EpCAM Inhibition Sensitizes Chemoresistant Leukemia to Immune Surveillance

Zheng, Xiaohu; Fan, Xiaolei; Fu, Binqing; Zheng, Meijuan; Zhang, Aimei; Zhong, Kai; Yan, Jun; Sun, Rui; Tian, Zhigang; Wei, Haiming

doi:10.1158/0008-5472.can-16-0842

Cited by 24 publications

(35 citation statements)

References 41 publications

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“…EPCAM is an another example, the gene having a high negative weight on the second axis in the plot of mCIA and ssmCIA in the Affymetrix dataset. This gene is known to be frequently over-expressed in patients with acute myeloid leukemia (AML) [42]. The gene EBF1, another example, has a high weight on the second axis in plot of ssmCIA in the Agilent data, which can be supported by recent studies discussing the relationship between this gene and leukemia [30].…”

Section: Nci60 Datasetmentioning

confidence: 64%

Sparse multiple co-Inertia analysis with application to integrative analysis of multi -Omics data

Min

Long

2020

BMC Bioinformatics

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Background: Multiple co-inertia analysis (mCIA) is a multivariate analysis method that can assess relationships and trends in multiple datasets. Recently it has been used for integrative analysis of multiple high-dimensional -omics datasets. However, its estimated loading vectors are non-sparse, which presents challenges for identifying important features and interpreting analysis results. We propose two new mCIA methods: 1) a sparse mCIA method that produces sparse loading estimates and 2) a structured sparse mCIA method that further enables incorporation of structural information among variables such as those from functional genomics. Results: Our extensive simulation studies demonstrate the superior performance of the sparse mCIA and structured sparse mCIA methods compared to the existing mCIA in terms of feature selection and estimation accuracy. Application to the integrative analysis of transcriptomics data and proteomics data from a cancer study identified biomarkers that are suggested in the literature related with cancer disease. Conclusion: Proposed sparse mCIA achieves simultaneous model estimation and feature selection and yields analysis results that are more interpretable than the existing mCIA. Furthermore, proposed structured sparse mCIA can effectively incorporate prior network information among genes, resulting in improved feature selection and enhanced interpretability.

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Section: Nci60 Datasetmentioning

confidence: 64%

Sparse multiple co-Inertia analysis with application to integrative analysis of multi -Omics data

Min

Long

2020

BMC Bioinformatics

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“…This discrepancy may also be associated with differences in the tumor microenvironment in vivo and in vitro. Zheng et al (27) did not observe any effect of anti-EpCAM antibodies on the proliferation and induction of apoptosis in K562 and HL60 cells in vitro, even though the same antibodies inhibited the growth of EpCAM-overexpressing solid tumors and subcutaneously transplanted A549 tumors in vivo.…”

Section: Discussionmentioning

confidence: 95%

IL‑6 prevents CXCL8‑induced stimulation of EpCAM expression in ovarian cancer cells

et al. 2019

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Epithelial cell adhesion molecule (EpCAM), which is expressed in the majority of epithelial tissues, exhibits tumor growth promoting abilities and is overexpressed in human epithelial ovarian cancer. Therefore, EpCAM is considered to be a promising target for specific immune-based therapies. The present study evaluated the role of IL-6 and IL-8 in the expression of EpCAM in the A2780 human ovarian cancer cell line. Furthermore, the cellular localization of the EpCAM protein in A2780 cells was determined and the effect of EpCAM inhibition on the proliferation of the A2780 cells was investigated. An MTT assay demonstrated that blocking EpCAM with anti-EPCAM antibodies had no effect on cellular metabolic activity (proliferation). Gene expression analysis revealed that IL-8 increased EpCAM expression, whereas IL-6 and the combination of IL-6/IL-8 had no effect on EpCAM expression. Immunofluorescence analysis confirmed that EpCAM is expressed on A2780 cell membranes. The present results demonstrated that IL-8 increased EpCAM expression at the mRNA level in ovarian cancer cells and suggested a potential role of IL-6 as an inhibitor of IL-8-stimulated EpCAM expression.

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“…However, there are also cancer types such as gastric cancer in which the association of EpCAM expression with the outcome for patients was inconclusive (37). Recently, EpCAM was found to also be expressed on tumor cells of acute myeloid leukemia, with EpCAM-positive leukemic cells showing a greater resistance to chemotherapy (41).…”

Section: Epithelial Cell-adhesion Molecule (Epcam) Is a Transmembranementioning

confidence: 99%

A high-content screen for small-molecule regulators of epithelial cell-adhesion molecule (EpCAM) cleavage yields a robust inhibitor

Tretter

Schorpp

Luxenburger³

et al. 2018

Journal of Biological Chemistry

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Epithelial cell-adhesion molecule (EpCAM) is a transmembrane protein that regulates cell cycle progression and differentiation and is overexpressed in many carcinomas. The EpCAM-induced mitogenic cascade is activated via regulated intramembrane proteolysis (RIP) of EpCAM by ADAM and γ-secretases, generating the signaling-active intracellular domain EpICD. Because of its expression pattern and molecular function, EpCAM is a valuable target in prognostic and therapeutic approaches for various carcinomas. So far, several immunotherapeutic strategies have targeted the extracellular domain of EpCAM. However, targeting the intracellular signaling cascade of EpCAM holds promise for specifically interfering with EpCAM's proliferation-stimulating signaling cascade. Here, using a yellow fluorescence protein-tagged version of the C-terminal fragment of EpCAM, we established a high-content screening (HCS) of a small-molecule compound library ( = 27,280) and characterized validated hits that target EpCAM signaling. In total, 128 potential inhibitors were initially identified, of which one compound with robust inhibitory effects on RIP of EpCAM was analyzed in greater detail. In summary, our study demonstrates that the development of an HCS for small-molecule inhibitors of the EpCAM signaling pathway is feasible. We propose that this approach may also be useful for identifying chemical compounds targeting other disorders involving membrane cleavage-dependent signaling pathways.

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EpCAM Inhibition Sensitizes Chemoresistant Leukemia to Immune Surveillance

Cited by 24 publications

References 41 publications

Sparse multiple co-Inertia analysis with application to integrative analysis of multi -Omics data

Sparse multiple co-Inertia analysis with application to integrative analysis of multi -Omics data

IL‑6 prevents CXCL8‑induced stimulation of EpCAM expression in ovarian cancer cells

A high-content screen for small-molecule regulators of epithelial cell-adhesion molecule (EpCAM) cleavage yields a robust inhibitor

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