed abundantly in the ileum and mediates bile acid absorption across the apical membranes. Caudal-type homeobox proteins CDX1 and CDX2 are transcription factors that regulate genes involved in intestinal epithelial differentiation and proliferation. Aberrant expression of both ASBT and CDXs in Barrett's esophagus (BE) prompted us to study, whether the expression of the ASBT gene is regulated by CDXs. Short interfering RNA-mediated knockdown of CDXs resulted in reduced ASBT mRNA expression in intestinal cells. CDXs strongly induced the activity of the ASBT promoter in reporter assays in esophageal and intestinal cells. Nine CDX binding sites were predicted in silico within the ASBT promoter, and binding of CDXs to six of them was verified in vitro and within living cells by electrophoretic mobility shift assays and chromatin immunoprecipitation assays, respectively. RNAs were extracted from esophageal biopsies from 20 BE patients and analyzed by real-time PCR. Correlation with ASBT expression was found for CDX1, CDX2, and HNF-1␣ in BE biopsies. In conclusion, the human ASBT promoter is activated transcriptionally by CDX1 and CDX2. Our finding provides a possible explanation for the reported observation that ASBT is aberrantly expressed in esophageal metaplasia that also expresses CDX transcription factors.

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“…Interestingly, CDX2 plays a paradoxical role in oesophageal adenocarcinoma tumorigenesis; first, its expression is required for the generation of a pre-neoplastic and metaplastic columnar phenotype, but it subsequently shows a progressive decline in expression through dysplasia to adenocarcinoma, in keeping with function as a tumour suppressor gene 3 4. In relation to the above paradigm, the development of metaplasia could represent an initiation of normally silent signalling in somatic cells, controlling development and placentation.…”

mentioning

confidence: 99%

“…In comparison with the sequence of large intestinal adenocarcinoma tumorigenesis, CDX2 appears to show considerably earlier downregulation in oesophageal tumorigenesis (ie, downregulation during dysplasia, as opposed to invasion) 3 4. It is uncertain why this is the case, but it may relate to an absence of CDX2 expression in the normal oesophagus, leading to its subsequent unstable expression in Barrett's metaplasia and later stages of tumorigenesis.…”

mentioning

confidence: 99%

Downregulation of CDX2 in gastrointestinal neoplasia

et al. 2013

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Immunohistochemical assessment for Cdx2 expression in the Barrett metaplasia–dysplasia–adenocarcinoma sequence

Abstract: Such downregulation of Cdx2 expression could be in keeping with a role as a tumour suppressor gene, but a simpler explanation would be downregulation of a differentiation marker.

Cited by 23 publications

References 20 publications

Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia

Role of the ductal transcription factors HNF6 and Sox9 in pancreatic acinar-to-ductal metaplasia

Regulation of the gene encoding the intestinal bile acid transporter ASBT by the caudal-type homeobox proteins CDX1 and CDX2

Downregulation of CDX2 in gastrointestinal neoplasia

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