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EpCAM is overexpressed in local and metastatic prostate cancer, suppressed by chemotherapy and modulated by MET-associated miRNA-200c/205.

Massoner P, Thomm T, Mack B, Untergasser G, Martowicz A, Bobowski K, Klocker H, Gires O, Puhr M - Br. J. Cancer (2014)

Bottom Line: Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells.Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression.

View Article: PubMed Central - PubMed

Affiliation: 1] Experimental Urology, Department of Urology, Innsbruck Medical University, Innsbruck, Austria [2] Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-University, Munich, Germany.

ABSTRACT

Background: Expression of epithelial cell adhesion molecule (EpCAM) is deregulated in epithelial malignancies. Beside its role in cell adhesion, EpCAM acts as signalling molecule with tumour-promoting functions. Thus, EpCAM is part of the molecular network of oncogenic receptors and considered an interesting therapeutic target.

Methods: Here, we thoroughly characterised EpCAM expression on mRNA and protein level in comprehensive tissue studies including non-cancerous prostate specimens, primary tumours of different grades and stages, metastatic lesions, and therapy-treated tumour specimens, as well as in prostate cancer cell lines.

Results: Epithelial cell adhesion molecule was overexpressed at mRNA and at protein level in prostate cancer tissues and cell lines. Altered EpCAM expression was an early event in prostate carcinogenesis with an upregulation in low-grade cancers and further induction in high-grade tumours and metastatic lesions. Interestingly, EpCAM was repressed upon induction of epithelial-to-mesenchymal transition (EMT) following chemotherapeutic treatment with docetaxel. Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells. Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.

Conclusions: In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression. Epithelial cell adhesion molecule displays a dynamic, heterogeneous expression and associates with epithelial cells rather than mesenchymal, chemoresistant cells along with processes of EMT and MET.

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Related in: MedlinePlus

EpCAM mRNA expression is elevated in PCa. (A) EpCAM is overexpressed in a variety of human cancers. Oncomine query, status January 2014: number of datasets meeting the threshold (P>0.001, fold-change >1.5) for EpCAM compared to total datasets are given. Outlier analysis revealed high variations of EpCAM expression in all analysed datasets. (B) Meta-analysis on published gene expression data identified a significantly increased EpCAM mRNA expression in PCa compared to normal prostate tissue. Meta-analysis was performed on 678 prostate tissue samples deriving from eight independent patient cohorts measured in eight different studies. EpCAM mRNA expression is significantly elevated in an independent expression analysis on 98 prostate tissues of the Innsbruck PCa biobank. Statistics were calculated using Fisher's combined P-value (B) and Mann–Whitney U testing (C). ***P<0.001.
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fig1: EpCAM mRNA expression is elevated in PCa. (A) EpCAM is overexpressed in a variety of human cancers. Oncomine query, status January 2014: number of datasets meeting the threshold (P>0.001, fold-change >1.5) for EpCAM compared to total datasets are given. Outlier analysis revealed high variations of EpCAM expression in all analysed datasets. (B) Meta-analysis on published gene expression data identified a significantly increased EpCAM mRNA expression in PCa compared to normal prostate tissue. Meta-analysis was performed on 678 prostate tissue samples deriving from eight independent patient cohorts measured in eight different studies. EpCAM mRNA expression is significantly elevated in an independent expression analysis on 98 prostate tissues of the Innsbruck PCa biobank. Statistics were calculated using Fisher's combined P-value (B) and Mann–Whitney U testing (C). ***P<0.001.

Mentions: In order to get an overview on EpCAM expression in cancer compared to normal tissues, we performed an Oncomine (Rhodes et al, 2004) query including data of 20 different cancer entities investigated in 183 studies (Figure 1A, number of significant datasets meeting the threshold P<0.001, fold-change >1.5 for EpCAM compared to total datasets). Epithelial cell adhesion molecule was overexpressed in several cancers compared to normal tissue (e.g., oesophageal, ovarian, lung and PCa). Some cancer entities were characterised by EpCAM downregulation including kidney cancer and sarcomas. Strikingly, EpCAM emerged in the Oncomine outlier analysis of almost every investigated study (www.oncomine.org; outlier analysis identifies genes regulated in a subset of samples thus reflecting expression heterogeneity), indicating that there is a high overall heterogeneity of EpCAM expression within and across tissues. To further evaluate EpCAM expression in PCa, we extended our analysis to data from a meta-analysis study performed on published gene expression data of 678 prostate tissues measured on the Affymetrix (Santa Clara, CA, USA) platform in eight independent studies (Massoner et al, 2013; Figure 1B) and data of an independent expression study performed on 98 patients of the Innsbruck PCa biobank applying Illumina BeadChip arrays (Kuner et al, 2012; Figure 1C). In all studies, EpCAM was significantly elevated in PCa compared to benign, non-cancerous prostate tissue (2.3±0.9-fold elevated in PCa, mean±s.d., P<0.001). Different patient cohorts, diverse technologies and independent data analyses were combined in our approach and, therefore, we consider our data free of methodological or population-dependent bias.


EpCAM is overexpressed in local and metastatic prostate cancer, suppressed by chemotherapy and modulated by MET-associated miRNA-200c/205.

Massoner P, Thomm T, Mack B, Untergasser G, Martowicz A, Bobowski K, Klocker H, Gires O, Puhr M - Br. J. Cancer (2014)

EpCAM mRNA expression is elevated in PCa. (A) EpCAM is overexpressed in a variety of human cancers. Oncomine query, status January 2014: number of datasets meeting the threshold (P>0.001, fold-change >1.5) for EpCAM compared to total datasets are given. Outlier analysis revealed high variations of EpCAM expression in all analysed datasets. (B) Meta-analysis on published gene expression data identified a significantly increased EpCAM mRNA expression in PCa compared to normal prostate tissue. Meta-analysis was performed on 678 prostate tissue samples deriving from eight independent patient cohorts measured in eight different studies. EpCAM mRNA expression is significantly elevated in an independent expression analysis on 98 prostate tissues of the Innsbruck PCa biobank. Statistics were calculated using Fisher's combined P-value (B) and Mann–Whitney U testing (C). ***P<0.001.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4150273&req=5

fig1: EpCAM mRNA expression is elevated in PCa. (A) EpCAM is overexpressed in a variety of human cancers. Oncomine query, status January 2014: number of datasets meeting the threshold (P>0.001, fold-change >1.5) for EpCAM compared to total datasets are given. Outlier analysis revealed high variations of EpCAM expression in all analysed datasets. (B) Meta-analysis on published gene expression data identified a significantly increased EpCAM mRNA expression in PCa compared to normal prostate tissue. Meta-analysis was performed on 678 prostate tissue samples deriving from eight independent patient cohorts measured in eight different studies. EpCAM mRNA expression is significantly elevated in an independent expression analysis on 98 prostate tissues of the Innsbruck PCa biobank. Statistics were calculated using Fisher's combined P-value (B) and Mann–Whitney U testing (C). ***P<0.001.
Mentions: In order to get an overview on EpCAM expression in cancer compared to normal tissues, we performed an Oncomine (Rhodes et al, 2004) query including data of 20 different cancer entities investigated in 183 studies (Figure 1A, number of significant datasets meeting the threshold P<0.001, fold-change >1.5 for EpCAM compared to total datasets). Epithelial cell adhesion molecule was overexpressed in several cancers compared to normal tissue (e.g., oesophageal, ovarian, lung and PCa). Some cancer entities were characterised by EpCAM downregulation including kidney cancer and sarcomas. Strikingly, EpCAM emerged in the Oncomine outlier analysis of almost every investigated study (www.oncomine.org; outlier analysis identifies genes regulated in a subset of samples thus reflecting expression heterogeneity), indicating that there is a high overall heterogeneity of EpCAM expression within and across tissues. To further evaluate EpCAM expression in PCa, we extended our analysis to data from a meta-analysis study performed on published gene expression data of 678 prostate tissues measured on the Affymetrix (Santa Clara, CA, USA) platform in eight independent studies (Massoner et al, 2013; Figure 1B) and data of an independent expression study performed on 98 patients of the Innsbruck PCa biobank applying Illumina BeadChip arrays (Kuner et al, 2012; Figure 1C). In all studies, EpCAM was significantly elevated in PCa compared to benign, non-cancerous prostate tissue (2.3±0.9-fold elevated in PCa, mean±s.d., P<0.001). Different patient cohorts, diverse technologies and independent data analyses were combined in our approach and, therefore, we consider our data free of methodological or population-dependent bias.

Bottom Line: Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells.Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression.

View Article: PubMed Central - PubMed

Affiliation: 1] Experimental Urology, Department of Urology, Innsbruck Medical University, Innsbruck, Austria [2] Department of Otorhinolaryngology, Head and Neck Surgery, Ludwig-Maximilians-University, Munich, Germany.

ABSTRACT

Background: Expression of epithelial cell adhesion molecule (EpCAM) is deregulated in epithelial malignancies. Beside its role in cell adhesion, EpCAM acts as signalling molecule with tumour-promoting functions. Thus, EpCAM is part of the molecular network of oncogenic receptors and considered an interesting therapeutic target.

Methods: Here, we thoroughly characterised EpCAM expression on mRNA and protein level in comprehensive tissue studies including non-cancerous prostate specimens, primary tumours of different grades and stages, metastatic lesions, and therapy-treated tumour specimens, as well as in prostate cancer cell lines.

Results: Epithelial cell adhesion molecule was overexpressed at mRNA and at protein level in prostate cancer tissues and cell lines. Altered EpCAM expression was an early event in prostate carcinogenesis with an upregulation in low-grade cancers and further induction in high-grade tumours and metastatic lesions. Interestingly, EpCAM was repressed upon induction of epithelial-to-mesenchymal transition (EMT) following chemotherapeutic treatment with docetaxel. Oppositely, re-induction of the epithelial phenotype through miRNAs miR-200c and miR-205, two inducers of mesenchymal-to-epithelial transition (MET), led to re-induction of EpCAM in chemoresistant cells. Furthermore, we prove that EpCAM cleavage, the first step of EpCAM signalling takes place in prostate cancer cells but in contrast to other cancer entities, EpCAM has no measurable impact on the proliferative behaviour of prostate cells, in vitro.

Conclusions: In conclusion, our data confirm that EpCAM overexpression is an early event during prostate cancer progression. Epithelial cell adhesion molecule displays a dynamic, heterogeneous expression and associates with epithelial cells rather than mesenchymal, chemoresistant cells along with processes of EMT and MET.

Show MeSH
Related in: MedlinePlus