Nuclear EpICD expression and its role in hepatocellular carcinoma

Park, Shin Young; Bae, Jong Seok; Jung, Eun Jung; Chu, Hyun Hee; Sohn, Jang Sihn; Moon, Woo Sung

doi:10.3892/or.2016.4789

Cited by 10 publications

(13 citation statements)

References 30 publications

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“…Likewise, MSC migrates better towards Hep3B cells expressing high levels of endogenous EpCAM when compared to EpCAM-null MHCC97H ( Supplementary Figure 4D ). In a recent publication, EpICD was shown to serve as an oncogenic signal transducer in HCC by activating β-catenin, c-myc and cyclin D 1 to promote cell proliferation [ 29 ]. At present, it is unclear why MSC migrates to pathological lesion tissues.…”

Section: Discussionmentioning

confidence: 99%

Human mesenchymal stem cells preferentially migrate toward highly oncogenic human hepatocellular carcinoma cells with activated EpCAM signaling

et al. 2017

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The epithelial cell adhesion molecule (EpCAM) is a type I transmembrane glycoprotein that is regarded as one of the markers for tumor initiating cells (TIC) in human hepatocellular carcinoma (HCC). Much work has been directed towards targeting these TICs as a mean of placing these master regulators of cell proliferation and drug resistance under control. Human bone marrow-derived mesenchymal stem cells are known to exhibit an innate property of tumor tropism. However, the possible relationship between MSC and TIC is not well understood. In this study, we show that MSC migration to HCC can be effectively inhibited by TACE and γ-secretase inhibitors that stop the activation of EpCAM signaling event. Silencing of EpCAM expression through siRNA and antibody approaches also resulted in impaired MSC migration. By contrast, increase levels of EpICD proteins in HCC cells and HCC mouse xenografts resulted in enhanced MSC migration. Taken together, these findings show that MSC is drawn to the more oncogenic population of HCC, and could potentially serve as a cell-based carrier of therapeutic genes to target EpICD-enriched hepatic tumor cells.

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Section: Discussionmentioning

confidence: 99%

Human mesenchymal stem cells preferentially migrate toward highly oncogenic human hepatocellular carcinoma cells with activated EpCAM signaling

et al. 2017

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“…EpCAM is another abundant, calcium-independent, transmembrane glycoprotein that exerts homophilic cell-cell interaction in epithelial cells. 45 Recent studies observed that EpCAM is also involved in the b-catenin/Wnt (wingless-type MMTV integration site family) signaling pathway; [46][47][48] cleavage of EpCAM by ADAM or presenilin leads to cell signaling by an EpCAM intracellular domain/FHL2 (four and a half LIM domains 2)/b-catenin complex, 12 that result in cell proliferation, 49,50 and release of the extracellular domain. Although EpCAM is an adhesion molecule, it could act as a negative dominant of E-and N-cadherin on cellcell adhesion 11,12 and has an important role in cell motility.…”

Section: Biology and Biogenesismentioning

confidence: 99%

Cell-adhesion molecules and their soluble forms: Promising predictors of “tumor progression” and relapse in leukemia

et al. 2018

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Some surface markers are used to discriminate certain leukemic subpopulations that retain a greater oncogenic potential than others, and, for this reason, they were termed as leukemic stem cells, similar to the concept of cancer stem cells in carcinoma. Among these surface markers are proteins involved in cell-cell adhesion or cell-matrix adhesion, and they may play a role in the relapse of leukemia, similar to metastasis in carcinomas. The most important are epithelial cadherin, neural cadherin, epithelial cell-adhesion molecule, and CD44, which can be cleaved and released, and their soluble forms were found increased in serum levels of cancer patients, being implicated, in some cases, with progression, metastases, and relapse. In this review, we highlighted the role of these four adhesion molecules in carcinomas and hematological malignancies, mainly leukemia, and discuss if the serum levels of soluble forms can be correlated with the surface protein status on the leukemic cells. Accession of the soluble forms looks attractive, but their use as markers in cancer must be studied in association with other parameters, as there are significant changes in levels in other pathological conditions besides cancer. Studies correlating the levels of the forms with the status of the membrane-bound proteins in leukemic (stem) cells and correlating those parameters with relapse in leukemia may afford important knowledge and applicability of those serum markers in clinical practice. For instance, the expression of the membrane-bound forms of these adhesion proteins may have promising clinical use in leukemia and other hematological malignancies.

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“…Intriguingly, EpICD has also been reported to be a poor prognostic marker in hepatocellular carcinoma and breast cancer. 12 , 13 …”

Section: Introductionmentioning

confidence: 99%

In Silico Identification of Potential Phosphorylation in the Cytoplasmic Domain of Epithelial Cell Adhesion Molecule

et al. 2020

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The epithelial cell adhesion molecule (EpCAM) is a transmembrane cell adhesion glycoprotein, which primarily contributes to stemness, proliferation, and metastasis properties of tumor cells. Regulated intramembrane proteolysis by ADAM proteases and γ-secretase cleaves EpCAM into an ∼27 kDa soluble extracellular and an ∼4 kDa cytoplasmic domain (EpICD). After the EpICD fragment is released inside the cell, the formation of a nuclear signaling complex with the FHL2 molecule is critical for exerting its regulatory role. Trop-2, a homologous protein of EpCAM, undergoes phosphorylation in its cytoplasmic domain (Trop-IC). The phosphorylation of Trop-2 is reported to be crucial for its function. This led us to ask the fundamental question if EpCAM does undergo similar post-translational modification(PTM) like its homologous protein to carry out its diverse biological function. Here, we identify a putative phosphorylation site at Tyr297 located in the cytoplasmic domain of EpCAM. Molecular dynamic simulation (MDS) of 90 ns was carried out to understand the biological/functional relevance of the putative phosphorylation. It was observed that this phosphorylation stabilizes the α-helical structure of the EpICD. Though Tyr297 does not affect the γ-secretase mediated cleavage of EpCAM, it affects the binding of EpICD to FHL2. Docking analysis revealed that phosphorylation mediated structural stability of EpICD positively impacts its binding affinity with FHL2, which was further validated using 100 ns MDS. Phosphorylated EpICD forms higher numbers of hydrogen bonds, salt bridges, and other non-bonded interactions with FHL2, leading to enhanced interactions. This in silico study reveals a potential PTM in the EpICD, providing the basis for future research in understanding the mechanism behind the diverse biological function of EpCAM.

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Nuclear EpICD expression and its role in hepatocellular carcinoma

Cited by 10 publications

References 30 publications

Human mesenchymal stem cells preferentially migrate toward highly oncogenic human hepatocellular carcinoma cells with activated EpCAM signaling

Human mesenchymal stem cells preferentially migrate toward highly oncogenic human hepatocellular carcinoma cells with activated EpCAM signaling

Cell-adhesion molecules and their soluble forms: Promising predictors of “tumor progression” and relapse in leukemia

In Silico Identification of Potential Phosphorylation in the Cytoplasmic Domain of Epithelial Cell Adhesion Molecule

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