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.

scholarly journals Circ_0026416 downregulation blocks the development of colorectal cancer through depleting MYO6 expression by enriching miR-545-3p

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lei Zhang ◽  
Ranran Yu ◽  
Chunhua Li ◽  
Yu Dang ◽  
Xiaoyu Yi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cell Proliferation ◽  
Colony Formation ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
List Type ◽  
Mesenchymal Transition

Abstract Background Emerging evidence reveals that the initiation and development of human cancers, including colorectal cancer (CRC), are associated with the deregulation of circular RNAs (circRNAs). Our study intended to disclose the role of circ_0026416 in the malignant behaviors of CRC. Methods The detection for circ_0026416 expression, miR-545-3p expression, and myosin VI (MYO6) mRNA expression was performed using quantitative real-time PCR (qPCR). CCK-8 assay, colony formation assay, transwell assay, and flow cytometry assay were applied for functional analysis to monitor cell proliferation, migration, invasion, and apoptosis. The protein levels of MYO6 and epithelial mesenchymal-transition (EMT) markers were detected by western blot. Mouse models were used to determine the role of circ_0026416 in vivo. The potential relationship between miR-545-3p and circ_0026416 or MYO6 was verified by dual-luciferase reporter assay and RIP assay. Results The expression of circ_0026416 was increased in CRC tumor tissues and cell lines. Circ_0026416 downregulation inhibited CRC cell proliferation, colony formation, migration, invasion, and EMT but induced cell apoptosis in vitro, and circ_0026416 knockdown also blocked tumor growth in vivo. MiR-545-3p was a target of circ_0026416, and rescue experiments indicated that circ_0026416 knockdown blocked CRC development by enriching miR-545-3p. In addition, miR-545-3p targeted MYO6 and inhibited MYO6 expression. MiR-545-3p enrichment suppressed CRC cell malignant behaviors by sequestering MYO6. Importantly, circ_0026416 knockdown depleted MYO6 expression by enriching miR-545-3p. Conclusion Circ_0026416 downregulation blocked the development of CRC through depleting MYO6 expression by enriching miR-545-3p. Highlights Circ_0026416 downregulation inhibits CRC development in vitro and in vivo. Circ_0026416 regulates the expression of MYO6 by targeting miR-545-3p. Circ_0026416 governs the miR-545-3p/MYO6 axis to regulate CRC progression.

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 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 The role of miR-200b/c in balancing EMT and proliferation revealed by an activity reporter

Oncogene ◽  
2021 ◽  
Vol 40 (12) ◽  
pp. 2309-2322 ◽  
Author(s):  
Paradesi Naidu Gollavilli ◽  
Beatrice Parma ◽  
Aarif Siddiqui ◽  
Hai Yang ◽  
Vignesh Ramesh ◽  
...  
Keyword(s):  
Epithelial To Mesenchymal Transition ◽  
Fluorescent Sensor ◽  
Biological Properties ◽  
Cellular Mechanisms ◽  
Mesenchymal Transition ◽  
Screening Platform ◽  
Differentiation And Proliferation

AbstractSince their discovery, microRNAs (miRNAs) have been widely studied in almost every aspect of biology and medicine, leading to the identification of important gene regulation circuits and cellular mechanisms. However, investigations are generally focused on the analysis of their downstream targets and biological functions in overexpression and knockdown approaches, while miRNAs endogenous levels and activity remain poorly understood. Here, we used the cellular plasticity-regulating process of epithelial-to-mesenchymal transition (EMT) as a model to show the efficacy of a fluorescent sensor to separate cells with distinct EMT signatures, based on miR-200b/c activity. The system was further combined with a CRISPR-Cas9 screening platform to unbiasedly identify miR-200b/c upstream regulating genes. The sensor allows to infer miRNAs fundamental biological properties, as profiling of sorted cells indicated miR-200b/c as a molecular switch between EMT differentiation and proliferation, and suggested a role for metabolic enzymes in miR-200/EMT regulation. Analysis of miRNAs endogenous levels and activity for in vitro and in vivo applications could lead to a better understanding of their biological role in physiology and disease.

scholarly journals Operative ubiquitin-specific protease 22 deubiquitination confers a more invasive phenotype to cholangiocarcinoma

2021 ◽  
Vol 12 (7) ◽  
Author(s):  
Yu Tian ◽  
Bo Tang ◽  
Chengye Wang ◽  
Yan Wang ◽  
Jiakai Mao ◽  
...  
Keyword(s):  
Tumour Growth ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Sirtuin 1 ◽  
Mesenchymal Transition ◽  
Specific Protease ◽  
Ubiquitin Specific Protease ◽  
Paired Tumour

AbstractOncogenic ubiquitin-specific protease 22 (USP22) is implicated in a variety of tumours; however, evidence of its role and underlying molecular mechanisms in cholangiocarcinoma (CCA) development remains unknown. We collected paired tumour and adjacent non-tumour tissues from 57 intrahepatic CCA (iCCA) patients and evaluated levels of the USP22 gene and protein by qPCR and immunohistochemistry. Both the mRNA and protein were significantly upregulated, correlated with the malignant invasion and worse OS of iCCA. In cell cultures, USP22 overexpression increased CCA cell proliferation and mobility, and induced epithelial-to-mesenchymal transition (EMT). Upon an interaction, USP22 deubiquitinated and stabilized sirtuin-1 (SIRT1), in conjunction with Akt/ERK activation. In implantation xenografts, USP22 overexpression stimulated tumour growth and metastasis to the lungs of mice. Conversely, the knockdown by USP22 shRNA attenuated the tumour growth and invasiveness in vitro and in vivo. Furthermore, SIRT1 overexpression reversed the USP22 functional deficiency, while the knockdown acetylated TGF-β-activated kinase 1 (TAK1) and Akt. Our present study defines USP22 as a poor prognostic predictor in iCCA that cooperates with SIRT1 and facilitates tumour development.

scholarly journals Inhibition of Lysine 63 Ubiquitination Prevents the Progression of Renal Fibrosis in Diabetic DBA/2J Mice

2021 ◽  
Vol 22 (10) ◽  
pp. 5194
Author(s):  
Paola Pontrelli ◽  
Francesca Conserva ◽  
Rossella Menghini ◽  
Michele Rossini ◽  
Alessandra Stasi ◽  
...  
Keyword(s):  
Diabetic Nephropathy ◽  
Epithelial To Mesenchymal Transition ◽  
Selective Inhibition ◽  
Collagen I ◽  
Protein Accumulation ◽  
Mesenchymal Transition ◽  
Collagen Iii ◽  
Proximal Tubular Epithelial Cells

Diabetic nephropathy (DN) is the most frequent cause of end-stage renal disease. Tubulointerstitial accumulation of lysine 63 (K63)-ubiquitinated (Ub) proteins is involved in the progression of DN fibrosis and correlates with urinary miR-27b-3p downregulation. We explored the renoprotective effect of an inhibitor of K63-Ub (NSC697923), alone or in combination with the ACE-inhibitor ramipril, in vitro and in vivo. Proximal tubular epithelial cells and diabetic DBA/2J mice were treated with NSC697923 and/or ramipril. K63-Ub protein accumulation along with α-SMA, collagen I and III, FSP-1, vimentin, p16INK4A expression, SA-α Gal staining, Sirius Red, and PAS staining were measured. Finally, we measured the urinary albumin to creatinine ratio (uACR), and urinary miR-27b-3p expression in mice. NSC697923, both alone and in association with ramipril, in vitro and in vivo inhibited hyperglycemia-induced epithelial to mesenchymal transition by significantly reducing K63-Ub proteins, α-SMA, collagen I, vimentin, FSP-1 expression, and collagen III along with tubulointerstitial and glomerular fibrosis. Treated mice also showed recovery of urinary miR-27b-3p and restored expression of p16INK4A. Moreover, NSC697923 in combination with ramipril demonstrated a trend in the reduction of uACR. In conclusion, we suggest that selective inhibition of K63-Ub, when combined with the conventional treatment with ACE inhibitors, might represent a novel treatment strategy to prevent the progression of fibrosis and proteinuria in diabetic nephropathy and we propose miR-27b-3p as a biomarker of treatment efficacy.

KCNN4 promotes the progression of lung adenocarcinoma by activating the AKT and ERK signaling pathways

2021 ◽  
pp. 1-15
Author(s):  
Ping Xu ◽  
Xiao Mo ◽  
Ruixue Xia ◽  
Long Jiang ◽  
Chengfei Zhang ◽  
...  
Keyword(s):  
Potassium Channels ◽  
Lung Adenocarcinoma ◽  
Potassium Channel ◽  
Signaling Pathways ◽  
Epithelial To Mesenchymal Transition ◽  
Tumor Biology ◽  
Erk Signaling ◽  
Mesenchymal Transition

BACKGROUND: Potassium channels, encoded by more than seventy genes, are cell excitability transmembrane proteins and become evident to play essential roles in tumor biology. OBJECTIVE: The deregulation of potassium channel genes has been related to cancer development and patient prognosis. The objective of this study is to understand the role of potassium channels in lung cancer. METHODS: We examined all potassium channel genes and identified that KCNN4 is the most significantly overexpressed one in lung adenocarcinoma. The role and mechanism of KCNN4 in lung adenocarcinoma were further investigated by in vitro cell and molecular assay and in vivo mouse xenograft models. RESULTS: We revealed that the silencing of KCNN4 significantly inhibits cell proliferation, migration, invasion, and tumorigenicity of lung adenocarcinoma. Further studies showed that knockdown of KCNN4 promotes cell apoptosis, induces cell cycle arrested in the S phase, and is associated with the epithelial to mesenchymal transition (EMT) process. Most importantly, we demonstrated that KCNN4 regulates the progression of lung adenocarcinoma through P13K/AKT and MEK/ERK signaling pathways. The use of inhibitors that targeted AKT and ERK also significantly inhibit the proliferation and metastasis of lung adenocarcinoma cells. CONCLUSIONS: This study investigated the function and mechanism of KCNN4 in lung adenocarcinoma. On this basis, this means that KCNN4 can be used as a tumor marker for lung adenocarcinoma and is expected to become an important target for a potential drug.

scholarly journals Molecular mechanisms underpinning sarcomas and implications for current and future therapy

2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Victoria Damerell ◽  
Michael S. Pepper ◽  
Sharon Prince
Keyword(s):  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Treatment Strategies ◽  
Mesenchymal Transition ◽  
Mesenchymal To Epithelial Transition ◽  
Cells Of Origin ◽  
Novel Treatment Strategies ◽  
Future Therapy

AbstractSarcomas are complex mesenchymal neoplasms with a poor prognosis. Their clinical management is highly challenging due to their heterogeneity and insensitivity to current treatments. Although there have been advances in understanding specific genomic alterations and genetic mutations driving sarcomagenesis, the underlying molecular mechanisms, which are likely to be unique for each sarcoma subtype, are not fully understood. This is in part due to a lack of consensus on the cells of origin, but there is now mounting evidence that they originate from mesenchymal stromal/stem cells (MSCs). To identify novel treatment strategies for sarcomas, research in recent years has adopted a mechanism-based search for molecular markers for targeted therapy which has included recapitulating sarcomagenesis using in vitro and in vivo MSC models. This review provides a comprehensive up to date overview of the molecular mechanisms that underpin sarcomagenesis, the contribution of MSCs to modelling sarcomagenesis in vivo, as well as novel topics such as the role of epithelial-to-mesenchymal-transition (EMT)/mesenchymal-to-epithelial-transition (MET) plasticity, exosomes, and microRNAs in sarcomagenesis. It also reviews current therapeutic options including ongoing pre-clinical and clinical studies for targeted sarcoma therapy and discusses new therapeutic avenues such as targeting recently identified molecular pathways and key transcription factors.

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 OMRT-11. The effect of microenvironment on glioblastoma stem cells therapeutic resistance

2021 ◽  
Vol 3 (Supplement_2) ◽  
pp. ii9-ii9
Author(s):  
Tamara Lah Turnsek ◽  
Barbara Breznik ◽  
Bernarda Majc ◽  
Metka Novak ◽  
Andrej Porčnik ◽  
...  
Keyword(s):  
Stem Cells ◽  
Epithelial To Mesenchymal Transition ◽  
Combined Treatment ◽  
Cell Plasticity ◽  
Glioblastoma Stem Cells ◽  
Mesenchymal Transition ◽  
Non Invasive ◽  
Differential Gene

Abstract Epithelial-to-mesenchymal transition (EMT) is an essential molecular and cellular process in physiologic processes and invasion of various types of carcinoma and glioblastoma (GBM) cells. EMT is activated and regulated by specific endogenous triggers in complex network of intercellular interactions and signaling pathways. The hallmark of cancer-linked EMT are intermediate states that show notable cell plasticity, characteristic of cancer stem cells (CSCs), including glioblastoma stem cells – GSCs. GSCs resistance to irradiation (IR) and temozolomide (TMZ) chemotherapy is responsible for early relapses, even at distant brain sites. As GSCs are mostly homing to their “niches” as slowly-dividing GSC-subtype, mimicking a proneural-like non- invasive phenotype PN-genotype, we assume that this, by undergoing an EMT-like transition, GSCs are-reprogrammed to an invasive mesenchymal (MES) GBs/GSCs phenotype in a processes, called PMT (1). However, it is not known, if and by which environmental cues within the niche, this transition of GSCs is induced in vivo. In this work, we are presenting the transriptome data obtained when we exposed GSC spheroids to irradiation alone, TMZ alone and to the combined treatment in vitro and compared their differential genetic fingerprints related to EMT/PMT transition to the GSCs PMT transition, when embedded in their natural microenvironment in the GBM organoid model. The differential gene expression upon GSCs therapeutic perturbation (when alone and vs in the tumoroid microenvironment) will reveal the effects of the major candidate genes, associated with micronevironmendt stromal cells and matrix are contributing their observed EMT/PMT transition of GSCs in vivo. •1. Majc, B., Sever, T., Zarić, M, Breznik, B., Turk, B, Lah Turnšek, T. Epithelial- to-mesenchymal transition as the driver of changing carcinoma and glioblastoma microenvironment. DOI: 10.1016/j.bbamcr.2020.118782

Sign in / Sign up

Export Citation Format

Share Document