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p63 transcriptionally regulates the expression of matrix metallopeptidase 13.

Celardo I, Antonov A, Amelio I, Annicchiarico-Petruzzelli M, Melino G - Oncotarget (2014)

Bottom Line: p63 is a transcriptional factor belonging to p53 family of genes.Here we show that p63 transcriptionally controls the expression of the matrix metallopeptidase 13 (MMP13). p63 binds a p53-like responsive element in the human promoter of MMP13, thus promoting the activation of its transcription.Our results demonstrate that p63 directly controls MMP13 expression.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.

ABSTRACT
p63 is a transcriptional factor belonging to p53 family of genes. Beside the role in cancer, partially shared with p53 and the other member p73, p63 also plays exclusive roles in development and homeostasis of ectodermal/epidermal-related organs. Here we show that p63 transcriptionally controls the expression of the matrix metallopeptidase 13 (MMP13). p63 binds a p53-like responsive element in the human promoter of MMP13, thus promoting the activation of its transcription. The catalytic activity of MMP13 is required in high invasion capacity of metastatic cancer cells, however, although p63 and MMP13 expression correlates in cancer patients, their co-expression does not predict cancer patient survival. Our results demonstrate that p63 directly controls MMP13 expression.

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p63 and MMP13 expression directly correlates in human breast and melanoma cancers(a,b) Expression data from Oncomine website (www.oncomine.org). We used the following filters: gene ‘TP63’ Analysis Type: ‘Coexpression analysis’ Cancer Type: Breast (a) or Melanoma Cancer (b). The colour changes according to a weaker (blue) or higher (red) expression, passing by white, with fluctuating colour intensity. The reporters indicate probes used for the analysis.
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Figure 3: p63 and MMP13 expression directly correlates in human breast and melanoma cancers(a,b) Expression data from Oncomine website (www.oncomine.org). We used the following filters: gene ‘TP63’ Analysis Type: ‘Coexpression analysis’ Cancer Type: Breast (a) or Melanoma Cancer (b). The colour changes according to a weaker (blue) or higher (red) expression, passing by white, with fluctuating colour intensity. The reporters indicate probes used for the analysis.

Mentions: To confirm the existence and to assess the relevance of p63/MMP13 axis, we searched for expression correlation of these two genes in human cancer patient datasets. Breast cancer represents a heterogeneous group of diseases with different biological and morphological features, although strong efforts have been placed in identification of biomarkers of high-grade/metastatic forms of this disease[90-92], still much is expected to improve prognostic and predictive marker assessment. Melanoma is among the most aggressive cancer, with high incidence of metastasis and advanced stages progression [93-96]. Therefore to confirm p63/MMP13 relevance in cancer, we selected two cancer datasets: a breast carcinoma cohort [97] of 87 samples and a melanoma cohort, which included 25 melanomas [98], 9 non-neoplastic nevus and 3 normal samples. Coexpression analysis showed direct association between p63 and MMP13 mRNA level in both the datasets analysed. The breast cancer dataset presented a correlation factor of 0.293, while the melanoma dataset of 0.298 (Fig. 3A,B). These data confirm a coexpression and a direct correlation of p63 and MMP13 in human cancers. The melanoma dataset included normal and non-neoplastic specimens. Interestingly, a clear switch from high p63/MMP13 expression to low p63/MMP13 occurred in the transition towards the malignant state of melanocytes (Fig. 3B). To further investigate the function of p63/MMP13 in cancer, we decided to analysed MMP13 ability to function as prognostic factor of human cancer. We used three different publicly available datasets of human cancer, which included patient survival information (lung adenocarcinoma GSE31210, breast cancer GSE2034, and liposarcoma GSE30929). Patient datasets were clustered according to the expression of MMP13 (high expressing, low expressing). Kaplan-Mayer curve for survival estimation showed that a high MMP13 expression was predictive of poor survival (Fig. 4A-C), suggesting that MMP13 plays an important role in cancer aggressiveness. In order to elucidate whether p63 functions as a controller of MMP13 expression in cancer, we evaluated the biological consequence of p63/MMP13 coexpression in cancer patients. We selected the datasets analyzed in figure 4 (lung adenocarcinoma GSE31210, breast cancer GSE2034, and liposarcoma GSE30929) and we split the samples in two cohorts. The first cohort included all the samples to maximize positive correlation between p63 and MMP13, while in the second cohort all the other samples were included (Fig. 5). Thus, we clustered the dataset in two biological groups: one where p63/MMP13 axis was present (p63/MMP13 interaction), and second in which it was absent (p63/MMP13 NO interaction). Performing Kaplan-Mayer survival estimation the two cohorts did not show any significant difference in the survival expectation (Fig. 5). These data suggest that, although p63 is able to control MMP13 expression, it is very unlikely this axis plays any relevant role in cancer biology.


p63 transcriptionally regulates the expression of matrix metallopeptidase 13.

Celardo I, Antonov A, Amelio I, Annicchiarico-Petruzzelli M, Melino G - Oncotarget (2014)

p63 and MMP13 expression directly correlates in human breast and melanoma cancers(a,b) Expression data from Oncomine website (www.oncomine.org). We used the following filters: gene ‘TP63’ Analysis Type: ‘Coexpression analysis’ Cancer Type: Breast (a) or Melanoma Cancer (b). The colour changes according to a weaker (blue) or higher (red) expression, passing by white, with fluctuating colour intensity. The reporters indicate probes used for the analysis.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4012734&req=5

Figure 3: p63 and MMP13 expression directly correlates in human breast and melanoma cancers(a,b) Expression data from Oncomine website (www.oncomine.org). We used the following filters: gene ‘TP63’ Analysis Type: ‘Coexpression analysis’ Cancer Type: Breast (a) or Melanoma Cancer (b). The colour changes according to a weaker (blue) or higher (red) expression, passing by white, with fluctuating colour intensity. The reporters indicate probes used for the analysis.
Mentions: To confirm the existence and to assess the relevance of p63/MMP13 axis, we searched for expression correlation of these two genes in human cancer patient datasets. Breast cancer represents a heterogeneous group of diseases with different biological and morphological features, although strong efforts have been placed in identification of biomarkers of high-grade/metastatic forms of this disease[90-92], still much is expected to improve prognostic and predictive marker assessment. Melanoma is among the most aggressive cancer, with high incidence of metastasis and advanced stages progression [93-96]. Therefore to confirm p63/MMP13 relevance in cancer, we selected two cancer datasets: a breast carcinoma cohort [97] of 87 samples and a melanoma cohort, which included 25 melanomas [98], 9 non-neoplastic nevus and 3 normal samples. Coexpression analysis showed direct association between p63 and MMP13 mRNA level in both the datasets analysed. The breast cancer dataset presented a correlation factor of 0.293, while the melanoma dataset of 0.298 (Fig. 3A,B). These data confirm a coexpression and a direct correlation of p63 and MMP13 in human cancers. The melanoma dataset included normal and non-neoplastic specimens. Interestingly, a clear switch from high p63/MMP13 expression to low p63/MMP13 occurred in the transition towards the malignant state of melanocytes (Fig. 3B). To further investigate the function of p63/MMP13 in cancer, we decided to analysed MMP13 ability to function as prognostic factor of human cancer. We used three different publicly available datasets of human cancer, which included patient survival information (lung adenocarcinoma GSE31210, breast cancer GSE2034, and liposarcoma GSE30929). Patient datasets were clustered according to the expression of MMP13 (high expressing, low expressing). Kaplan-Mayer curve for survival estimation showed that a high MMP13 expression was predictive of poor survival (Fig. 4A-C), suggesting that MMP13 plays an important role in cancer aggressiveness. In order to elucidate whether p63 functions as a controller of MMP13 expression in cancer, we evaluated the biological consequence of p63/MMP13 coexpression in cancer patients. We selected the datasets analyzed in figure 4 (lung adenocarcinoma GSE31210, breast cancer GSE2034, and liposarcoma GSE30929) and we split the samples in two cohorts. The first cohort included all the samples to maximize positive correlation between p63 and MMP13, while in the second cohort all the other samples were included (Fig. 5). Thus, we clustered the dataset in two biological groups: one where p63/MMP13 axis was present (p63/MMP13 interaction), and second in which it was absent (p63/MMP13 NO interaction). Performing Kaplan-Mayer survival estimation the two cohorts did not show any significant difference in the survival expectation (Fig. 5). These data suggest that, although p63 is able to control MMP13 expression, it is very unlikely this axis plays any relevant role in cancer biology.

Bottom Line: p63 is a transcriptional factor belonging to p53 family of genes.Here we show that p63 transcriptionally controls the expression of the matrix metallopeptidase 13 (MMP13). p63 binds a p53-like responsive element in the human promoter of MMP13, thus promoting the activation of its transcription.Our results demonstrate that p63 directly controls MMP13 expression.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council, Toxicology Unit, Leicester University, Leicester LE1 9HN, UK.

ABSTRACT
p63 is a transcriptional factor belonging to p53 family of genes. Beside the role in cancer, partially shared with p53 and the other member p73, p63 also plays exclusive roles in development and homeostasis of ectodermal/epidermal-related organs. Here we show that p63 transcriptionally controls the expression of the matrix metallopeptidase 13 (MMP13). p63 binds a p53-like responsive element in the human promoter of MMP13, thus promoting the activation of its transcription. The catalytic activity of MMP13 is required in high invasion capacity of metastatic cancer cells, however, although p63 and MMP13 expression correlates in cancer patients, their co-expression does not predict cancer patient survival. Our results demonstrate that p63 directly controls MMP13 expression.

Show MeSH
Related in: MedlinePlus