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

Abstract

Epithelial-mesenchymal transition (EMT) is an important biologic process that has been implicated in cancer metastasis. Epithelial cell adhesion molecule (EpCAM) is expressed at the basolateral membrane of most normal epithelial cells, but is overexpressed in many epithelial cancers. In our studies of the role of EpCAM in cancer biology, we observed that EpCAM expression is decreased in mesenchymal-like primary cancer specimens in vivo, and following induction of EMT in cancer cell lines in vitro. Extracellular signal-related kinase (ERK) is a key regulator of EMT. We observed that EpCAM expression is decreased with activation of the ERK pathway in primary cancer specimens in vivo and in cancer cell lines in vitro. In experimental models, growth factor stimulation and/or oncogene-induced ERK2 activation suppressed EpCAM expression, whereas genetic or pharmacologic inhibition of the ERK pathway restored EpCAM expression. In detailed studies of the EpCAM promoter region, we observed that ERK2 suppresses EpCAM transcription directly by binding to a consensus ERK2 binding site in the EpCAM promoter, and indirectly through activation of EMT-associated transcription factors SNAI1, SNAI2, TWIST1, and ZEB1, which bind to E-box sites in the EpCAM promoter. Surprisingly, EpCAM appears to modulate ERK activity. Using multiple cell lines, we demonstrated that specific ablation of EpCAM resulted in increased ERK pathway activity, SNAI2 expression, migration and invasion, whereas forced expression of EpCAM resulted in decreased ERK pathway activity, decreased SNAI2 expression, migration and invasion. These observations provide important insights into the regulation of EpCAM expression during EMT, demonstrate an unexpected role for EpCAM in the regulation of ERK, and define a novel double-negative feedback loop between EpCAM and ERK that contributes to the regulation of EMT. These studies have important translational implications as both EpCAM and ERK are currently being targeted in human clinical trials.

High Expression of EpCAM and Sox2 is a Positive Prognosticator of Clinical Outcome for Head and Neck Carcinoma

“…Induction of EpCAM results in various cellular outcome including cell-cell adhesion 37 , enhanced tumor cell proliferation 19 , 38 and regulation of stem cell features 20 , 39 – 41 . Itself, EpCAM is prone to substantial regulation throughout cancer progression 27 , 42 , 43 , stem cell differentiation 22 , and during EMT related to treatment resistance, e . g .…”

Tunicamycin inhibits cell proliferation and migration in hepatocellular carcinoma through suppression of CD44s and the ERK1/2 pathway

“…The ERK pathway has been implicated in malignant transformation and in the regulation of cellular proliferation and metastasis of several tumor types . Furthermore, we found that overexpression of CD44s increased ERK1/2 activation in HCC cells (Figure ).…”

lncRNA DRHC inhibits proliferation and invasion in hepatocellular carcinoma via c‐Myb‐regulated MEK/ERK signaling

“…EMT is a key step toward cancer metastasis . Wnt, TGF‐β, Notch, NF‐κB, and MAPK/ERK have been implicated as the key pathways involved in EMT process. Several lncRNAs participate in EMT process .…”

“…21,22 In this study, a novel lncRNA, lncRNA DRHC, was shown to be EMT is a key step toward cancer metastasis. 26 Wnt, 27 TGF-β, 28,29 Notch, 30,31 NF-κB, 32,33 and MAPK/ERK 34 have been implicated as the key pathways involved in EMT process. Several lncRNAs participate in EMT process.…”