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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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EpCAM expression is reduced in docetaxel-treated patients as well as in docetaxel-resistant cell lines and is a marker for an epithelial phenotype. (A and B) EpCAM protein expression is significantly reduced in prostate tissues of patients who received neoadjuvant chemotherapy with docetaxel before radical prostatectomy. Co-staining of EpCAM (brown) and p63 (blue, marker for basal cells) ensured correct discrimination between benign and cancer glands. (C) EpCAM mRNA and protein expression is reduced in docetaxel-resistant PC3-DR and Du-145-DR cells compared to parental cells. (D) EpCAM is a marker for an epithelial phenotype. Transfection of mature miR-200c and miR-205 leads to re-expression of EpCAM mRNA and protein in docetaxel-resistant cells, respectively. Semiquantitative immunohistochemistry analysis was performed applying quickscore criteria. Statistics were calculated using Mann–Whitney U testing (A) or Student's t-testing (C and D); *P<0.05; **P<0.01; ***P<0.001; bar, 100 μM. Abbreviation: IRS, immunoreactivity staining score.
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fig6: EpCAM expression is reduced in docetaxel-treated patients as well as in docetaxel-resistant cell lines and is a marker for an epithelial phenotype. (A and B) EpCAM protein expression is significantly reduced in prostate tissues of patients who received neoadjuvant chemotherapy with docetaxel before radical prostatectomy. Co-staining of EpCAM (brown) and p63 (blue, marker for basal cells) ensured correct discrimination between benign and cancer glands. (C) EpCAM mRNA and protein expression is reduced in docetaxel-resistant PC3-DR and Du-145-DR cells compared to parental cells. (D) EpCAM is a marker for an epithelial phenotype. Transfection of mature miR-200c and miR-205 leads to re-expression of EpCAM mRNA and protein in docetaxel-resistant cells, respectively. Semiquantitative immunohistochemistry analysis was performed applying quickscore criteria. Statistics were calculated using Mann–Whitney U testing (A) or Student's t-testing (C and D); *P<0.05; **P<0.01; ***P<0.001; bar, 100 μM. Abbreviation: IRS, immunoreactivity staining score.

Mentions: Treatment with the chemotherapeutic drug docetaxel is a standard therapy for patients with metastatic castration-resistant PCa. An acquired resistance to docetaxel has been associated with an EMT of cancer cells and subsequent dysregulation of cell surface proteins such as E-cadherin (Puhr et al, 2012). Therefore we anticipated EpCAM to be affected by EMT and analysed EpCAM expression in a set of PCa patients, who underwent neoadjuvant chemotherapy with docetaxel before radical prostatectomy and patients who did not got adjuvant treatment. Epithelial cell adhesion molecule was significantly lower in docetaxel-treated compared to untreated tumours (Figure 6A and B). In agreement with these in vivo data, EpCAM expression was found to be downregulated in docetaxel-resistant sublines of PCa cell lines (DU145 and PC3) at mRNA and protein level, respectively, (Figure 6C; Puhr et al, 2012). In summary our data reveal that EpCAM expression is suppressed by chemotherapeutic treatment, an effect that correlates with an EMT shift as previously shown (Puhr et al, 2012).


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 expression is reduced in docetaxel-treated patients as well as in docetaxel-resistant cell lines and is a marker for an epithelial phenotype. (A and B) EpCAM protein expression is significantly reduced in prostate tissues of patients who received neoadjuvant chemotherapy with docetaxel before radical prostatectomy. Co-staining of EpCAM (brown) and p63 (blue, marker for basal cells) ensured correct discrimination between benign and cancer glands. (C) EpCAM mRNA and protein expression is reduced in docetaxel-resistant PC3-DR and Du-145-DR cells compared to parental cells. (D) EpCAM is a marker for an epithelial phenotype. Transfection of mature miR-200c and miR-205 leads to re-expression of EpCAM mRNA and protein in docetaxel-resistant cells, respectively. Semiquantitative immunohistochemistry analysis was performed applying quickscore criteria. Statistics were calculated using Mann–Whitney U testing (A) or Student's t-testing (C and D); *P<0.05; **P<0.01; ***P<0.001; bar, 100 μM. Abbreviation: IRS, immunoreactivity staining score.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig6: EpCAM expression is reduced in docetaxel-treated patients as well as in docetaxel-resistant cell lines and is a marker for an epithelial phenotype. (A and B) EpCAM protein expression is significantly reduced in prostate tissues of patients who received neoadjuvant chemotherapy with docetaxel before radical prostatectomy. Co-staining of EpCAM (brown) and p63 (blue, marker for basal cells) ensured correct discrimination between benign and cancer glands. (C) EpCAM mRNA and protein expression is reduced in docetaxel-resistant PC3-DR and Du-145-DR cells compared to parental cells. (D) EpCAM is a marker for an epithelial phenotype. Transfection of mature miR-200c and miR-205 leads to re-expression of EpCAM mRNA and protein in docetaxel-resistant cells, respectively. Semiquantitative immunohistochemistry analysis was performed applying quickscore criteria. Statistics were calculated using Mann–Whitney U testing (A) or Student's t-testing (C and D); *P<0.05; **P<0.01; ***P<0.001; bar, 100 μM. Abbreviation: IRS, immunoreactivity staining score.
Mentions: Treatment with the chemotherapeutic drug docetaxel is a standard therapy for patients with metastatic castration-resistant PCa. An acquired resistance to docetaxel has been associated with an EMT of cancer cells and subsequent dysregulation of cell surface proteins such as E-cadherin (Puhr et al, 2012). Therefore we anticipated EpCAM to be affected by EMT and analysed EpCAM expression in a set of PCa patients, who underwent neoadjuvant chemotherapy with docetaxel before radical prostatectomy and patients who did not got adjuvant treatment. Epithelial cell adhesion molecule was significantly lower in docetaxel-treated compared to untreated tumours (Figure 6A and B). In agreement with these in vivo data, EpCAM expression was found to be downregulated in docetaxel-resistant sublines of PCa cell lines (DU145 and PC3) at mRNA and protein level, respectively, (Figure 6C; Puhr et al, 2012). In summary our data reveal that EpCAM expression is suppressed by chemotherapeutic treatment, an effect that correlates with an EMT shift as previously shown (Puhr et al, 2012).

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