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CD44 expression in intestinal epithelium and colorectal cancer is independent of p53 status.

Zeilstra J, Joosten SP, Vermeulen L, Koster J, Medema JP, Versteeg R, Spaargaren M, Pals ST - PLoS ONE (2013)

Bottom Line: CD44 marks stem cell-like cells in a number of tumour types, including colorectal cancer (CRC), while aberrant CD44 expression conveys increased tumourigenic, invasive, and metastatic potential.In the present study, we therefore explored the relation between p53 mutational status and CD44 expression in a cohort of 90 localized primary CRCs and studied the effect of radiation-induced p53 activation on CD44 expression.Moreover, DNA-damage induced p53 activation did not result in repression of CD44 expression, neither in colon cancer cells nor in normal intestinal epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
CD44 marks stem cell-like cells in a number of tumour types, including colorectal cancer (CRC), while aberrant CD44 expression conveys increased tumourigenic, invasive, and metastatic potential. Previous data indicate that CD44 is a direct target of p53-mediated transcriptional repression in breast cancer. Since inactivating p53 mutations are frequent genetic events in CRC these could unleash expression of CD44. In the present study, we therefore explored the relation between p53 mutational status and CD44 expression in a cohort of 90 localized primary CRCs and studied the effect of radiation-induced p53 activation on CD44 expression. Interestingly, we observed that, in contrast to breast cancer, loss of function p53 mutations were not associated with elevated CD44 expression in colon cancer. Moreover, DNA-damage induced p53 activation did not result in repression of CD44 expression, neither in colon cancer cells nor in normal intestinal epithelial cells. Our data demonstrate that CD44 expression in normal and malignant intestinal epithelial cells is not regulated by p53, implying that regulation of this potentially important therapeutic target is tissue and cancer-type specific.

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Loss of function mutation of p53 is not associated with elevated CD44 expression in colon cancer.Relative gene expression levels in p53 mutant and p53 wild-type adenocarcinomas for (A) CDKN1A (p21) (**, P<0.01), (B) MDM2 (***, P<0.001), (C) CD44, (**, P<0.01).
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pone-0072849-g001: Loss of function mutation of p53 is not associated with elevated CD44 expression in colon cancer.Relative gene expression levels in p53 mutant and p53 wild-type adenocarcinomas for (A) CDKN1A (p21) (**, P<0.01), (B) MDM2 (***, P<0.001), (C) CD44, (**, P<0.01).

Mentions: The recent identification of p53 as a transcriptional repressor of CD44 in breast cancer and mammary epithelium [16], prompted us to explore whether a similar functional relation exists in colon cancer and intestinal epithelium. We therefore examined the relation between p53 mutational status and CD44 mRNA levels in a cohort of 90 colorectal carcinomas. All tumours included in this study were adenocarcinomas with invasion through the muscularis propria, but without lymph node or distant metastasis (Dukes B, AJCC Stage II). Mutational status was assessed by cDNA sequencing of the entire coding region of the p53 gene, spanning exons 1 to 11. Sequence analysis identified 25 tumours (28%) with a mutation, resulting in a transcriptionally inactive p53 protein according to the definition of Soussi et al. [22] (Table 2). Comparison between the groups with wild-type and mutant p53 revealed a significantly decreased mRNA expression of two canonical p53 transcriptional targets, CDKN1A (p21) (P<0.01) [23] and MDM2 (P<0.001) [24] in the tumours with p53 loss of function mutations (Figure 1A and B). Interestingly, in contrast to mammary tumours in which loss of p53 function was found to be significantly correlated with elevated CD44 expression [16], p53 mutation in colon carcinomas was correlated with decreased CD44 mRNA expression levels (P<0.01; Figure 1C). These results imply that p53 does not act as a transcriptional repressor of CD44 expression in CRC.


CD44 expression in intestinal epithelium and colorectal cancer is independent of p53 status.

Zeilstra J, Joosten SP, Vermeulen L, Koster J, Medema JP, Versteeg R, Spaargaren M, Pals ST - PLoS ONE (2013)

Loss of function mutation of p53 is not associated with elevated CD44 expression in colon cancer.Relative gene expression levels in p53 mutant and p53 wild-type adenocarcinomas for (A) CDKN1A (p21) (**, P<0.01), (B) MDM2 (***, P<0.001), (C) CD44, (**, P<0.01).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3756983&req=5

pone-0072849-g001: Loss of function mutation of p53 is not associated with elevated CD44 expression in colon cancer.Relative gene expression levels in p53 mutant and p53 wild-type adenocarcinomas for (A) CDKN1A (p21) (**, P<0.01), (B) MDM2 (***, P<0.001), (C) CD44, (**, P<0.01).
Mentions: The recent identification of p53 as a transcriptional repressor of CD44 in breast cancer and mammary epithelium [16], prompted us to explore whether a similar functional relation exists in colon cancer and intestinal epithelium. We therefore examined the relation between p53 mutational status and CD44 mRNA levels in a cohort of 90 colorectal carcinomas. All tumours included in this study were adenocarcinomas with invasion through the muscularis propria, but without lymph node or distant metastasis (Dukes B, AJCC Stage II). Mutational status was assessed by cDNA sequencing of the entire coding region of the p53 gene, spanning exons 1 to 11. Sequence analysis identified 25 tumours (28%) with a mutation, resulting in a transcriptionally inactive p53 protein according to the definition of Soussi et al. [22] (Table 2). Comparison between the groups with wild-type and mutant p53 revealed a significantly decreased mRNA expression of two canonical p53 transcriptional targets, CDKN1A (p21) (P<0.01) [23] and MDM2 (P<0.001) [24] in the tumours with p53 loss of function mutations (Figure 1A and B). Interestingly, in contrast to mammary tumours in which loss of p53 function was found to be significantly correlated with elevated CD44 expression [16], p53 mutation in colon carcinomas was correlated with decreased CD44 mRNA expression levels (P<0.01; Figure 1C). These results imply that p53 does not act as a transcriptional repressor of CD44 expression in CRC.

Bottom Line: CD44 marks stem cell-like cells in a number of tumour types, including colorectal cancer (CRC), while aberrant CD44 expression conveys increased tumourigenic, invasive, and metastatic potential.In the present study, we therefore explored the relation between p53 mutational status and CD44 expression in a cohort of 90 localized primary CRCs and studied the effect of radiation-induced p53 activation on CD44 expression.Moreover, DNA-damage induced p53 activation did not result in repression of CD44 expression, neither in colon cancer cells nor in normal intestinal epithelial cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

ABSTRACT
CD44 marks stem cell-like cells in a number of tumour types, including colorectal cancer (CRC), while aberrant CD44 expression conveys increased tumourigenic, invasive, and metastatic potential. Previous data indicate that CD44 is a direct target of p53-mediated transcriptional repression in breast cancer. Since inactivating p53 mutations are frequent genetic events in CRC these could unleash expression of CD44. In the present study, we therefore explored the relation between p53 mutational status and CD44 expression in a cohort of 90 localized primary CRCs and studied the effect of radiation-induced p53 activation on CD44 expression. Interestingly, we observed that, in contrast to breast cancer, loss of function p53 mutations were not associated with elevated CD44 expression in colon cancer. Moreover, DNA-damage induced p53 activation did not result in repression of CD44 expression, neither in colon cancer cells nor in normal intestinal epithelial cells. Our data demonstrate that CD44 expression in normal and malignant intestinal epithelial cells is not regulated by p53, implying that regulation of this potentially important therapeutic target is tissue and cancer-type specific.

Show MeSH
Related in: MedlinePlus