Methylation and colorectal cancer

Jubb, A. M.; Bell, Sandra; Quirke, Philip

doi:10.1002/path.923

Cited by 118 publications

(96 citation statements)

References 205 publications

(431 reference statements)

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“…This signaling, however, only affects CDX1 expression if the CDX1 promoter is either unmethylated or partially methylated, as is expected on the basis that promoter methylation prevents access to regulatory transcription factors (25). We suggest, therefore, that CDX1 promoter demethylation is the key trigger for the development of BM.…”

Section: Discussionmentioning

confidence: 51%

CDX1 is an important molecular mediator of Barrett's metaplasia

Wong

Wilding

Bartlett

et al. 2005

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

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The molecular pathogenesis of Barrett's metaplasia (BM) of the esophagus is poorly understood. The change to an intestinal phenotype occurs on a background of esophagitis due to refluxing acid and bile. CDX1, an important regulator of normal intestinal development, was studied as a potential key molecule in the pathogenesis of BM. CDX1 mRNA and protein were universally expressed in all samples of BM tested but not in normal esophageal squamous or gastric body epithelia. This tissue-specific expression was attributable to the methylation status of the CDX1 promoter. Conjugated bile salts and the inflammatory cytokines ⌻NF-␣ and IL-1␤ were all found to increase CDX1 mRNA expression in vitro. These effects were primarily mediated by NF-B signaling but only occurred when the CDX1 promoter was unmethylated or partially methylated. The data suggest that CDX1 is a key molecule linking etiological agents of BM to the development of an intestinal phenotype. Although the initial trigger for CDX1 promoter demethylation is not yet identified, it seems likely that demethylation of its promoter may be the key to the induction and maintenance of CDX1 expression and so of the BM phenotype.colorectal carcinoma ͉ deoxycytidine ͉ gastroesophageal reflux disease ͉ intestinal metaplasia ͉ promoter methylation

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Section: Discussionmentioning

confidence: 51%

CDX1 is an important molecular mediator of Barrett's metaplasia

Wong

Wilding

Bartlett

et al. 2005

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

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“…Regional hypermethylation plays an important role in the alteration of gene expression in carcinoma formation and in the progression of carcinoma (Bird, 1996;Jubb et al, 2001;Jones and Baylin, 2002). We found evidence for hypermethylation in the KLF4 5′-UTR in a subset of surgically resected CRC specimens.…”

Section: Discussionmentioning

confidence: 58%

Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer

et al. 2004

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Krüppel-like factor 4 (KLF4 or GKLF) is an inhibitor of the cell cycle. The gene encoding KLF4 is localized on chromosome 9q, previously shown to exhibit allelic loss in colorectal cancer (CRC). In this study, we show that the mean level of KLF4 mRNA in a panel of 30 CRC was 52% that of paired normal colonic tissues. Similarly, the levels of KLF4 mRNA and protein in a panel of six established CRC cell lines were significantly lower than those of an untransformed colonic epithelial cell line. Using highly polymorphic DNA markers that .ank the KLF4 locus, we found evidence for loss of heterozygosity (LOH) in two of eight surgically resected CRC specimens. In addition, LOH was observed in .ve of six CRC cell lines with one additional cell line exhibiting hemizygous deletion in the KLF4 gene. We also found that the 5′-untranslated region of KLF4 was hypermethylated in a subset of resected CRC specimens and cell lines. Lastly, the open-reading frame of KLF4 in two of three CRC cell lines examined contained several point mutations that resulted in a diminished ability to activate the p21 WAF1/Cip1 promoter. These findings indicate that KLF4 is a potential tumor suppressor gene in CRC.

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“…The colonic crypt can be considered to consist of a group of clonal cells, because each one of its cells arises from a single stem cell (9,11). It is known that the expression of the cell molecules may be influenced by epigenetic mechanisms during colonic car- (22). Recently, it has been observed that exposure to a non-genotoxic dietrelated compound modulates the chemical carcinogenic effects of nitroso compounds for the induction of crypt-restricted MT immunopositivity (12).…”

Section: Resultsmentioning

confidence: 99%

Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis

Escalante

Oliveira

Cunha

et al. 2006

Braz J Med Biol Res

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Trypanosoma cruzi infection and nonsteroidal anti-inflammatory drugs inhibit colorectal carcinogenesis by mechanisms not completely known and metallothionein proteins (MTs) may be involved in this process. Sixty-six male Wistar rats weighing 90 to 120 g were randomly divided into seven groups (GI to GVII). GI, GII and GIII animals were subcutaneously infected with 200,000 trypomastigote forms of the Y strain of T. cruzi. After 8 weeks, GI, GII, GIV, and GVI were injected with one weekly subcutaneous dose of 12 mg/kg dimethylhydrazine for 4 weeks. In sequence, GI, GIV and GV were treated with nimesulide (10 mg/kg per dose, five times per week for 8 weeks). Groups I, III, IV, and VI had 12 animals, and each of the other groups had 6 animals. All the animals were euthanized 8 weeks after the last dimethylhydrazine injection. The colons were fixed and processed for MT immunohistochemistry. The index of MT-overexpressing colonic crypts (MTEC) was estimated as the percentage of MT-stained crypts in relation to the total number of crypts scored. Five hundred crypts per animal were scored. Data were analyzed by the Kruskal-Wallis test followed by the Dunn test. There was an increase in MTEC index in the groups either infected with T. cruzi or treated with nimesulide or both infected and treated when compared to control (401, 809, and 1011%, respectively). We suggest that the increased formation of MTEC may be related to the protection against carcinogenesis provided both by T. cruzi infection and nimesulide.

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Methylation and colorectal cancer

Cited by 118 publications

References 205 publications

CDX1 is an important molecular mediator of Barrett's metaplasia

CDX1 is an important molecular mediator of Barrett's metaplasia

Identification of Krüppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer

Trypanosoma cruzi infection and/or administration of the nonsteroidal anti-inflammatory nimesulide increase the number of colonic crypts overexpressing metallothioneins in rat colon carcinogenesis

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