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Suppression of cancer stemness p21-regulating mRNA and microRNA signatures in recurrent ovarian cancer patient samples.

Gallagher MF, Heffron CC, Laios A, O'Toole SA, Ffrench B, Smyth PC, Flavin RJ, Elbaruni SA, Spillane CD, Martin CM, Sheils OM, O'Leary JJ - J Ovarian Res (2012)

Bottom Line: Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component.We present a p53-p21 cancer stemness signature model for ovarian cancer.Targeting CSCs within ovarian cancer represents a potential therapeutic avenue.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Histopathology, University of Dublin, Trinity College, Trinity Centre for Health Sciences, St James' Hospital, Dublin 8, Ireland. gallagmi@tcd.ie.

ABSTRACT

Background: Malignant ovarian disease is characterised by high rates of mortality due to high rates of recurrent chemoresistant disease. Anecdotal evidence indicates this may be due to chemoresistant properties of cancer stem cells (CSCs). However, our understanding of the role of CSCs in recurrent ovarian disease remains sparse. In this study we used gene microarrays and meta-analysis of our previously published microRNA (miRNA) data to assess the involvement of cancer stemness signatures in recurrent ovarian disease.

Methods: Microarray analysis was used to characterise early regulation events in an embryonal carcinoma (EC) model of cancer stemness. This was then compared to our previously published microarray data from a study of primary versus recurrent ovarian disease. In parallel, meta-analysis was used to identify cancer stemness miRNA signatures in tumor patient samples.

Results: Microarray analysis demonstrated a 90% difference between gene expression events involved in early regulation of differentiation in murine EC (mEC) and embryonic stem (mES) cells. This contrasts the known parallels between mEC and mES cells in the undifferentiated and well-differentiated states. Genelist comparisons identified a cancer stemness signature set of genes in primary versus recurrent data, a subset of which are known p53-p21 regulators. This signature is present in primary and recurrent or in primary alone but essentially never in recurrent tumors specifically. Meta-analysis of miRNA expression showed a much stronger cancer stemness signature within tumor samples. This miRNA signature again related to p53-p21 regulation and was expressed prominently in recurrent tumors. Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component.

Conclusion: We present a p53-p21 cancer stemness signature model for ovarian cancer. We propose that this may, at least partially, differentially regulate the p53-p21 mechanism in ovarian disease. Targeting CSCs within ovarian cancer represents a potential therapeutic avenue.

No MeSH data available.


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Expression of 2102Ep stemness signature miRNAs in recurrent tumors. Twenty six miRNAs were identified as differentially expressed in undifferentiated 2102Ep compared to undifferentiated NTera2 hEC cells and in tumor data. Data is presented as log10 (fold change). miRNAs presented showed altered expression in undifferentiated 2102Ep cells compared to undifferentiated NTera2 (blue) and in recurrent tumors compared to primary (red). Values represent the mean of at least n = 3 and error bars the standard error of the mean.
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Figure 5: Expression of 2102Ep stemness signature miRNAs in recurrent tumors. Twenty six miRNAs were identified as differentially expressed in undifferentiated 2102Ep compared to undifferentiated NTera2 hEC cells and in tumor data. Data is presented as log10 (fold change). miRNAs presented showed altered expression in undifferentiated 2102Ep cells compared to undifferentiated NTera2 (blue) and in recurrent tumors compared to primary (red). Values represent the mean of at least n = 3 and error bars the standard error of the mean.

Mentions: Having identified gene level overlaps, we next conducted overlap meta-analysis of our previously published miRNA data for primary and recurrent patient samples and human EC (hEC) early (three day) differentiation [5,6,15]. The earlier study identified cancer stemness signature miRNAs: those miRNAs involved in the differentiation of hEC cells. Specifically, our previous tumor study highlighted 60 miRNAs (52 up and 8 downregulated) in recurrent disease [6]. Of these, 55 miRNAs (92%) are expressed in hEC cells (Additional File 5). 21 recurrent disease-specific miRNAs are linked to differentiation of pluripotent NTera2 hEC cells (Figure 4). We have previously shown that ipotent 2102Ep hEC cells express a large number of miRNAs at substantially higher levels than NTera2 cells [15]. Here we report that 26 (43%) recurrent disease-specific miRNAs are expressed at higher levels in 2102Ep cells than in NTera2 (Figure 5). Thus, development of recurrent tumors involves recruitment of cancer stemness signature miRNAs. Specific examples include miR-9, which is the most downregulated miRNA in recurrent tumors and is > 1000% higher expressed in undifferentiated 2102Ep cells compared to NTera2, and miR-206, which is in the top ten miRNAs upregulated by recurrent tumors and downregulated during NTera2 differentiation. Molecular pathway relationships between predicted gene targets of the miRNAs highlighted were identified using DIANAmirPATH (Additional file 5). While little pathway overlap was observed in gene array data, miRNA data showed strong pathway associations. Pathway analysis highlighted alteration of several cancer pathways (miRs-10b, -100, -106, -107, -128 and let-7g) as well as Wnt and TGF-β stemness signaling pathways (mirs-10b, -100, -106, -128a and 137). Finally, we assessed the expression of p53-p21 regulating miRNAs in these datasets. Two miRNAs, miRs-106a and b, are validated targets of p21 [52] that are upregulated in recurrent disease and expressed in hEC cells. Notably, miR-106b expression in 2102Ep cells is double that of NTera2 cells. In contrast, miR-155, the only validated p53-regulating miRNA, is unaltered in recurrent tumors. We note that the p53 signaling pathway was highlighted for let-7g and miRs-106b and -107 in pathway analysis (Additional file 5). In overview, we find that miRNAs linked to 2102Ep malignancy are highly relevant to primary and recurrent tumors.


Suppression of cancer stemness p21-regulating mRNA and microRNA signatures in recurrent ovarian cancer patient samples.

Gallagher MF, Heffron CC, Laios A, O'Toole SA, Ffrench B, Smyth PC, Flavin RJ, Elbaruni SA, Spillane CD, Martin CM, Sheils OM, O'Leary JJ - J Ovarian Res (2012)

Expression of 2102Ep stemness signature miRNAs in recurrent tumors. Twenty six miRNAs were identified as differentially expressed in undifferentiated 2102Ep compared to undifferentiated NTera2 hEC cells and in tumor data. Data is presented as log10 (fold change). miRNAs presented showed altered expression in undifferentiated 2102Ep cells compared to undifferentiated NTera2 (blue) and in recurrent tumors compared to primary (red). Values represent the mean of at least n = 3 and error bars the standard error of the mean.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3285047&req=5

Figure 5: Expression of 2102Ep stemness signature miRNAs in recurrent tumors. Twenty six miRNAs were identified as differentially expressed in undifferentiated 2102Ep compared to undifferentiated NTera2 hEC cells and in tumor data. Data is presented as log10 (fold change). miRNAs presented showed altered expression in undifferentiated 2102Ep cells compared to undifferentiated NTera2 (blue) and in recurrent tumors compared to primary (red). Values represent the mean of at least n = 3 and error bars the standard error of the mean.
Mentions: Having identified gene level overlaps, we next conducted overlap meta-analysis of our previously published miRNA data for primary and recurrent patient samples and human EC (hEC) early (three day) differentiation [5,6,15]. The earlier study identified cancer stemness signature miRNAs: those miRNAs involved in the differentiation of hEC cells. Specifically, our previous tumor study highlighted 60 miRNAs (52 up and 8 downregulated) in recurrent disease [6]. Of these, 55 miRNAs (92%) are expressed in hEC cells (Additional File 5). 21 recurrent disease-specific miRNAs are linked to differentiation of pluripotent NTera2 hEC cells (Figure 4). We have previously shown that ipotent 2102Ep hEC cells express a large number of miRNAs at substantially higher levels than NTera2 cells [15]. Here we report that 26 (43%) recurrent disease-specific miRNAs are expressed at higher levels in 2102Ep cells than in NTera2 (Figure 5). Thus, development of recurrent tumors involves recruitment of cancer stemness signature miRNAs. Specific examples include miR-9, which is the most downregulated miRNA in recurrent tumors and is > 1000% higher expressed in undifferentiated 2102Ep cells compared to NTera2, and miR-206, which is in the top ten miRNAs upregulated by recurrent tumors and downregulated during NTera2 differentiation. Molecular pathway relationships between predicted gene targets of the miRNAs highlighted were identified using DIANAmirPATH (Additional file 5). While little pathway overlap was observed in gene array data, miRNA data showed strong pathway associations. Pathway analysis highlighted alteration of several cancer pathways (miRs-10b, -100, -106, -107, -128 and let-7g) as well as Wnt and TGF-β stemness signaling pathways (mirs-10b, -100, -106, -128a and 137). Finally, we assessed the expression of p53-p21 regulating miRNAs in these datasets. Two miRNAs, miRs-106a and b, are validated targets of p21 [52] that are upregulated in recurrent disease and expressed in hEC cells. Notably, miR-106b expression in 2102Ep cells is double that of NTera2 cells. In contrast, miR-155, the only validated p53-regulating miRNA, is unaltered in recurrent tumors. We note that the p53 signaling pathway was highlighted for let-7g and miRs-106b and -107 in pathway analysis (Additional file 5). In overview, we find that miRNAs linked to 2102Ep malignancy are highly relevant to primary and recurrent tumors.

Bottom Line: Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component.We present a p53-p21 cancer stemness signature model for ovarian cancer.Targeting CSCs within ovarian cancer represents a potential therapeutic avenue.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Histopathology, University of Dublin, Trinity College, Trinity Centre for Health Sciences, St James' Hospital, Dublin 8, Ireland. gallagmi@tcd.ie.

ABSTRACT

Background: Malignant ovarian disease is characterised by high rates of mortality due to high rates of recurrent chemoresistant disease. Anecdotal evidence indicates this may be due to chemoresistant properties of cancer stem cells (CSCs). However, our understanding of the role of CSCs in recurrent ovarian disease remains sparse. In this study we used gene microarrays and meta-analysis of our previously published microRNA (miRNA) data to assess the involvement of cancer stemness signatures in recurrent ovarian disease.

Methods: Microarray analysis was used to characterise early regulation events in an embryonal carcinoma (EC) model of cancer stemness. This was then compared to our previously published microarray data from a study of primary versus recurrent ovarian disease. In parallel, meta-analysis was used to identify cancer stemness miRNA signatures in tumor patient samples.

Results: Microarray analysis demonstrated a 90% difference between gene expression events involved in early regulation of differentiation in murine EC (mEC) and embryonic stem (mES) cells. This contrasts the known parallels between mEC and mES cells in the undifferentiated and well-differentiated states. Genelist comparisons identified a cancer stemness signature set of genes in primary versus recurrent data, a subset of which are known p53-p21 regulators. This signature is present in primary and recurrent or in primary alone but essentially never in recurrent tumors specifically. Meta-analysis of miRNA expression showed a much stronger cancer stemness signature within tumor samples. This miRNA signature again related to p53-p21 regulation and was expressed prominently in recurrent tumors. Our data indicate that the regulation of p53-p21 in ovarian cancer involves, at least partially, a cancer stemness component.

Conclusion: We present a p53-p21 cancer stemness signature model for ovarian cancer. We propose that this may, at least partially, differentially regulate the p53-p21 mechanism in ovarian disease. Targeting CSCs within ovarian cancer represents a potential therapeutic avenue.

No MeSH data available.


Related in: MedlinePlus