scholarly journals Novel role of Snail 1 in promoting tumor neoangiogenesis

2019 ◽  
Vol 39 (5) ◽  
Author(s):  
Yi-Kun Zhang ◽  
Hua Wang ◽  
Yu-Wei Guo ◽  
Yang Yue
Keyword(s):  
Tumor Metastasis ◽  
Epithelial To Mesenchymal Transition ◽  
Tube Formation ◽  
Fibroblast Growth ◽  
Quantitative Real Time Pcr ◽  
Potential Therapeutic Target ◽  
Mesenchymal Transition ◽  
Tumor Neoangiogenesis

Abstract Snail1 plays an important role in epithelial to mesenchymal transition (EMT) during tumor metastasis; however, whether Snai1 potentiates the process of neoangiogenesis is completely unknown. In the present study, tube formation assay was used to evaluate neoangiogenesis in vitro. The expression of Snai1 and other pro-neoangiogenic factors was measured by quantitative real time PCR. Tumor derived endothelial cells (TDECs) were stimulated with fibroblast growth factor 1 (FGF1) or VEGF and formed more tubes compared with untreated, whereas cells treated with Sulforaphane had less tube formation. Silencing SNAI1 significantly attenuated tube formation accompanied by decreased CD31, CD34, and VWF expression in TDECs compared with control. In contrast, overexpression of Snai1 led to more CD31, CD34, and VWF expression and tube formation. To determine if the observed effects of SNAI1 on tube formation was a global phenomenon, the same assay was conducted in normal mesenchymal stem cells (MSCs). SNAI1 silencing did not have any effect on tube formation in MSCs. The expression of TIMP2, ENG, and HIF1A was up-regulated 3-fold or higher after silencing SNAI1, and ID1, VEGFA, PLG, LECT1, HPSE were shown down-regulated. Taken together, our study elucidates an important role of EMT inducer Snai1 in regulating tumor neoangiogenesis, suggesting a potential therapeutic target for overcoming tumor EMT.

scholarly journals Phosphorylation of Serine 11 and Serine 92 as New Positive Regulators of Human Snail1 Function: Potential Involvement of Casein Kinase-2 and the cAMP-activated Kinase Protein Kinase A

2010 ◽  
Vol 21 (2) ◽  
pp. 244-253 ◽  
Author(s):  
Matthew Reid MacPherson ◽  
Patricia Molina ◽  
Serhiy Souchelnytskyi ◽  
Christer Wernstedt ◽  
Jorge Martin-Pérez ◽  
...  
Keyword(s):  
Nuclear Export ◽  
Tumor Metastasis ◽  
Epithelial Mesenchymal Transition ◽  
Cop9 Signalosome ◽  
Mesenchymal Transition ◽  
Depth Analysis ◽  
Positive Regulators

Snail1 is a major factor for epithelial-mesenchymal transition (EMT), an important event in tumor metastasis and in other pathologies. Snail1 is tightly regulated at transcriptional and posttranscriptional levels. Control of Snail1 protein stability and nuclear export by GSK3β phosphorylation is important for Snail1 functionality. Stabilization mechanisms independent of GSK3β have also been reported, including interaction with LOXL2 or regulation of the COP9 signalosome by inflammatory signals. To get further insights into the role of Snail1 phosphorylation, we have performed an in-depth analysis of in vivo human Snail1 phosphorylation combined with mutational studies. We identify new phosphorylation sites at serines 11, 82, and 92 and confirmed previously suggested phosphorylations at serine 104 and 107. Serines 11 and 92 participate in the control of Snail1 stability and positively regulate Snail1 repressive function and its interaction with mSin3A corepressor. Furthermore, serines 11 and 92 are required for Snail1-mediated EMT and cell viability, respectively. PKA and CK2 have been characterized as the main kinases responsible for in vitro Snail1 phosphorylation at serine 11 and 92, respectively. These results highlight serines 11 and 92 as new players in Snail1 regulation and suggest the participation of CK2 and PKA in the modulation of Snail1 functionality.

scholarly journals Senescent Breast Luminal Cells Promote Carcinogenesis through Interleukin-8-Dependent Activation of Stromal Fibroblasts

2018 ◽  
Vol 39 (2) ◽  
Author(s):  
Huda H. Al-Khalaf ◽  
Hazem Ghebeh ◽  
Rabia Inass ◽  
Abdelilah Aboussekhra
Keyword(s):  
Breast Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Normal Breast ◽  
Dependent Manner ◽  
Stromal Fibroblasts ◽  
Mesenchymal Transition ◽  
Lamin B1 ◽  
Luminal Cells

ABSTRACT Aging and stress promote senescence, which has intrinsic tumor suppressor functions and extrinsic tumor promoting properties. Therefore, it is of utmost importance to delineate the effects of senescence inducers on the various types of cells that compose the different organs. We show here that primary normal breast luminal (NBL) cells are more sensitive than their corresponding stromal fibroblasts to proliferative as well as oxidative damage-induced senescence. Like fibroblasts, senescent NBL cells secreted elevated amounts of various cytokines, including interleukin-6 (IL-6) and IL-8, and expressed high levels of p16, p21, and p53, while lamin B1 was downregulated. When senescent, luminal cells activated stromal fibroblasts in an IL-8-dependent manner, through the activation of the STAT3 pathway. These myofibroblasts promoted the epithelial-to-mesenchymal transition and the stemness processes in breast cancer cells in a paracrine manner both in vitro and in a breast cancer animal model. These results show the role of senescent breast luminal cells in promoting the inflammatory/carcinogenic microenvironment through the activation of fibroblasts in an IL-8-dependent manner.

scholarly journals SLUG and Truncated TAL1 Reduce Glioblastoma Stem Cell Growth Downstream of Notch1 and Define Distinct Vascular Subpopulations in Glioblastoma Multiforme

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5393
Author(s):  
Sophie Guelfi ◽  
Béatrice Orsetti ◽  
Virginie Deleuze ◽  
Valérie Rigau ◽  
Luc Bauchet ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Growth Factor Receptor ◽  
Treatment Resistance ◽  
Mesenchymal Transition ◽  
Glioblastoma Stem Cell ◽  
A Minor

Glioblastomas (GBM) are high-grade brain tumors, containing cells with distinct phenotypes and tumorigenic potentials, notably aggressive and treatment-resistant multipotent glioblastoma stem cells (GSC). The molecular mechanisms controlling GSC plasticity and growth have only partly been elucidated. Contact with endothelial cells and the Notch1 pathway control GSC proliferation and fate. We used three GSC cultures and glioma resections to examine the expression, regulation, and role of two transcription factors, SLUG (SNAI2) and TAL1 (SCL), involved in epithelial to mesenchymal transition (EMT), hematopoiesis, vascular identity, and treatment resistance in various cancers. In vitro, SLUG and a truncated isoform of TAL1 (TAL1-PP22) were strongly upregulated upon Notch1 activation in GSC, together with LMO2, a known cofactor of TAL1, which formed a complex with truncated TAL1. SLUG was also upregulated by TGF-β1 treatment and by co-culture with endothelial cells. In patient samples, the full-length isoform TAL1-PP42 was expressed in all glioma grades. In contrast, SLUG and truncated TAL1 were preferentially overexpressed in GBMs. SLUG and TAL1 are expressed in the tumor microenvironment by perivascular and endothelial cells, respectively, and to a minor extent, by a fraction of epidermal growth factor receptor (EGFR) -amplified GBM cells. Mechanistically, both SLUG and truncated TAL1 reduced GSC growth after their respective overexpression. Collectively, this study provides new evidence for the role of SLUG and TAL1 in regulating GSC plasticity and growth.

scholarly journals LncRNA TUG1 promotes the progression of colorectal cancer via the miR-138-5p/ZEB2 axis

2020 ◽  
Vol 40 (6) ◽  
Author(s):  
Zhenkun Yan ◽  
Miaomiao Bi ◽  
Qiyu Zhang ◽  
Yumei Song ◽  
Sen Hong
Keyword(s):  
Colorectal Cancer ◽  
Epithelial To Mesenchymal Transition ◽  
Area Under The Curve ◽  
Luciferase Reporter ◽  
Mesenchymal Transition ◽  
Diagnosis And Prognosis ◽  
Non Coding Rna ◽  
Tissue Specimens

Abstract To explore the role of long-chain non-coding RNA (lncRNA) taurine up-regulated gene 1 (TUG1) in the development of colorectal cancer (CRC) via the miR-138-5p/zinc finger E-box-binding homeobox 2 (ZEB2) axis. Eighty-four CRC tissue specimens and 84 corresponding paracancerous tissue specimens were sampled from 84 patients with CRC admitted to the First Hospital of Jilin University from January 2018 to September 2019. The TUG1 expression in the specimens was determined, and its value in diagnosis and prognosis of CRC was analyzed. Additionally, constructed stable and transient overexpresison vectors and inhibition vectors were transfected into CRC cells. The MTT, transwell, and flow cytometry were adopted for analysis on the proliferation, invasion, and apoptosis of transfected cells, respectively, and a dual luciferase reporter (DLR) assay was carried out for correlation determination between TUG1 and miR-138-5p and between miR-138-5p and ZEB2. TUG1 was up-regulated in CRC, and serum TUG1 could be adopted as a diagnostic marker of CRC, with area-under-the-curve (AUC) larger than 0.8. In addition, siRNA-TUG1, shRNA-TUG1, miR-138-5p-mimics, and miR-138-5p-inhibitor were transfected into cells, and it turned out that overexpressing miR-138-5p and inhibiting ZEB2 exerted the same effects. The DLR assay revealed that TUG1 was able to targetedly regulate miR-138-5p, and miR-138-5p could targetedly regulate ZEB2, and in vitro experiments revealed that TUG1 could affect the epithelial-to-mesenchymal transition (EMT) of CRC via the miR-138-5p/ZEB2 axis. TUG1 could promote the development of CRC via the miR-138-5p/ZEB2 axis.

scholarly journals lncRNA HOTAIR Overexpression Induced Downregulation of c-Met Signaling Promotes Hybrid Epithelial/Mesenchymal Phenotype in Hepatocellular Carcinoma Cells

2020 ◽  
Author(s):  
Hande Topel ◽  
Ezgi Bagirsakci ◽  
Dehan Comez ◽  
Gulsun Bagci ◽  
Gulcin Cakan-Akdogan ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Fate ◽  
Epithelial To Mesenchymal Transition ◽  
Biological Significance ◽  
Metastatic Potential ◽  
Mesenchymal Transition ◽  
Lncrna Hotair

Abstract Background: Epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) are both reversible processes, and regulation of phenotypical transition is very important for progression of several cancers including hepatocellular carcinoma (HCC). Recently, it is defined that cancer cells can attain a hybrid epithelial/mesenchymal (hybrid E/M) phenotype. Cells with hybrid E/M phenotype comprise mixed epithelial and mesenchymal properties, they can be more resistant to therapeutics and also more capable of initiating metastatic lesions. However, the mechanisms regulating hybrid E/M in HCC are not well described yet. In this study, we investigated the role of the potential crosstalk between lncRNA HOTAIR and c-Met receptor tyrosine kinase, which are two essential regulators of EMT and MET, in acquiring of hybrid E/M phenotype in HCC. Methods: Expression of c-Met and HOTAIR were defined in HCC cell lines and patient tissues through HCC progression. lncRNA HOTAIR was overexpressed in SNU-449 cells and its effects on c-Met signaling were analyzed. c-Met was overexpressed in SNU-398 cells and its effect on HOTAIR expression was analyzed. Biological significance of HOTAIR/c-Met interplay was defined in means of adhesion, proliferation, motility behavior, invasion, spheroid formation and metastatic ability. Effect of ectopic HOTAIR expression on phenotype was defined with investigation of molecular epithelial and mesenchymal traits. Results: In vitro and in vivo experiments verified the pivotal role of lncRNA HOTAIR in acquisition of hybrid E/M phenotype through modulating expression and activation of c-Met and its membrane co-localizing partner Caveolin-1, and membrane organization to cope with the rate limiting steps of metastasis such as survival in adhesion independent microenvironment, escaping from anoikis and resisting to fluidic shear stress (FSS) in HCC. Conclusions: Our work provides the first evidence suggesting a role for lncRNA HOTAIR in the modulation of c-Met to promote hybrid E/M phenotype. The balance between lncRNA HOTAIR and c-Met might be critical for cell fate decision and metastatic potential of HCC cells.

scholarly journals Cyclophilin A/CD147 Induces the Epithelial-to-mesenchymal Transition and Renal Fibrosis in Chronic Allograft Dysfunction by Regulating MAPK Signaling

2021 ◽  
Author(s):  
Xuzhong Liu ◽  
Zhiwang Tang ◽  
Xi Jiang ◽  
Tianwei Wang ◽  
Lun Zhao ◽  
...  
Keyword(s):  
Renal Transplant ◽  
Epithelial To Mesenchymal Transition ◽  
Renal Allograft ◽  
Cyclophilin A ◽  
Mapk Signaling ◽  
Chronic Allograft Dysfunction ◽  
Mesenchymal Transition ◽  
Allograft Dysfunction

Abstract Objectives: Our study was designed to explore the role of Cyclophilin A (CyPA)/CD147 interactions in renal allograft fibrosis and chronic allograft dysfunction (CAD). Methods and materials: A rat renal transplant model with significant CAD was successfully identified. Renal allograft tissues and blood samples were collected. HE, Masson and immunohistochemistry staining were performed. Then human HK-2 cells were intervened by certain concentrations of CyPA, and total protein and mRNA were extracted. Western blot assay and PCR were performed to explore the protein and mRNA expression of CyPA, CD147 and epithelial-to-mesenchymal transition (EMT)-related biomarkers. CD147 siRNA and specific inhibitor of MAPK were used to explore the involved cellular mechanism.Results: We have successfully established and identified a 20-weeks renal transplant CAD model. We observed significant distributed and expressed CyPA and CD147 in the renal allograft fibrosis tissues. We also found the significant expression of CD147 and EMT-related markers in the HK-2 cells stimulated by CyPA. The CD147 siRNA confirmed the previous results in vitro. The selective inhibition of MAPK suggested the notable role of MAPK signaling pathway in the CyP/CD147 interactions involved in renal allograft fibrosis.Conclusions: Our study reported the positive relationship of CyPA/CD147 interactions with the renal allograft dysfunction. In vitro study suggested that CyPA could bind to CD147 and then induce the development of EMT process by MAPK signaling, thus contributing to the renal allograft fibrosis and CAD.

scholarly journals Microcalcifications Drive Breast Cancer Occurrence and Development by Macrophage-Mediated Epithelial to Mesenchymal Transition

2019 ◽  
Vol 20 (22) ◽  
pp. 5633 ◽  
Author(s):  
Manuel Scimeca ◽  
Rita Bonfiglio ◽  
Erika Menichini ◽  
Loredana Albonici ◽  
Nicoletta Urbano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Calcium Oxalate ◽  
Epithelial To Mesenchymal Transition ◽  
Benign Lesions ◽  
Mesenchymal Transition ◽  
Cancer Occurrence ◽  
Vitro Data ◽  
In Vitro Data

Background: This study aims to investigate: (a) the putative association between the presence of microcalcifications and the expression of both epithelial-to-mesenchymal transition and bone biomarkers, (b) the role of microcalcifications in the breast osteoblast-like cells (BOLCs) formation, and (c) the association between microcalcification composition and breast cancer progression. Methods: We collected 174 biopsies on which we performed immunohistochemical and ultrastructural analysis. In vitro experiments were performed to demonstrate the relationship among microcalcification, BOLCs development, and breast cancer occurrence. Ex vivo investigations demonstrated the significant increase of breast osteoblast-like cells in breast lesions with microcalcifications with respect to those without microcalcifications. Results: In vitro data displayed that in the presence of calcium oxalate and activated monocytes, breast cancer cells undergo epithelial to mesenchymal transition. Also, in this condition, cells acquired an osteoblast phenotype, thus producing hydroxyapatite. To further confirm in vitro data, we studied 15 benign lesions with microcalcification from patients that developed a malignant condition in the same breast quadrant. Immunohistochemical analysis showed macrophages’ polarization in benign lesions with calcium oxalate. Conclusions: Altogether, our data shed new light about the role of microcalcifications in breast cancer occurrence and progression.

scholarly journals ELK1 Promotes Epithelial-Mesenchymal Transition and the Progression of Lung Adenocarcinoma by Upregulating B7-H3

2021 ◽  
Vol 2021 ◽  
pp. 1-16
Author(s):  
Ting-ting Yu ◽  
Tao Zhang ◽  
Fei Su ◽  
Ying-long Li ◽  
Li Shan ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Epithelial Mesenchymal Transition ◽  
Transcriptional Regulator ◽  
Mesenchymal Transition ◽  
Poor Patient ◽  
Patient Prognosis

In previous studies, we found that B7 homolog 3 (B7-H3) was highly expressed in lung adenocarcinoma (LUAD) and promoted epithelial-to-mesenchymal transition (EMT) of LUAD cells. However, the underlying molecular mechanism is unclear. This study is aimed at evaluating the role of Ets-like protein 1 (ELK1) as a transcriptional regulator of B7-H3 for mediating the development and progression of LUAD in vitro and in vivo. We confirmed that ELK1 is highly expressed in LUAD and is associated with poor patient prognosis. ELK1 was found to promote proliferation, invasion, migration, and EMT of LUAD cells through in vivo and in vitro experiments. In terms of mechanism, ELK1 binds to the B7-H3 promoter region and induces the upregulation of B7-H3 in LUAD. Our data suggest that ELK1 plays an important role in the development of LUAD and could be used as a prognostic marker and therapeutic target for LUAD.

scholarly journals CDKL3 promotes osteosarcoma progression by activating Akt/PKB

2020 ◽  
Vol 3 (5) ◽  
pp. e202000648 ◽  
Author(s):  
Aina He ◽  
Lanjing Ma ◽  
Yujing Huang ◽  
Haijiao Zhang ◽  
Wei Duan ◽  
...  
Keyword(s):  
Tumor Metastasis ◽  
Bone Neoplasm ◽  
Cyclin Dependent Kinase ◽  
Potential Therapeutic Target ◽  
High Frequencies ◽  
Akt Activation ◽  
Downstream Effects

Osteosarcoma (OS) is a primary malignant bone neoplasm with high frequencies of tumor metastasis and recurrence. Although the Akt/PKB signaling pathway is known to play key roles in tumorigenesis, the roles of cyclin-dependent kinase–like 3 (CDKL3) in OS progression remain largely elusive. We have demonstrated the high expression levels of CDKL3 in OS human specimens and comprehensively investigated the role of CDKL3 in promoting OS progression both in vitro and in vivo. We found that CDKL3 regulates Akt activation and its downstream effects, including cell growth and autophagy. The up-regulation of CDKL3 in OS specimens appeared to be associated with Akt activation and shorter overall patient survival (P = 0.003). Our findings identify CDKL3 as a critical regulator that stimulates OS progression by enhancing Akt activation. CDKL3 represents both a biomarker for OS prognosis, and a potential therapeutic target in precision medicine by targeting CDKL3 to treat Akt hyper-activated OS.

scholarly journals Simulation of multiple microenvironments shows a putative role of RPTPs on the control of Epithelial-to-Mesenchymal Transition

2019 ◽  
Author(s):  
Ricardo Jorge Pais
Keyword(s):  
Chronic Inflammation ◽  
Epithelial To Mesenchymal Transition ◽  
Control Mechanism ◽  
Cell Contact ◽  
List Type ◽  
Mesenchymal Transition ◽  
Cell Contacts

AbstractEpithelial-to-Mesenchymal Transition (EMT) together with Mesenchymal-to-Epithelial Transition (MET) are two natural processes thought to participate in the process of metastasis. Multiple signals from the microenvironment have been reported to drive EMT. However, microenvironment signals that control EMT and promote MET are still unknown. Here, we analysed a regulatory network of EMT involving 8 microenvironment signals to evaluate the role of cell contact signals on the switching between Epithelial and Mesenchymal-like phenotypes. The results demonstrated that RPTP activation by cell contacts have the potential to control EMT and promote MET in the presence of 5 EMT driving signals under physiological scenarios. These simulations also showed that hypoxia inhibits the RPTPs capacity of controlling EMT. In this case, FAT4 activation by cell contacts functions as an alternative control mechanism of EMT except under chronic inflammation, providing a theoretical explanation for the observed correlation between hypoxia and metastasis under chronic inflammation. Taken together, we propose here a natural control mechanism of EMT that supports the idea that this process is tightly regulated by the microenvironment.HighlightsCell contact dependent RPTP inhibit EMT and triggers MET in the presence of 5 EMT driving signals in silico.A proposed molecular mechanism for the control of EMT by cell contact dependent RPTPs.A proposed explanation for the observed MET in vitro and the correlation between hypoxia and metastasis in vivo.

Sign in / Sign up

Export Citation Format

Share Document