From cell membrane to the nucleus: an emerging role of E‐cadherin in gene transcriptional regulation

Du, Wenjun; Liu, Xi; Fan, Guijuan; Zhao, Xingsheng; Sun, Ying; Wang, Tianzhen; Zhao, Ruihua; Wang, Guangyu; Zhao, Chunyu; Zhu, Yuanyuan; Ye, Fei; Jin, Xiaoming; Zhang, Fengmin; Zhong, Zhaohua; Li, Xiaobo

doi:10.1111/jcmm.12340

Cited by 48 publications

(35 citation statements)

References 85 publications

(107 reference statements)

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“…This inclusion appears plausible, since we could detect fluorescence merger of E‐Cadherin and EGF‐R, which indicates their co‐localization at the plasma membrane. In line with our data, obtained from IIF, it has been reported for cancer cells as well as normal epithelial cells that E‐Cadherin can bind EGF‐R at the plasma membrane …”

Section: Discussionsupporting

confidence: 92%

Gelatin nonwovens‐based epithelial morphogenesis involves a signaling axis comprising EGF‐receptor, MAP kinases ERK 1/2, and β1 integrin

Jedrusik

Steinberg

Husari

et al. 2018

J Biomedical Materials Res

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In biomaterials research, biomechanics which support tissue regeneration steadily gains of importance. Hence, we have previously shown that gelatin‐based electrospun nonwoven mats (NWMs) with a distinct modulus of elasticity (3.2 kPa) promotes epithelial morphogenesis. Since molecular mechanisms of this morphogenesis are still unknown, the present study aims at identifying molecules, involved herein. Epithelia established on the NMWs showed persistence of the activated state of the epidermal growth factor receptor (EGF‐R), phosphorylated at the src‐specific tyrosine 845 (EGF‐RT845) throughout the observation period of 10 days. To elucidate whether the observed morphogenesis mechanistically involves EGF‐R signaling, we inhibited EGF‐R, by employing the EGF‐RT845 specific inhibitor Gefitinib (IRESSA®). Gefitinib administration yielded a reduced expression of the β1 integrin subunit, a well‐known cell–matrix interaction receptor, concomitant with downregulation of p42/44 ERK1/2 MAP‐kinase activity. To elucidate whether the observed downregulation of β1 is EGF‐RT845‐dependent or emerging from ERK1/2 signaling, we exposed epithelia, grown on the NWMs, with the ERK1/2‐directed inhibitor U0126. In the absence of Gefitinib, inhibition of p42/44 MAP‐kinase activity resulted in decreased β1 integrin protein levels, thus indicating that β1 expression is dependent on ERK1/2 and not EGF‐RT845. Our results showed the first time that an EGF‐R‐β1 integrin‐signaling axis, including ERK1/2, promotes NWM‐elasticity‐based epithelial morphogenesis. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 107A: 663–677, 2019.

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Section: Discussionsupporting

confidence: 92%

Gelatin nonwovens‐based epithelial morphogenesis involves a signaling axis comprising EGF‐receptor, MAP kinases ERK 1/2, and β1 integrin

Jedrusik

Steinberg

Husari

et al. 2018

J Biomedical Materials Res

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“…Loss of E-cadherin expression during EMT and tumor progression is accompanied by β-catenin translocation to the nucleus where it acts as oncogenic transcription factor [32, 33]. Since Gö6976-treatment induces the expression of E-cadherin at the cellular junctions in the E-cadherin-negative metastatic melanoma cells (M2 cells), the status of β-catenin in these cells and the effect of the PKC inhibitors (Gö6976 and Gö6983) on its subcellular localization and expression were determined (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…3c). This translocation of the β-catenin from the nucleus to the plasma membrane favors its tumor suppressor role of insuring the stability of E-cadherin-mediated intercellular interactions to its oncogenic role of transcription factor [32, 33], as further supported by the inhibition of the expression of its target cyclin D1 after Gö6976 treatment. These observations also suggest that the Gö6976-induced E-cadherin molecules are functional.…”

Section: Discussionmentioning

confidence: 99%

Protein kinase C inhibitor Gö6976 but not Gö6983 induces the reversion of E- to N-cadherin switch and metastatic phenotype in melanoma: identification of the role of protein kinase D1

et al. 2017

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BackgroundMelanoma is a highly metastatic type of cancer that is resistant to all standard anticancer therapies and thus has a poor prognosis. Therefore, metastatic melanoma represents a significant clinical problem and requires novel and effective targeted therapies. The protein kinase C (PKC) family comprises multiple isoforms of serine/threonine kinases that possess distinct roles in cancer development and progression. In this study, we determined whether inhibition of PKC could revert a major process required for melanoma progression and metastasis; i.e. the E- to N-cadherin switch.MethodsThe cadherin switch was analyzed in different patient-derived primary tumors and their respective metastatic melanoma cells to determine the appropriate cellular model (aggressive E-cadherin-negative/N-cadherin-positive metastasis-derived melanoma cells). Next, PKC inhibition in two selected metastatic melanoma cell lines, was performed by using either pharmacological inhibitors (Gö6976 and Gö6983) or stable lentiviral shRNA transduction. The expression of E-cadherin and N-cadherin was determined by western blot. The consequences of cadherin switch reversion were analyzed: cell morphology, intercellular interactions, and β-catenin subcellular localization were analyzed by immunofluorescence labeling and confocal microscopy; cyclin D1 expression was analyzed by western blot; cell metastatic potential was determined by anchorage-independent growth assay using methylcellulose as semi-solid medium and cell migration potential by wound healing and transwell assays.ResultsGö6976 but not Gö6983 reversed the E- to N-cadherin switch and as a consequence induced intercellular interactions, profound morphological changes from elongated mesenchymal-like to cuboidal epithelial-like shape, β-catenin translocation from the nucleus to the plasma membrane inhibiting its oncogenic function, and reverting the metastatic potential of the aggressive melanoma cells. Comparison of the target spectrum of these inhibitors indicated that these observations were not the consequence of the inhibition of conventional PKCs (cPKCs), but allowed the identification of a novel serine/threonine kinase, i.e. protein kinase Cμ, also known as protein kinase D1 (PKD1), whose specific inhibition allows the reversion of the metastatic phenotype in aggressive melanoma.ConclusionIn conclusion, our study suggests, for the first time, that while cPKCs don’t embody a pertinent therapeutic target, inhibition of PKD1 represents a novel attractive approach for the treatment of metastatic melanoma.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-3007-5) contains supplementary material, which is available to authorized users.

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“…E-cadherin is often split into fragments in the cytoplasm, which in theory its functions would not play an inhibitory effect on EMT [46, 49]. As a result, we further performed a subgroup according to the location of E-cadherin expression.…”

Section: Discussionmentioning

confidence: 99%

Prognostic value of reduced E-cadherin expression in breast cancer: a meta-analysis

Yin

Zhang

et al. 2017

Oncotarget

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The prognostic value of E-cadherin expression in patients with breast cancer has been studied for years, yet results remain controversial. We thus performed a comprehensive evaluation of the association between E-cadherin expression and prognosis through a meta-analysis. The databases PubMed, Embase and Cochrane Library were searched. A total of 7,353 patients from 33 studies were subject to final analysis. The results showed there was a significant association between reduced expression of E-cadherin and overall survival (OS) (HR 1.79, 95% CI 1.41–2.27) and disease-free survival (DFS) (HR 1.62, 95% CI 1.31–1.99) in breast cancer. Downregulated expression of E-cadherin significantly correlated with tumor histological grade (OR 1.44, 95% CI 1.06–1.96), TNM stage (OR 2.44, 95% CI 1.75–3.41), tumor size (OR 1.38, 95% CI 1.18–1.60), lymph node status (OR 1.55, 95% CI 1.15–2.10), and progesterone receptor status (OR 1.44, 95% CI 1.10–1.88).This meta-analysis suggested that reduced E-cadherin expression might be a predictor of a poorer prognosis and could be a potentially new gene therapy target for breast cancer patients.

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From cell membrane to the nucleus: an emerging role of E‐cadherin in gene transcriptional regulation

Cited by 48 publications

References 85 publications

Gelatin nonwovens‐based epithelial morphogenesis involves a signaling axis comprising EGF‐receptor, MAP kinases ERK 1/2, and β1 integrin

Gelatin nonwovens‐based epithelial morphogenesis involves a signaling axis comprising EGF‐receptor, MAP kinases ERK 1/2, and β1 integrin

Protein kinase C inhibitor Gö6976 but not Gö6983 induces the reversion of E- to N-cadherin switch and metastatic phenotype in melanoma: identification of the role of protein kinase D1

Prognostic value of reduced E-cadherin expression in breast cancer: a meta-analysis

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