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

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.

Aberrantly expressed microRNAs in bladder cancer and renal cell carcinoma

“…55 The miR-200 family has been reported to be associated with the EMT, either inhibiting or inducing the EMT depending on the cancer type. 55,59 In RCC, many reports have indicated that miRNAs in this family have tumor-suppressive roles and inhibit the EMT. 55,60 Nakada et al 60 reported that miR-141 and miR-200c are downregulated in clear-cell RCC and that these miRNAs may be involved in suppression of CDH1/E-cadherin transcription by upregulation of ZFHX1B.…”

A double-negative feedback loop between EpCAM and ERK contributes to the regulation of epithelial–mesenchymal transition in cancer

“…In addition, a negative correlation between the activity of EMT-associated transcription factors SNAI1 26, 56 , and ZEB1 16, 54 and EpCAM expression has been reported. Specific ablation of ZEB1 by ZEB1 shRNA, or forced expression of miR-200c or miR-205 (ZEB1 suppressors) was associated with increased EpCAM expression 30 . These reports are consistent with the hypothesis that EpCAM expression is dynamically regulated during EMT.…”

Analogous detection of circulating tumor cells using the AccuCyte®—CyteFinder® system and ISET system in patients with locally advanced and metastatic prostate cancer

“…It is now understood that the expression of epithelial markers varies with tumor type and that the expression of those markers, especially EpCAM, is downregulated by epithelial‐to‐mesenchymal transition (EMT) to increase the ability of the tumor cells to mobilize, invade, and thus facilitate metastasis . Therefore, epithelial markers do not formally establish the metastatic nature of CTCs . CTC detection methods that rely on EpCAM expression of the tumor cells, like CellSearch ® , fail to detect CTCs with more mesenchymal, and possibly more aggressive, features …”

“…9,10 Therefore, epithelial markers do not formally establish the metastatic nature of CTCs. [11][12][13][14] CTC detection methods that rely on EpCAM expression of the tumor cells, like CellSearch ® , fail to detect CTCs with more mesenchymal, and possibly more aggressive, features. 11 Based on this knowledge, this study prospectively compared the performance of two different methods that both do not solely rely on EpCAM.…”