scholarly journals E-cadherin represses anchorage-independent growth in sarcomas through both signaling and mechanical mechanisms

2018 ◽  
Author(s):  
Mohit Kumar Jolly ◽  
Kathryn E Ware ◽  
Shengnan Xu ◽  
Shivee Gilja ◽  
Samantha Shetler ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Intracellular Signaling ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Specific Cell ◽  
Mesenchymal Transition ◽  
Anchorage Independent Growth ◽  
Sarcoma Cells ◽  
E Cadherin ◽  
Cell Cell

E-cadherin, an epithelial-specific cell-cell adhesion molecule, plays multiple roles in maintaining adherens junctions, regulating migration and invasion, and mediating intracellular signaling. Downregulation of E-cadherin is a hallmark of epithelial-mesenchymal transition (EMT) and correlates with poor prognosis in multiple carcinomas. Conversely, upregulation of E-cadherin is prognostic for improved survival in sarcomas. Yet, despite the prognostic benefit of E-cadherin expression in sarcoma, the mechanistic significance of E-cadherin in sarcomas remains poorly understood. Here, by combining mathematical models with wet-bench experiments, we identify the core regulatory networks mediated by E-cadherin in sarcomas, and decipher their functional consequences. Unlike in carcinomas, E-cadherin overexpression in sarcomas does not induce a mesenchymal-epithelial transition (MET). However, E-cadherin acts to reduce both anchorage-independent growth and spheroid formation of sarcoma cells. Ectopic E-cadherin expression acts to downregulate phosphorylated CREB (p-CREB) and the transcription factor, TBX2, to inhibit anchorage-independent growth. RNAi-mediated knockdown of TBX2 phenocopies the effect of E-cadherin on p-CREB levels and restores sensitivity to anchorage-independent growth in sarcoma cells. Beyond its signaling role, E-cadherin expression in sarcoma cells can also strengthen cell-cell adhesion and restricts spheroid growth through mechanical action. Together, our results demonstrate that E-cadherin inhibits sarcoma aggressiveness by preventing anchorage-independent growth.

scholarly journals INDUCTION OF EPITHELIAL-TO-MESENCHYMAL TRANSITION IN MCF-7-SNAI1 CELLS LEADS TO REORGANIZATION OF ADHERENS JUNCTIONS AND ACQUISITION OF MIGRATORY ACTIVITY

2018 ◽  
Vol 17 (4) ◽  
pp. 24-29
Author(s):  
I. Y. Zhitnyak ◽  
N. I. Litovka ◽  
S. N. Rubtsova ◽  
N. A. Gloushankova
Keyword(s):  
Cell Adhesion ◽  
Culture Medium ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Mesenchymal Phenotype ◽  
Mesenchymal Transition ◽  
Migratory Activity ◽  
Mcf 7 ◽  
E Cadherin ◽  
Cell Cell

Using DIC and confocal microscopy, changes in morphology, migratory characteristics and adherence junctions (AJs) were analyzed in the mammary carcinoma cell line MCF-7-SNAI1  after activation of the EMT transcription factor SNAI1. Western Blot analysis showed that  after removal of tetracycline from the cell culture medium expression of SNAI1 reached its  peak in 24 hours and then plateaued for 7 days. During the 7 days the cells continued to  express E-cadherin; however, tangential AJs typical for cells with stable cell-cell adhesion,  changed into radial AJs. The radial AJs continued to accumulate E-cadherin during 24‑72  hours after tetracycline removal. As a result of SNAI1 activation, the cells underwent  epithelial-mesenchymal transition (EMT) and became migratory. On a two-dimensional  substrate, cells exhibited both individual and collective migration. As the tetracycline  washout period progressed, the fraction of the cells capable of migrating through migration chamber membranes increased; on the contrary, cells’ ability to invade an epithelial  monolayer decreased. These results demonstrate that retaining a hybrid epithelial/mesenchymal  phenotype and accumulation of E-cadherin in AJs during early stages of EMT do not impede  disruption of stable cell-cell adhesion and cells’ acquisition of migratory activity.

scholarly journals Early Events in Actin Cytoskeleton Dynamics and E-Cadherin-Mediated Cell-Cell Adhesion during Epithelial-Mesenchymal Transition

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 578 ◽  
Author(s):  
Irina Y. Zhitnyak ◽  
Svetlana N. Rubtsova ◽  
Nikita I. Litovka ◽  
Natalya A. Gloushankova
Keyword(s):  
Cell Adhesion ◽  
Epithelial Mesenchymal Transition ◽  
Immunofluorescent Staining ◽  
Actin Binding ◽  
Mesenchymal Transition ◽  
Actin Bundle ◽  
Cell Contacts ◽  
The Stability ◽  
E Cadherin ◽  
Cell Cell

Epithelial-mesenchymal transition (EMT) plays an important role in development and also in initiation of metastasis during cancer. Disruption of cell-cell contacts during EMT allowing cells to detach from and migrate away from their neighbors remains poorly understood. Using immunofluorescent staining and live-cell imaging, we analyzed early events during EMT induced by epidermal growth factor (EGF) in IAR-20 normal epithelial cells. Control cells demonstrated stable adherens junctions (AJs) and robust contact paralysis, whereas addition of EGF caused rapid dynamic changes at the cell-cell boundaries: fragmentation of the circumferential actin bundle, assembly of actin network in lamellipodia, and retrograde flow. Simultaneously, an actin-binding protein EPLIN was phosphorylated, which may have decreased the stability of the circumferential actin bundle. Addition of EGF caused gradual replacement of linear E-cadherin–based AJs with dynamic and unstable punctate AJs, which, unlike linear AJs, colocalized with the mechanosensitive protein zyxin, confirming generation of centripetal force at the sites of cell-cell contacts during EMT. Our data show that early EMT promotes heightened dynamics at the cell-cell boundaries—replacement of stable AJs and actin structures with dynamic ones—which results in overall weakening of cell-cell adhesion, thus priming the cells for front-rear polarization and eventual migration.

scholarly journals Role of Cadherins in Cancer—A Review

2020 ◽  
Vol 21 (20) ◽  
pp. 7624
Author(s):  
Ilona Kaszak ◽  
Olga Witkowska-Piłaszewicz ◽  
Zuzanna Niewiadomska ◽  
Bożena Dworecka-Kaszak ◽  
Felix Ngosa Toka ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Tumor Progression ◽  
Signaling Pathways ◽  
Rho Gtpases ◽  
Epithelial Mesenchymal Transition ◽  
Clinical Importance ◽  
Mesenchymal Transition ◽  
E Cadherin ◽  
Cell Cell

Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin complex may result in tumor progression. Epithelial mesenchymal transition (EMT) is a mechanism in which epithelial cadherin (E-cadherin) expression is lost during tumor progression. However, during tumorigenesis, many processes take place, and downregulation of E-cadherin, nuclear β-catenin and p120 catenin (p120) signaling are among the most critical. Additional signaling pathways, such as Receptor tyrosine kinase (RTK), Rho GTPases, phosphoinositide 3-kinase (PI3K) and Hippo affect cadherin cell-cell adhesion and also contribute to tumor progression and metastasis. Many signaling pathways may be activated during tumorigenesis; thus, cadherin-targeting drugs seem to limit the progression of malignant tumor. This review discusses the role of cadherins in selected signaling mechanisms involved in tumor growth. The clinical importance of cadherin will be discussed in cases of human and animal cancers.

scholarly journals Microgravity Induces Transient EMT in Human Keratinocytes by Early Down-Regulation of E-Cadherin and Cell-Adhesion Remodeling

2020 ◽  
Vol 11 (1) ◽  
pp. 110
Author(s):  
Giulia Ricci ◽  
Alessandra Cucina ◽  
Sara Proietti ◽  
Simona Dinicola ◽  
Francesca Ferranti ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Human Keratinocytes ◽  
Short Exposure ◽  
Migration And Invasion ◽  
Hacat Cells ◽  
Invasive Phenotype ◽  
Adhesion Properties ◽  
Mesenchymal Transition ◽  
Cell Matrix ◽  
E Cadherin

Changes in cell–matrix and cell-to-cell adhesion patterns are dramatically fostered by the microgravity exposure of living cells. The modification of adhesion properties could promote the emergence of a migrating and invasive phenotype. We previously demonstrated that short exposure to the simulated microgravity of human keratinocytes (HaCaT) promotes an early epithelial–mesenchymal transition (EMT). Herein, we developed this investigation to verify if the cells maintain the acquired invasive phenotype after an extended period of weightlessness exposure. We also evaluated cells’ capability in recovering epithelial characteristics when seeded again into a normal gravitational field after short microgravity exposure. We evaluated the ultra-structural junctional features of HaCaT cells by Transmission Electron Microscopy and the distribution pattern of vinculin and E-cadherin by confocal microscopy, observing a rearrangement in cell–cell and cell–matrix interactions. These results are mirrored by data provided by migration and invasion biological assay. Overall, our studies demonstrate that after extended periods of microgravity, HaCaT cells recover an epithelial phenotype by re-establishing E-cadherin-based junctions and cytoskeleton remodeling, both being instrumental in promoting a mesenchymal–epithelial transition (MET). Those findings suggest that cytoskeletal changes noticed during the first weightlessness period have a transitory character, given that they are later reversed and followed by adaptive modifications through which cells miss the acquired mesenchymal phenotype.

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

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.

SETD1A to induce epithelial-mesenchymal transition to promote invasion and metastasis through epigenetic reprogramming of snail in gastric cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 241-241
Author(s):  
Jugang Wu ◽  
Jiwei Yu ◽  
Yan Gu
Keyword(s):  
Gastric Cancer ◽  
Molecular Mechanisms ◽  
Epithelial Mesenchymal Transition ◽  
Epigenetic Modification ◽  
Epigenetic Reprogramming ◽  
Migration And Invasion ◽  
Mrna Levels ◽  
Invasion And Metastasis ◽  
Mesenchymal Transition ◽  
E Cadherin

241 Background: Aberrant epigenetic modification induces oncogenes expression and promotes cancer development. The histone lysine methyltransferase SETD1A, which specifically methylates H3K4, is involved in tumor growth and metastasis, and its ectopic expression has been detected in aggressive malignancies. Our previous study had reported that SETD1A promoted gastric cancer (GC) proliferation and tumorigenesis. However, the function and molecular mechanisms of SETD1A in GC metastasis remain to be elucidated. Methods: Transwell migration and invasion assay were performed to determine GC cell migration and invasion. Lung metastasis assay was used to detect GC cell metastasis. Western Blot and Real-time qPCR were performed to measure the protein and mRNA levels, respectively. ChIP assay was performed to investigate the methylation of H3K4. The correlation between SETD1A and EMT associated key genes in GC were performed by bioinformatic analysis. Results: In this study, we found that overexpression of SETD1A promotes GC migration and invasion, whereas knockdown of SETD1A suppressed GC migration, invasion and metastasis. Furthermore, knockdown of SETD1A suppressed GC epithelial-mesenchymal transition (EMT) by increasing the expression of epithelial marker E-cadherin, and decreasing the expression of mesenchymal markers, including N-cadherin, Fibronectin and Vimentin. Mechanistically, knockdown of SETD1A reduced the EMT key transcriptional factors snail. SETD1A was recruited to the promoter of snail, where SETD1A could methylate H3K4. However, knockdown of SETD1A decreased the methylation of H3K4 on snail promoter. Rescue of snail restored SETD1A knockdown-induced GC migration and invasion inhibition. In addition, linear correlation between SETD1A and several key EMT genes, including E-cadherin, Fibronectin and snail, in GC specimens obtained from TCGA dataset. Conclusions: In summary, our data reveals that SETD1A mediated EMT process and induced metastasis through epigenetic reprogramming of snail.

Aquaporin-5 regulation of cell-cell adhesion proteins: an elusive "tail" story

2020 ◽  
Author(s):  
Frédéric H. Login ◽  
Johan Palmfeldt ◽  
Joleen Cheah ◽  
Soichiro Yamada ◽  
Lene N. Nejsum
Keyword(s):  
Cell Adhesion ◽  
Water Transport ◽  
Epithelial Mesenchymal Transition ◽  
Tail Domain ◽  
Aquaporin 5 ◽  
Mesenchymal Transition ◽  
Cancer Spread ◽  
Aqp5 Expression ◽  
Migration Capacity ◽  
Cell Cell

Aquaporins (AQPs) are water channels that facilitate transport of water across cellular membranes. AQPs are overexpressed in several cancers. Especially in breast cancer, AQP5 overexpression correlates with spread to lymph nodes and poor prognosis. Previously, we showed that AQP5 expression reduced cell-cell adhesion by reducing levels of adherens and tight junction proteins (e.g., ZO1, plakoglobin and β-catenin) at the actual junctions. Here, we show that when targeted to the plasma membrane, the AQP5 C-terminal tail domain regulated junctional proteins. Moreover, that AQP5 interacted with ZO1, plakoglobin, β-catenin and desmoglein-2, which were all reduced at junctions upon AQP5 overexpression. Thus, our data suggest that AQP5 mediates the effect on cell-cell adhesion via interactions with junctional protein independently of AQP5 mediated water transport. AQP5 overexpression in cancers may thus contribute to carcinogenesis and cancer spread by two independent mechanisms: reduced cell-cell adhesion, a characteristic of epithelial-mesenchymal transition, and increased cell migration capacity via water transport.

scholarly journals Disruption of Cancer Metabolic SREBP1/miR-142-5p Suppresses Epithelial–Mesenchymal Transition and Stemness in Esophageal Carcinoma

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 7 ◽  
Author(s):  
Chih-Ming Huang ◽  
Chin-Sheng Huang ◽  
Tung-Nien Hsu ◽  
Mao-Suan Huang ◽  
Iat-Hang Fong ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Survival Rate ◽  
Tumor Suppressor ◽  
Poor Prognosis ◽  
Epithelial Mesenchymal Transition ◽  
Therapeutic Potential ◽  
Regulatory Element ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
E Cadherin

Elevated activity of sterol regulatory element-binding protein 1 (SREBP1) has been implicated in the tumorigenesis of different cancer types. However, the functional roles of SREBP1 in esophageal cancer are not well appreciated. Here, we aimed to investigate the therapeutic potential of SREBP1 and associated signaling in esophageal cancer. Our initial bioinformatics analyses showed that SREBP1 expression was overexpressed in esophageal tumors and correlated with a significantly lower overall survival rate in patients. Additionally, tumor suppressor miR-142-5p was predicted to target SREBP1/ZEB1 and a lower miR-142-5p was correlated with poor prognosis. We then performed in vitro experiments and showed that overexpressing SREBP1 in OE33 cell line led to increased abilities of colony formation, migration, and invasion; the opposite was observed in SREBP1-silenced OE21cells and SREBP1-silencing was accompanied by the reduced mesenchymal markers, including vimentin (Vim) and ZEB1, while E-cadherin and tumor suppressor miR-142-5p were increased. Subsequently, we first demonstrated that both SREBP1 and ZEB1 were potential targets of miR-142-5p, followed by the examination of the regulatory circuit of miR-142-5p and SREBP1/ZEB1. We observed that increased miR-142-5p level led to the reduced tumorigenic properties, such as migration and tumor sphere formation, and both observations were accompanied by the reduction of ZEB1 and SREBP1, and increase of E-cadherin. We then explored the potential therapeutic agent targeting SREBP1-associated signaling by testing fatostatin (4-hydroxytamoxifen, an active metabolite of tamoxifen). We found that fatostatin suppressed the cell viability of OE21 and OE33 cells and tumor spheres. Interestingly, fatostatin treatment reduced CD133+ population in both OE21 and OE33 cells in concert of increased miR-142-5p level. Finally, we evaluated the efficacy of fatostatin using a xenograft mouse model. Mice treated with fatostatin showed a significantly lower tumor burden and better survival rate as compared to their control counterparts. The treatment of fatostatin resulted in the reduced staining of SREBP1, ZEB1, and Vim, while E-cadherin and miR-142-5p were increased. In summary, we showed that increased SREBP1 and reduced miR-142-5p were associated with increased tumorigenic properties of esophageal cancer cells and poor prognosis. Preclinical tests showed that suppression of SREBP1 using fatostatin led to the reduced malignant phenotype of esophageal cancer via the reduction of EMT markers and increased tumor suppressor, miR-142-5p. Further investigation is warranted for the clinical use of fatostatin for the treatment of esophageal malignancy.

scholarly journals Inhibitor of DNA-Binding Protein 4 Suppresses Cancer Metastasis through the Regulation of Epithelial Mesenchymal Transition in Lung Adenocarcinoma

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 2021 ◽  
Author(s):  
Chi-Chung Wang ◽  
Yuan-Ling Hsu ◽  
Chi-Jen Chang ◽  
Chia-Jen Wang ◽  
Tzu-Hung Hsiao ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Dna Binding ◽  
Lung Adenocarcinoma ◽  
Cancer Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Inhibitor Of Dna Binding ◽  
E Cadherin

Metastasis is a predominant cause of cancer death and the major challenge in treating lung adenocarcinoma (LADC). Therefore, exploring new metastasis-related genes and their action mechanisms may provide new insights for developing a new combative approach to treat lung cancer. Previously, our research team discovered that the expression of the inhibitor of DNA binding 4 (Id4) was inversely related to cell invasiveness in LADC cells by cDNA microarray screening. However, the functional role of Id4 and its mechanism of action in lung cancer metastasis remain unclear. In this study, we report that the expression of Id4 could attenuate cell migration and invasion in vitro and cancer metastasis in vivo. Detailed analyses indicated that Id4 could promote E-cadherin expression through the binding of Slug, cause the occurrence of mesenchymal-epithelial transition (MET), and inhibit cancer metastasis. Moreover, the examination of the gene expression database (GSE31210) also revealed that high-level expression of Id4/E-cadherin and low-level expression of Slug were associated with a better clinical outcome in LADC patients. In summary, Id4 may act as a metastatic suppressor, which could not only be used as an independent predictor but also serve as a potential therapeutic for LADC treatment.

scholarly journals Atypical role of sprouty in colorectal cancer: sprouty repression inhibits epithelial–mesenchymal transition

Oncogene ◽  
2015 ◽  
Vol 35 (24) ◽  
pp. 3151-3162 ◽  
Author(s):  
Q Zhang ◽  
T Wei ◽  
K Shim ◽  
K Wright ◽  
K Xu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Cell Migration ◽  
Cancer Cells ◽  
Epithelial Mesenchymal Transition ◽  
Migration And Invasion ◽  
Colon Cancer Cells ◽  
Mesenchymal Transition ◽  
E Cadherin

Abstract Sprouty (SPRY) appears to act as a tumor suppressor in cancer, whereas we demonstrated that SPRY2 functions as a putative oncogene in colorectal cancer (CRC) (Oncogene, 2010, 29: 5241–5253). We investigated the mechanisms by which SPRY regulates epithelial–mesenchymal transition (EMT) in CRC. SPRY1 and SPRY2 mRNA transcripts were significantly upregulated in human CRC. Suppression of SPRY2 repressed AKT2 and EMT-inducing transcription factors and significantly increased E-cadherin expression. Concurrent downregulation of SPRY1 and SPRY2 also increased E-cadherin and suppressed mesenchymal markers in colon cancer cells. An inverse expression pattern between AKT2 and E-cadherin was established in a human CRC tissue microarray. SPRY2 negatively regulated miR-194-5p that interacts with AKT2 3′ untranslated region. Mir-194 mimics increased E-cadherin expression and suppressed cancer cell migration and invasion. By confocal microscopy, we demonstrated redistribution of E-cadherin to plasma membrane in colon cancer cells transfected with miR-194. Spry1 −/− and Spry2 −/− double mutant mouse embryonic fibroblasts exhibited decreased cell migration while acquiring several epithelial markers. In CRC, SPRY drive EMT and may serve as a biomarker of poor prognosis.

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