Molecular Mechanisms Of Epithelial-mesenchymal Transition Research Articles

CYTOR-NFAT1 feedback loop regulates epithelial-mesenchymal transition of retinal pigment epithelial cells.

Epithelial mesenchymal transition (EMT) occurring in retinal pigment epithelial cells (RPE) is a crucial mechanism that contributes to the development of age-related macular degeneration (AMD), a pivotal factor leading topermanent vision impairment. Long non-coding RNAs (lncRNAs) have emerged as critical regulators orchestrating EMT in RPE cells. In this study, we explored the function of the lncRNA CYTOR (cytoskeleton regulator RNA) in EMT of RPE cells and its underlying mechanisms. Through weighted correlation network analysis, we identified CYTOR as an EMT-related lncRNA associated with AMD. Experimental validation revealed that CYTOR orchestrates TGF-β1-induced EMT, as well as proliferation and migration of ARPE-19 cells. Further investigation demonstrated the involvement of CYTOR in regulating the WNT5A/NFAT1 pathway and NFAT1 intranuclear translocation in the ARPE-19 cell EMT model. Mechanistically, CHIP, EMSA and dual luciferase reporter assays confirmed NFAT1's direct binding to CYTOR's promoter, promoting transcription. Reciprocally, CYTOR overexpression promoted NFAT1 expression, while NFAT1 overexpression increased CYTOR transcription. These findings highlight a mutual promotion between CYTOR and NFAT1, forming a positive feedback loop that triggers the EMT phenotype in ARPE-19 cells. These discoveries provide valuable insights into the molecular mechanisms of EMT and its association with AMD, offering potential avenues for targeted therapies in EMT-related conditions, including AMD.

Approach for Elucidating the Molecular Mechanism of Epithelial to Mesenchymal Transition in Fibrosis of Asthmatic Airway Remodeling Focusing on Cl- Channels.

Airway remodeling caused by asthma is characterized by structural changes of subepithelial fibrosis, goblet cell metaplasia, submucosal gland hyperplasia, smooth muscle cell hyperplasia, and angiogenesis, leading to symptoms such as dyspnea, which cause marked quality of life deterioration. In particular, fibrosis exacerbated by asthma progression is reportedly mediated by epithelial-mesenchymal transition (EMT). It is well known that the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling is closely associated with several signaling pathways, including the TGF-β1/Smad, TGF-β1/non-Smad, and Wnt/β-catenin signaling pathways. However, the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling has not yet been fully clarified. Given that Cl- transport through Cl- channels causes passive water flow and consequent changes in cell volume, these channels may be considered to play a key role in EMT, which is characterized by significant morphological changes. In the present article, we highlight how EMT, which causes fibrosis and carcinogenesis in various tissues, is strongly associated with activation or inactivation of Cl- channels and discuss whether Cl- channels can lead to elucidation of the molecular mechanism of EMT in fibrosis of asthmatic airway remodeling.

Anti-Cancer Potential of Phytochemicals: The Regulation of the Epithelial-Mesenchymal Transition.

A biological process called epithelial-mesenchymal transition (EMT) allows epithelial cells to change into mesenchymal cells and acquire some cancer stem cell properties. EMT contributes significantly to the metastasis, invasion, and development of treatment resistance in cancer cells. Current research has demonstrated that phytochemicals are emerging as a potential source of safe and efficient anti-cancer medications. Phytochemicals could disrupt signaling pathways related to malignant cell metastasis and drug resistance by suppressing or reversing the EMT process. In this review, we briefly describe the pathophysiological properties and the molecular mechanisms of EMT in the progression of cancers, then summarize phytochemicals with diverse structures that could block the EMT process in different types of cancer. Hopefully, these will provide some guidance for future research on phytochemicals targeting EMT.

Emerging trends and research foci of epithelial-mesenchymal transition in gliomas: A scientometric analysis and review.

Epithelial-mesenchymal transition (EMT) is a key factor in the invasion and migration of glioma cells, and the study of EMT in gliomas has become a hot topic over the past decade. Scientometric analysis is gaining more attention since it can obtain hot topics and emerging trends in a research field. This article analyzed the research related to EMT in gliomas for the first time, including descriptions of research situations, evaluations of research foci, and predictions of emerging trends. We searched the topic-related original articles from January 2012 to December 2021 in the Web of Science Core Collection (WoSCC) by using a specific strategy, and a total of 1,217 publications were obtained. The WoS platform, VOS viewer, and CiteSpace were used to analyze the annual distribution of publications and citations, authors and density of keywords, and other analyses including countries, institutions, references, clustering, burst analysis, and the timeline view of keywords. Scientometric analysis identified that the study of EMT in gliomas has developed fast and received continuous attention in the last decade. Based on the results of data analysis, most publications on the topic came from China, and the United States had the highest betweenness centrality. The top 10 co-cited references revealed the landmark documents that had greatly promoted the development of this field. The major focus is on the cellular and molecular mechanisms of EMT in gliomas, and the therapy related to EMT target and non-coding RNAs has been developing fast in recent years. This study revealed the intimate connections between EMT and gliomas, and the complex mechanisms regulating EMT in gliomas had been studied widely in the last decade. Exploring the deep mechanisms of EMT in gliomas is the foundation of the targeted inhibitions, which can promote the development of therapies for gliomas.

The role of epithelial-mesenchymal transition in regulating radioresistance.

Cancer patients with different stages can benefit from radiotherapy, but there are still limited due to inherent or acquired radioresistance. The epithelial-mesenchymal transition (EMT) is a complex biological process that is implicated in malignant characteristics of cancer, such as radioresistance. Although the possible mechanisms of EMT-dependent radioresistance are being extensively studied, there is a lack of a clear picture of the overall signaling of EMT-mediated radioresistance. In this review, we highlight the role and possible molecular mechanisms of EMT in cancer radioresistance, in particular to EMT-associated signaling pathway, EMT-inducing transcription factors (EMT-TFs), EMT-related non-coding RNAs. The knowledge of EMT-associated mechanisms of radioresistance will offer more potent therapy targets to improve the radiotherapy responses.

Abstract 1447: Functional genomics identifying a TIS1-HIF-NOTCH signaling orchestrating epithelial-mesenchymal transition for tumor invasion

Abstract Human hepatocellular carcinoma (HCC) is characterized by frequent local invasion and recurrence, which are strongly associated with poor overall survival of HCC patients. Epithelial-mesenchymal transition (EMT) is an initiating event driving tumour invasion and metastasis. However, the molecular mechanisms of EMT in HCC remains largely unknown. We have performed a human kinome/phosphatome RNAi screen to identify novel genes that are involved in invasion and metastasis of HCC cells using Hep3B, a low motile HCC cell line, and identified TIS1 (Tumor Invasion Suppressor 1) as a potential cell motility suppressor. Mechanistic studies revealed that TIS1 was a novel actin binding protein that sequestrated globular actins and prevented actin filament (F-actin) formation, thereby suppressing the formation of filopodia, lamillepodia and invadopodia. Silencing of TIS1 enhanced EMT and tumor cell migration and invasion. Notably, F-actin polymerization induced by TIS1 silencing led to activation of the NOTCH signalling via induction of HIF1A, which in turn further supports EMT for sustaining tumor invasion and metastasis. Clinically, TIS1 was frequently downregulated in many human cancers including HCC and strongly associated with tumor recurrence, local invasion, and poor prognosis. In conclusion, a novel TIS1-HIF/NOTCH signaling forms a positive feedback loop sustainingly driving mesenchymal transition of cancer cells for invasion and metastasis. This TIS1-mediated tumor invasion and metastasis signaling may serve as therapeutic targets for prevention and treatment of HCC invasion and metastasis. Citation Format: Sen-Yung Hsieh. Functional genomics identifying a TIS1-HIF-NOTCH signaling orchestrating epithelial-mesenchymal transition for tumor invasion. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1447. doi:10.1158/1538-7445.AM2015-1447

MiR-21 and miR-155 in the regulation of TGF-β1/SMAD signaling pathway of the line breast cancer cells with different metastatic potential

Breast cancer (ВС) is the most common form of cancer, leading to high mortality rates among women worldwide. Metastasis is the main cause of fatal outcomes in ВС. In this regard, of particular interest takes the study of molecular mechanisms of epithelial-mesenchymal transition (EMT). In the EMT processes involved in TGF-β1/SMAD-signaling pathway through the regulation of which can affect the processes of metastasis in ВС. In this study we have analyzed changes of mRNA expression of the mRNA SMADs, miR-21, and miR-155 of the tumor ВС cells with different metastatic potential MCF-7, BT-474, ZR-75-1. High expression of miR-21 was detected in all the tumor cell lines (MCF-7, ZR-75-1 and BT-474). In the ВС cell lines, the expression level of miR-155 was significantly lower than that of miR-21. Analysis of mRNA expression has clearly shown impairments of intracellular mechanisms of regulation of SMAD2, SMAD4, SMAD7 in ВС. Investigated the correlation of expression of miR-21 and miR-155 regulation of SMADs in TGF-β1/SMAD signaling pathway in three carcinomas lines of the human breast with different metastatic potential (MCF-7, ZR-75-1, BT-474). A significant inverse correlation was observed between SMAD4 and miR-155 in MCF-7 cells. Inverse correlation between the expression of SMAD2, SMAD4, SMAD7 and miR-155; miR21 was found in the BT-474 cells. The results obtained in this study showed that miR-21 and miR-155 regulate activity of several genes SMAD2, SMAD4, SMAD7 in the tumor cell ZR-75-1 and on some genes they exhibited a cumulative effect. It should be noted that the miR-155 and miR-21 in various degrees influenced the expression of SMAD2, SMAD4, SMAD7, blocking the work of these genes and, thereby exacerbating the progression and degree of malignancy of ВС cells human; in some cases their effects on individual genes were cumulative.

Hepatocyte growth factor-induced up-regulation of Twist drives epithelial–mesenchymal transition in a canine mammary tumour cell line

Epithelial–mesenchymal transition (EMT) is a crucial step in tumour progression. However, the molecular mechanisms underlying EMT in canine tumours remain to be elucidated. In this study, the similarity or difference in the molecular mechanism of EMT in canine cells was evaluated and compared with that reported in human and mouse cells. We used eight cell lines derived from canine mammary cancers. Stimulation with hepatocyte growth factor (HGF) increased cell motility and changed EMT-related markers towards mesenchyme in CHMm cell line. These changes were accompanied by an increase in Twist expression and did not occur in CHMm transfected with Twist siRNA, indicating that Twist plays a key role in this phenomenon in CHMm. However, the down-regulation of E-cadherin was not observed by HGF stimulation. Further studies are required to elucidate the difference between human and canine Twist.

Molecular mechanism of epithelial-mesenchymal transition induced by activated vascular endothelial growth factor receptor-1 in cell line MHCC97-H

Objective To investigate the molecular mechanism of epithelial-mesenchymal transition (EMT) induced by activated vascular endothelial growth factor receptor-1 ( VEGFR-I ) in cell line MHCC97-H.Methods MHCC97-H cells were cultured in DMEM with 1％ fetal bovine serum (control group),10 μmol/L PP2 (PP2 group),10 μmol/L PBS (PBS group),50 μmol/L VEGF-B (VEGF-B group),l0μmol/L PP2 and 50 μmol/L VEGF-B (PP2 +VEGF group),10 μmol/L PBS and 50 μmol/L VEGF-B (PBS + VEGF-B group),respectively.Protein expressions of epithelial marker E-cadherin,α-catenin and mesenchymal marker vimentin and N-cadherin were detected by Western blot.The expression sites of E-cadherin,α-catenin and mesenchymal marker vimentin and N-cadherin were detected by cell immunofluorescence.The ability of invasion and migration of cell line MHCC97-H were assessed by cell invasion and migration test.All data were analyzed by the t test.Results The expressions of E-cadherin,α-catenin,vimentin and N-cadherin were 3.23 +0.76,3.01 ±0.25,3.01 +0.22 and 2.63 +0.40 in the control group,4.18 +0.32,3.29 +0.11,4.85 +0.36 and 3.02 +0.52 in the PP2 group,2.83 +0.65,3.03 +0.27,1.37 ±0.24 and 2.98 ±0.36 in the PBS group,2.06 ±0.15,2.84 ±0.76,5.79 ± 0.38 and 5.54 ± 0.28 in the VEGF-B group,6.12 ± 0.08,5.45 ± 0.37,3.36 ± 0.42 and 3.26 ±0.13 in the PP2 + VEGF-B group and 1.36 ±0.54,1.26 ±0.45,4.05 ±0.17 and 1.05 ±0.33 in the PBS +VEGF-B group.There was a significant difference in the expressions of E-cadherin and α-catenin between the PP2 +VEGF-B group and the VEGF-B group (t =7.625,9.931,P ＜ 0.05 ).The expressions of vimentin and N-cadherin in the PP2 + VEGF-B group were significantly lower than those in the VEGF-B group (t =12.001,11.910,P ＜ 0.05).Six hours after the treatment with VEGF-B,the numbers of MHCC97-H migrated were 19 ± 1,5 ± 2and 16 ± 1 in the VEGF-B group,PP2 + VEGF-B group and PBS + VEGF-B group,respectively.The number of MHCC97-H cells migrated in the VEGF-B group was greater than that in the PP2 ± VEGF-B group ( t =13.566,P ＜ 0.05 ).The number of MHCC97-H cells passed through the Boyden chamber was 4 + 2,which was significantly less than 16 ± 1 of the VEGF-B group (t =12.350,P ＜0.05).Conclusion EMT induced by activated VEGFR-1 was mediated via c-Src kinase signal transduction in MHCC91-H cell line,and c-Src may be a potential target to interfere the invasion and migration of hepatic cancer cells. Key words: Liver neoplasms; Vascular endothelial cell growth factor receptor-1 ; Epithelial-mesenchymal transition; Invasion; Migration

Encounter of cancer cells with bone. Epithelial-mesenchymal transition in cancer

Acquisition of invasive phenotypes of cancer cells is one of the key steps to promote metastasis. It has been reported that fibroblastic cells are involved in enhancement of proliferation and invasion of cancer cells. Thus, it is important to know the molecular mechanisms of EMT (epithelial-mesenchymal transition) for developing diagnosis and cancer therapy. Since TGF-βis a key mediator of EMT and frequently expressed in various tumors, it may regulate not only the EMT of cancer cells as they acquire metastatic properties, but also the EMT of normal epithelial cells that are adjacent to tumors. In this review, we will discuss the EMT induced by TGF-β.

Proteome Analysis of Membrane-Associated Events During Early Stages of the Epithelial-Mesenchymal Transition

Epithelial-Mesenchymal Transition (EMT) is a fundamental cellular process that occurs during embryonic development, wound healing, organ fibrosis and tumor invasion and metastasis. The molecular mechanism of EMT remains largely unknown; therefore, revealing the intricate mechanisms underlying EMT may help us to better understand how primary tumors become invasive and metastasize. The Madin-Darby canine kidney (MDCK) cell line is a polarized epithelial cell line that has been shown to be transformed into mesenchymal-like cells, when simultaneously stimulated by H-Ras and TGF- β. A hallmark of the early stage of EMT is the loss of cell polarity that occurs at the plasma membrane; moreover, a coordinated interaction of membrane proteins, such like transporters, linkers, receptors and enzyme, may play a crucial role in EMT progression. The main goal of this study is to develop a method for enriching membrane proteins and reducing proteomic complexity. Quantitative proteomic approaches will be used to compare the membrane proteome of modified MDCK cells in the early stage of EMT. Understanding of the molecular changes of the membrane proteome associated with EMT may help to provide a detailed insight into the mechanistic events underlying EMT.