CDX1 expression is reduced in colorectal carcinoma and is associated with promoter hypermethylation

Pilozzi, Emanuela; Onelli, Mariadele Rapazzotti; Ziparo, Vincenzo; Mercantini, Paolo; Ruco, Luigi

doi:10.1002/path.1641

Cited by 31 publications

(27 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As suggested by Wong et al (19), selection for reduced expression of CDX1 by methylation in colorectal cancers (17)(18)(19) is likely to be associated with a reduced capacity of the cancer stem cells to differentiate and so to contribute to an increased rate of growth. Studying the patterns of expression of CDX1 and its downstream-regulated differentiation markers, such as KRT20, should therefore enable better characterization of cancer stem cells both in CRC cell lines and in primary CRCs.…”

Section: Discussionmentioning

confidence: 94%

See 1 more Smart Citation

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

Chan

Wong

Liu

et al. 2009

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

104

View full text Add to dashboard Cite

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...

show abstract

Section: Discussionmentioning

confidence: 94%

“…CDX1 plays a role in intestinal epithelial cell differentiation (16) and is down-regulated in a number of CRC-derived cell lines as well as in patient samples (17)(18)(19). This suggests that absence of CDX1 expression is an advantage for the development of colorectal carcinomas.…”

mentioning

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.

104

View full text Add to dashboard Cite

show abstract

“…Another novel explanation for PITX1 tumorigenesis came from a study on the role of PITX1 in the transcription of the p53 tumor suppressor gene in human mammary carcinoma (MCF-7) cells, implying that p53 is a direct transcriptional target of PITX1 [24] . It has been long recognized that the inactivation of tumor suppressor genes results from mutation, loss of heterozygosity (LOH), aberrant methylation and haploinsufficiency [25,26] , among which aberrant promoter hyper methylation is well-known to par ticipate in homeobox gene silencing [27,28] ; however, PITX1 promoter hypermethylation has not been found in studies of lung cancer [19] . Therefore, we examined the PITX1 gene for the presence of mutations in order to explore the mechanism of inactivation of this candidate tumor suppressor gene.…”

Section: Discussionmentioning

confidence: 99%

Expression of pituitary homeobox 1 gene in human gastric carcinogenesis and its clinicopathological significance

Chen¹,

Chen²,

Yang³

et al. 2008

WJG

View full text Add to dashboard Cite

AIM:To investigate the effect of pituitary homeobox 1 (PITX1) expression in cases of human gastric cancer on cancer differentiation and progression, and carcinogenesis. METHODS:Using polyclonal PITX1 antibodies, we studied the expression of PITX1 in normal gastric mucosa, atypical hyperplasia, intestinal metaplasia, and cancer tissue samples from 83 gastric cancer patients by immunohistochemistry. Moreover, semi-reverse transcription polymerase chain reaction (semi-RT-PCR) was performed to detect the mRNA level of PITX1 in three gastric cancer cell lines and a normal gastric epithelial cell line. Subsequently, somatic mutations of the PITX1 gene in 71 gastric cancer patients were analyzed by a combination of denaturing high performance liquid chromatography (DHPLC) and DNA sequencing. RESULTS:Immunohistochemistry showed that PITX1 was strongly or moderately expressed in the parietal cells of normal gastric mucosa (100%), while 55 (66.3%) out of 83 samples of gastric cancers showed decreased PITX1 expression. Moreover, PITX1 expression was reduced in 20 out of 28 cases (71.5%) of intestinal metaplasia, but in only 1 out of 9 cases (11%) of atypical hyperplasia. More importantly, PITX1 expression was significantly associated with the differentiation, position and invasion depth of gastric cancers (r = -0.316, P < 0.01; r = 0.213, P < 0.05; r = -0.259, P < 0.05, respectively). Similarly, levels of PITX1 mRNA were significantly decreased in 2 gastric cancer cell lines, BGC-823 and SGC-7901, compared with the normal gastric epithelial cell line GES-1 (0.306 ± 0.060 vs 0.722 ± 0.102, P < 0.05; 0.356 ± 0.081 vs 0.722 ± 0.102, P < 0.05, respectively). Nevertheless, no somatic mutation of PITX1 gene was found in 71 samples of gastric cancer by DHPLC analysis followed by sequencing.CONCLUSION: Down-regulation of PITX1 may be a frequent molecular event in gastric carcinogenesis. Aberrant levels of PITX1 expression may be closely correlated with the progression and differentiation of gastric cancer.

show abstract

“…During intestinal carcinogenesis, Cdx1 overexpression may increase the severity of malignancy at least transiently at early stages in the case of small intestinal tumours, before being lost in advanced tumours by promoter hypermethylation and allelic loss (Domon-Dell et al, 2003;Pilozzi et al, 2004). The relatively limited impact of Cdx1 on intestinal development and cancer is in clear opposition with Cdx2 that controls intestinal morphogenesis (Beck et al, 1999) and is a tumour suppressor in the colon (Aoki et al, 2003;Bonhomme et al, 2003).…”

Section: Cdx1 In Mouse Intestinal Development and Cancer C Bonhomme Ementioning

confidence: 99%

“…In intestinal cells cultured in vitro, Cdx1 stimulates differentiation (Soubeyran et al, 1999) and either stimulates (Lorentz et al, 1997;Soubeyran et al, 1999) or inhibits proliferation (Lynch et al, 2000). In human colon cancers, Cdx1 expression increases in few adenomas and carcinomas but decreases or is even lost in the majority of carcinomas (Mallo et al, 1997;Silberg et al, 1997;Vider et al, 1997;Domon-Dell et al, 2003;Pilozzi et al, 2004). The aim of this study was to decipher the role of Cdx1 in the normal gut and the consequences of its alterations in intestinal cancers, using loss-and gain-of-function approaches in mice.…”

mentioning

confidence: 99%

Cdx1, a dispensable homeobox gene for gut development with limited effect in intestinal cancer

et al. 2008

View full text Add to dashboard Cite

The homeobox gene Cdx1 is involved in anteroposterior patterning in embryos and its expression selectively persists in the intestinal epithelium throughout life. In human colon cancers, Cdx1 is overexpressed in few cases and lost in the majority of adenocarcinomas. We used mouse models of gain and loss-of-function to investigate the role of Cdx1 in intestinal development and cancers. Transgenic mice overexpressing Cdx1 and knockout mice exhibited a morphologically normal intestine. Cell proliferation, specification into the four differentiated lineages and migration along the crypt-villus axis were unchanged compared to wild-type mice. Changing Cdx1 caused an inverse and dose-dependent modification of the expression of the paralogous gene Cdx2, indicating that Cdx1 fine-tunes Cdx2 activity. Transgenenic and knockout mice failed to spontaneously develop tumours. Overexpressing Cdx1 was without incidence on the frequency of intestinal tumours induced chemically by azoxymethane treatment or genetically in Apc D14/ þ mice. However, it augmented the severity of the tumours in Apc D14/ þ mice. Inversely, the loss-of-function of Cdx1 in knockout mice was without incidence on the growth of tumours induced by azoxymethane. We conclude that Cdx1 is dispensable for intestinal development and that its overexpression could increase malignancy in early stages of tumourigenesis.

show abstract

CDX1 expression is reduced in colorectal carcinoma and is associated with promoter hypermethylation

Cited by 31 publications

References 22 publications

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

Gastrointestinal differentiation marker Cytokeratin 20 is regulated by homeobox gene CDX1

Expression of pituitary homeobox 1 gene in human gastric carcinogenesis and its clinicopathological significance

Cdx1, a dispensable homeobox gene for gut development with limited effect in intestinal cancer

Contact Info

Product

Resources

About