The Mouse Snail Gene Encodes a Key Regulator of the Epithelial-Mesenchymal Transition

ABSTRACT Snail family genes encode DNA binding zinc finger proteins that act as transcriptional repressors. Mouse embryos deficient for the Snail (Sna) gene exhibit defects in the formation of the mesoderm germ layer. In Sna −/− mutant embryos, a mesoderm layer forms and mesodermal marker genes are induced but the mutant mesoderm is morphologically abnormal. Lacunae form within the mesoderm layer of the mutant embryos, and cells lining these lacunae retain epithelial characteristics. These cells resemble a columnar epithelium and have apical-basal polarity, with microvilli along the apical surface and intercellular electron-dense adhesive junctions that resemble adherens junctions. E-cadherin expression is retained in the mesoderm of the Sna −/− embryos. These defects are strikingly similar to the gastrulation defects observed insnail-deficient Drosophila embryos, suggesting that the mechanism of repression of E-cadherin transcription by Snail family proteins may have been present in the metazoan ancestor of the arthropod and mammalian lineages.

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Complement Component 3 (C3) Is a Mediator of Epithelial-Mesenchymal Transition (EMT)

Blood ◽

10.1182/blood.v124.21.1421.1421 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1421-1421

Author(s):

Min Soon Cho ◽

Qianghua Hu ◽

Rajesha Rupaimoole ◽

Anil Sood ◽

Vahid Afshar-Kharghan

Keyword(s):

Ovarian Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Malignant Tumors ◽

Mouse Embryos ◽

Ovarian Cancer Cells ◽

Mesenchymal Transition ◽

E Cadherin

Abstract We have shown that complement component 3 (C3) is expressed in malignant ovarian epithelial cells and enhances cell proliferation in vitro and tumor growth in vivo. C3 is secreted by cancer cells into the tumor microenvironment and promotes tumor growth through an autocrine loop. To understand the mechanism of upregulation of C3 expression in malignant epithelial cells, we studied the transcriptional regulation of C3, and found that TWIST1, a major regulator of EMT, binds to the C3 promoter and regulates C3 transcription. Knockdown of the TWIST1 gene reduced C3 mRNA, and TWIST1 overexpression increased C3 mRNA. TWIST1 promotes epithelial-mesenchymal transition (EMT) during normal development and in metastasis of malignant tumors. An important marker of EMT is a reduction in the surface expression of E-cadherin on cells facilitating migration and invasion of these cells. TWIST1 is a transcriptional repressor of E-cadherin; and because TWIST1 increases C3 expression, we investigated whether C3 is also a negative regulator of E-cadherin expression. We overexpressed C3 in ovarian cancer cells by stable transduction of lentivirus carrying C3 cDNA. Overexpression of C3 was associated with 32% reduction in the expression of E-cadherin resulting in enhanced migration ability of cells by 2.3 folds and invasiveness by 1.75 folds, as compared to control cells transduced with control lentivirus. To investigate whether TWIST1-induced reduction in E-cadherin is C3-mediated or not, we studied the effect of TWIST1 overexpression simultaneous with C3 knockdown in ovarian cancer cells. Overexpression of TWIST1 alone resulted in 70% reduction in E-cadherin mRNA and this was completely reversed after simultaneous C3 knockdown in these cells. To investigate the correlation between C3 and TWIST1 in vivo, we studied the co-expression of these two proteins in mouse embryos (physiologic EMT) and in malignant tumors (pathologic EMT). Given the role of EMT in embryogenesis we immunostained mouse embryos at different stages of development, using antibodies against TWIST1 or C3. Transverse section of 9.5-day post-coitum (9.5dpc) mouse embryos showed co-expression of TWIST1 and C3 in otocyst (ot) and hindbrain (hb) of neural crest. In the whole-mounted 11.5dpc mouse embryos, C3 and TWIST1 were co-expressed in limb buds. Given the role of EMT in malignancy, tumors induced in mice after intraperitoneal injection of murine ovarian cancer cells were resected and immunostained for C3 and TWIST1 proteins. TWIST1 and C3 co-localized at tumor edges, where EMT and tumor cells migration occur. Taken together, these data provide evidence that TWIST1 regulates C3 expression, and C3 promotes EMT through E-cadherin. Disclosures No relevant conflicts of interest to declare.

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Snail family proteins in cervical squamous carcinoma: Expression and significance

Clinical & Investigative Medicine ◽

10.25011/cim.v36i4.19956 ◽

2013 ◽

Vol 36 (4) ◽

pp. 223 ◽

Cited By ~ 14

Author(s):

Weidong Zhao ◽

Ying Zhou ◽

Hanjie Xu ◽

Yong Cheng ◽

Beihua Kong

Keyword(s):

Lymph Node ◽

Lymph Node Metastasis ◽

Epithelial Mesenchymal Transition ◽

Squamous Carcinoma ◽

Histological Differentiation ◽

Mesenchymal Transition ◽

Node Metastasis ◽

Nuclear Expression ◽

Snail Family ◽

E Cadherin

Purpose: Epithelial-mesenchymal transition (EMT) is crucial for tumor progression and metastasis. Snail family members, including Snail, Slug and Smuc, are the transcription factors that repress E-cadherin expression and induce epithelial-mesenchymal transition in some tumor tissues. In this study, the expression of snail family proteins in cervical squamous cancers was evaluated. Methods: A series of 144 samples, comprising 28 cases of normal cervical tissues and 116 cases of squamous cell carcinoma (SCC), were used for analysis. The expression of Snail, Slug, Smuc, E-cadherin and vimentin was assessed in the tissues by immunohistochemistry and was statistically analyzed by SPSS13.0. Results: The increase in nuclear expression of snail and smuc was associated with down-regulation of E-cadherin and up-regulation of vimentin. The nuclear expression of Snail and Smuc was positively associated with lymph node metastasis of the SCC, and the nuclear expression of Snail was also positively related with histological differentiation. In contrast, tumor size, histological differentiation, lymph node metastasis and stages of the SCC were not associated with the expression of Slug, cytpolasmic Smuc or cytoplasm levels of Snail. Conclusion: Snail and Smuc proteins, but not Slug, may contribute to the onset of EMT in SCC. Inhibiting the expression of Snail and Smuc might be a potential therapeutic target for the treatment of metastasis and invasion of cervical carcinomas.

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Regulation of E-cadherin

Breast Cancer Online ◽

10.1017/s1470903105003159 ◽

2005 ◽

Vol 8 (3) ◽

Cited By ~ 4

Author(s):

Z. Yang ◽

H. Zhang ◽

R. Kumar

Keyword(s):

Transcription Factors ◽

Present Article ◽

Zinc Finger ◽

Molecular Basis ◽

Epithelial Mesenchymal Transition ◽

Major Contributor ◽

Mesenchymal Transition ◽

Snail Family ◽

E Cadherin

Numerous studies suggest that loss of E-cadherin is necessary to induce Epithelial–mesenchymal transition (EMT) and metastasis. Snail is a major contributor to EMTs. The Snail family of zinc-finger transcription factors interact with the E-cadherin promoter to repress transcription during EMT. The present article reviews the regulation of E-cadherin and discusses recent novel insights into the molecular basis in the process of EMT.

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ID1 mediates resistance to osimertinib in EGFR T790M-positive non-small cell lung cancer through epithelial–mesenchymal transition

BMC Pulmonary Medicine ◽

10.1186/s12890-021-01540-4 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Kejun Liu ◽

Xianwen Chen ◽

Ligang Wu ◽

Shiyuan Chen ◽

Nianxin Fang ◽

...

Keyword(s):

Lung Cancer ◽

Cell Cycle ◽

Small Cell Lung Cancer ◽

Cell Line ◽

Epithelial Mesenchymal Transition ◽

Small Cell ◽

Small Cell Lung ◽

Mesenchymal Transition ◽

Egfr T790m ◽

E Cadherin

Abstract Background ID1 is associated with resistance to the first generation of EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC). However, the effect of ID1 expression on osimertinib resistance in EGFR T790M-positive NSCLC is not clear. Methods We established a drug-resistant cell line, H1975/OR, from the osimertinib-sensitive cell line H1975. Alterations in ID1 protein expression and Epithelial–mesenchymal transition (EMT)-related proteins were detected with western blot analysis. RT-PCR was used to evaluate the differences of gene mRNA levels. ID1 silencing and overexpression were used to investigate the effects of related gene on osimertinib resistance. Cell Counting Kit-8 (CCK8) was used to assess the proliferation rate in cells with altered of ID1 expression. Transwell assay was used to evaluate the invasion ability of different cells. The effects on the cell cycle and apoptosis were also compared using flow cytometry. Results In our study, we found that in osimertinib-resistant NSCLC cells, the expression level of the EMT-related protein E-cadherin was lower than that of sensitive cells, while the expression level of ID1 and vimentin were higher than those of sensitive cells. ID1 expression levels was closely related to E-cadherin and vimentin in both osimertinib-sensitive and resistant cells. Alteration of ID1 expression in H1975/OR cells could change the expression of E-cadherin. Downregulating ID1 expression in H1975/OR cells could inhibit cell proliferation, reduce cell invasion, promote cell apoptosis and arrested the cell cycle in the G1/G0 stage phase. Our study suggests that ID1 may induce EMT in EGFR T790M-positive NSCLC, which mediates drug resistance of osimertinib. Conclusions Our study revealed the mechanism of ID1 mediated resistance to osimertinib in EGFR T790M-positive NSCLC through EMT, which may provide new ideas and methods for the treatment of EGFR mutated NSCLC after osimertinib resistance.

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Distinct Ring1b complexes defined by DEAD-box helicases and EMT transcription factors synergistically enhance E-cadherin silencing in breast cancer

Cell Death and Disease ◽

10.1038/s41419-021-03491-4 ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Yawei Wang ◽

Yingying Sun ◽

Chao Shang ◽

Lili Chen ◽

Hongyu Chen ◽

...

Keyword(s):

Breast Cancer ◽

Transcription Factors ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Epigenetic Mechanism ◽

Regulation Mechanism ◽

Rna Helicases ◽

Mesenchymal Transition ◽

Dead Box ◽

E Cadherin

AbstractRing1b is a core subunit of polycomb repressive complex 1 (PRC1) and is essential in several high-risk cancers. However, the epigenetic mechanism of Ring1b underlying breast cancer malignancy is poorly understood. In this study, we showed increased expression of Ring1b promoted metastasis by weakening cell–cell adhesions of breast cancer cells. We confirmed that Ring1b could downregulate E-cadherin and contributed to an epigenetic rewiring via PRC1-dependent function by forming distinct complexes with DEAD-box RNA helicases (DDXs) or epithelial-mesenchymal transition transcription factors (EMT TFs) on site-specific loci of E-cadherin promoter. DDXs-Ring1b complexes moderately inhibited E-cadherin, which resulted in an early hybrid EMT state of epithelial cells, and EMT TFs-Ring1b complexes cooperated with DDXs-Ring1b complexes to further repress E-cadherin in mesenchymal-like cancer cells. Clinically, high expression of Ring1b with DDXs or EMT TFs predicted low levels of E-cadherin, metastatic behavior, and poor prognosis. These findings provide an epigenetic regulation mechanism of Ring1b complexes in E-cadherin expression. Ring1b complexes may be potential therapeutic targets and biomarkers for diagnosis and prognosis in invasion breast cancer.

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Absence of EpCAM in cervical cancer cells is involved in slug induced epithelial-mesenchymal transition

Cancer Cell International ◽

10.1186/s12935-021-01858-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xian Liu ◽

Qian Feng ◽

Yanru Zhang ◽

PengSheng Zheng ◽

Nan Cui

Keyword(s):

Cervical Cancer ◽

Cell Motility ◽

Cancer Cells ◽

Negative Correlation ◽

Epithelial Mesenchymal Transition ◽

Mesenchymal Transition ◽

Suppression Effect ◽

Epcam Expression ◽

Cervical Cancer Cells ◽

E Cadherin

Abstract Background Slug (Snai2) is a pivotal player in initiating epithelial-mesenchymal transition (EMT) through its trans-suppression effect on E-cadherin in various normal and malignant cells. In this study, the positive effect of Slug on promoting cell motility and metastasis in cervical cancer was further confirmed in this study. Methods RNA-Seq was performed to explore the potential molecules that participate in Slug-mediated EMT in cervical cancer cells. The negative correlation between Slug and EpCAM expression in cervical cancer cells was detected in this study, and linked them with in vitro migration and invasion assay, in vivo metastasis experiments, luciferase reporter assay and Chromatin immunoprecipitation. Results Transcriptome sequencing analysis revealed that epithelial cell adhesion molecule (EpCAM) was significantly decreased in Slug-overexpressing SiHa cells. Simultaneously, an absence of EpCAM expression was observed in Slug-overexpressing cells. Further studies revealed the trans-suppression effect of Slug on EpCAM through its binding to the E-boxes in the proximal promoter region of EpCAM in cervical cancer cells. Restoring EpCAM in Slug-overexpressing cells by transiently transfecting an EpCAM recombinant plasmid attenuated cell motility and promoted cell growth. Moreover, the negative correlation between Slug and EpCAM expression in human squamous cervical carcinoma (SCC) samples was verified by using Pearson correlation analysis. Conclusions These results demonstrated that the absence of EpCAM under Slug expression in cervical cancer cells probably participated in Slug-regulated EMT and further promoted tumor metastasis. Additionally, this study supports a potential way for Slug to initiate EMT progression in cervical cancer cells in addition to inhibiting E-cadherin.

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Epithelial-Mesenchymal Transition Phenotype, Metformin, and Survival for Colorectal Cancer Patients with Diabetes Mellitus II

Gastroenterology Research and Practice ◽

10.1155/2017/2520581 ◽

2017 ◽

Vol 2017 ◽

pp. 1-10 ◽

Cited By ~ 5

Author(s):

Yaodu Wang ◽

Zhiyang Wu ◽

Likuan Hu

Keyword(s):

Diabetes Mellitus ◽

Colorectal Cancer ◽

Epithelial Mesenchymal Transition ◽

Disease Free Survival ◽

Multivariate Regression Analysis ◽

Stage I ◽

Clinicopathological Parameters ◽

Mesenchymal Transition ◽

Patients With Diabetes ◽

E Cadherin

Objectives. We aimed to explore the association between metformin treatment and epithelial-mesenchymal transition (EMT) phenotype and further appraise the prognostic values of metformin and EMT markers E-cadherin and vimentin for colorectal cancer (CRC) in clinical practice. Methods. We collected specimens and evaluated clinicopathological parameters of 102 stage I to III CRC patients with prediagnosed type 2 diabetes mellitus (DM II). Expression of E-cadherin and vimentin in tumors was detected by immunohistochemistry (IHC), and statistical analysis was performed using SPSS 19.0. Results. In correlation tests, we found a lower tumor cell EMT degree (more E-cadherin (P=0.014) and less vimentin (P=0.011) expression in patients who used metformin, and the expression of E-cadherin and vimentin was associated with serum CA19-9 (P=0.048, P=0.009), tumor invasive depth (T) (P<0.001, P=0.045), and lymph invasion (N) (P=0.013, P=0.001). In Cox multivariate regression analysis, E-cadherin was identified as a prognostic factor for disease-free survival (DFS) (P=0.038) and metformin use (P=0.015P=0.044) and lymph invasion (P=0.016P=0.023) were considered as the prognostic factors for both DFS and overall survival (OS). Conclusion. Our study suggested that metformin may impede the EMT process and improve survival for stage I–III CRC patients with DM II.

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The Impacts of Bone Marrow Mesenchymal Stem Cells (BMSCs)-Derived Periostin on Epithelial-Mesenchymal Transition (EMT) of Cervical Cancer Cells

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2022.2958 ◽

2022 ◽

Vol 12 (4) ◽

pp. 820-826

Author(s):

Chengyong Wu ◽

Weifeng Wei ◽

Jing Li ◽

Shenglin Peng

Keyword(s):

Cervical Cancer ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Signal Transduction Pathway ◽

Underlying Mechanism ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Essential Components ◽

Cervical Cancer Cells ◽

E Cadherin

Epithelial-mesenchymal transition (EMT) is closely related to the migrating and invading behaviors of cells. Periostin is one of the essential components in the extracellular matrix and can induce EMT of cells and their sequential metastasis. But its underlying mechanism is unclear. The Hela and BMSC cell lines were assigned into Periostin-mimic group, Periostin-Inhibitor group and Periostin-NC group followed by analysis of cell migration and invasion, expression of E-Cadherin, Vimentin, β-Catenin, Snail, MMP-2, MMP-9, PTEN, and p-PTEN. Cells in Periostin-mimic group exhibited lowest migration, least number of invaded cells, as well as lowest levels of Vimentin, β-Catenin, Snail, MMP-2, MMP-9, p-PTEN, Akt, p-Akt, p-GSK-3β, p-PDK1 and p-cRcf, along with highest levels of E-cadherin and PTEN. Moreover, cells in Periostin-NC group had intermediate levels of these above indicators, while, the Periostin-Inhibitor group exhibited the highest migration rate, the most number of invaded cells, and the highest levels of these proteins (P < 0.05). In conclusion, BMSCs-derived Periostin can influence the EMT of cervical cancer cells possibly through restraining the activity of the PI3K/AKT signal transduction pathway, indicating that Periostin might be a target of chemotherapy in clinics for the treatment of cervical cancer.

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