EpCAM Signaling Promotes Tumor Progression and Protein Stability of PD-L1 through the EGFR Pathway

Chen, Hao-Nien; Liang, Kang-Hao; Lai, Jun-Kai; Lan, Chun-Hsin; Liao, Minfu; Hung, Shao-Hsi; Chuang, Yi-Ting; Chen, Kai-Chi; Tsuei, William Wei-Fu; Wu, Han-Chung

doi:10.1158/0008-5472.can-20-1264

Cited by 41 publications

(41 citation statements)

References 46 publications

(78 reference statements)

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“…The V H and V L domains of the neutralizing mAbs from hybridoma cell lines were identified and grafted onto a human IgG1 and kappa backbone to generate 12 chAb clones. The binding of all chAbs to SARS-CoV-2 RBD or S recombinant protein were evaluated by ELISA, and the EpEX-His protein [ 27 ] was used as a control protein ( Fig 1B–1G ). RBD-chAb-28, -45, and -51 exhibited the highest binding signals for recombinant RBD ( Fig 1B ).…”

Section: Resultsmentioning

confidence: 99%

Structure-guided antibody cocktail for prevention and treatment of COVID-19

Yang

et al. 2021

PLoS Pathog

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Development of effective therapeutics for mitigating the COVID-19 pandemic is a pressing global need. Neutralizing antibodies are known to be effective antivirals, as they can be rapidly deployed to prevent disease progression and can accelerate patient recovery without the need for fully developed host immunity. Here, we report the generation and characterization of a series of chimeric antibodies against the receptor-binding domain (RBD) of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein. Some of these antibodies exhibit exceptionally potent neutralization activities in vitro and in vivo, and the most potent of our antibodies target three distinct non-overlapping epitopes within the RBD. Cryo-electron microscopy analyses of two highly potent antibodies in complex with the SARS-CoV-2 spike protein suggested they may be particularly useful when combined in a cocktail therapy. The efficacy of this antibody cocktail was confirmed in SARS-CoV-2-infected mouse and hamster models as prophylactic and post-infection treatments. With the emergence of more contagious variants of SARS-CoV-2, cocktail antibody therapies hold great promise to control disease and prevent drug resistance.

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Section: Resultsmentioning

confidence: 99%

Structure-guided antibody cocktail for prevention and treatment of COVID-19

Yang

et al. 2021

PLoS Pathog

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“…There is a complex crosstalk between FOXO3a/AKT signaling pathway and PD-L1 involved in tumorigenesis (26,33). PD-L1 is a critical regulator in UC development and the level of functional PD-L1 plays a vital role in the effective immunotherapeutic treatments for UC (34,35).…”

Section: Discussionmentioning

confidence: 99%

FOXO3A Expression in Upper Tract Urothelial Carcinoma

et al. 2021

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BackgroundEpidemiological studies have reported various results regarding whether FOXO3A is related to various carcinomas. However, the prognostic significance of FOXO3A in upper tract urothelial carcinoma (UTUC) remains unclear. The purpose of this study was to validate the correlation between FOXO3A expression and oncological outcomes in UTUC.MethodsThe expression levels of FOXO3A in 107 UTUC patients were examined by immunohistochemistry (IHC). We examined the prognostic role of FOXO3A by using the Cox proportional hazard model.ResultsThe results indicated that FOXO3A expression was notably decreased in UTUC tissue compared with control tissue. Decreased expression of FOXO3A was also related to advanced pathologic stage (P = 0.026), lymph node metastasis (P = 0.040), lymphovascular invasion (P < 0.001), and adjuvant therapy (P = 0.048). In addition, UTUC patients with low FOXO3A expression had a significantly shorter survival time, including both overall survival (OS) [hazard ratio (HR) 2.382, P = 0.004] and recurrence-free survival (RFS) (HR 2.385, P = 0.004), than those with high expression. Multivariate analyses showed that FOXO3A was a significant predictor for OS (HR 2.145, P = 0.014) and RFS (HR 2.227, P = 0.010) in UTUC patients.ConclusionOur results indicate that FOXO3A may be involved in the recurrence of UTUC and that it has certain clinical value in the therapeutic targeting and prognostic evaluation of UTUC.

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“…Recently, EpEX-EGFR signaling was shown to promote PD-L1 expression in colon and lung cancer cell lines. This suggests that EpEX may play a significant role in cancer cell evasion of the host immunity [72], which is frequently observed with EMT [73]. In an in vitro analysis of bone marrow derived mesenchymal stem cells, EpEX treatment stimulated elaboration of stemness markers, and this occurred, in part, through EGFR signaling [74].…”

Section: Epcam Is Regulated By Egfr Signaling During Emt and Epex Is An Egfr Ligand That Affects Emtmentioning

confidence: 96%

Functional Implications of the Dynamic Regulation of EpCAM during Epithelial-to-Mesenchymal Transition

2021

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Epithelial cell adhesion molecule (EpCAM) is a transmembrane glycoprotein expressed in epithelial tissues. EpCAM forms intercellular, homophilic adhesions, modulates epithelial junctional protein complex formation, and promotes epithelial tissue homeostasis. EpCAM is a target of molecular therapies and plays a prominent role in tumor biology. In this review, we focus on the dynamic regulation of EpCAM expression during epithelial-to-mesenchymal transition (EMT) and the functional implications of EpCAM expression on the regulation of EMT. EpCAM is frequently and highly expressed in epithelial cancers, while silenced in mesenchymal cancers. During EMT, EpCAM expression is downregulated by extracellular signal-regulated kinases (ERK) and EMT transcription factors, as well as by regulated intramembrane proteolysis (RIP). The functional impact of EpCAM expression on tumor biology is frequently dependent on the cancer type and predominant oncogenic signaling pathways, suggesting that the role of EpCAM in tumor biology and EMT is multifunctional. Membrane EpCAM is cleaved in cancers and its intracellular domain (EpICD) is transported into the nucleus and binds β-catenin, FHL2, and LEF1. This stimulates gene transcription that promotes growth, cancer stem cell properties, and EMT. EpCAM is also regulated by epidermal growth factor receptor (EGFR) signaling and the EpCAM ectoderm (EpEX) is an EGFR ligand that affects EMT. EpCAM is expressed on circulating tumor and cancer stem cells undergoing EMT and modulates metastases and cancer treatment responses. Future research exploring EpCAM’s role in EMT may reveal additional therapeutic opportunities.

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EpCAM Signaling Promotes Tumor Progression and Protein Stability of PD-L1 through the EGFR Pathway

Cited by 41 publications

References 46 publications

Structure-guided antibody cocktail for prevention and treatment of COVID-19

Structure-guided antibody cocktail for prevention and treatment of COVID-19

FOXO3A Expression in Upper Tract Urothelial Carcinoma

Functional Implications of the Dynamic Regulation of EpCAM during Epithelial-to-Mesenchymal Transition

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