Tranilast inhibits the expression of genes related to epithelial-mesenchymal transition and angiogenesis in neurofibromin-deficient cells

AbstractThe functional role of U2AF1 mutations in lung adenocarcinomas (LUADs) remains incompletely understood. Here, we report a significant co-occurrence of U2AF1 S34F mutations with ROS1 translocations in LUADs. To characterize this interaction, we profiled effects of S34F on the transcriptome-wide distribution of RNA binding and alternative splicing in cells harboring the ROS1 translocation. Compared to its wild-type counterpart, U2AF1 S34F preferentially binds and modulates splicing of introns containing CAG trinucleotides at their 3′ splice junctions. The presence of S34F caused a shift in cross-linking at 3′ splice sites, which was significantly associated with alternative splicing of skipped exons. U2AF1 S34F induced expression of genes involved in the epithelial-mesenchymal transition (EMT) and increased tumor cell invasion. Finally, S34F increased splicing of the long over the short SLC34A2-ROS1 isoform, which was also associated with enhanced invasiveness. Taken together, our results suggest a mechanistic interaction between mutant U2AF1 and ROS1 in LUAD.

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Regulation of Epithelial-Mesenchymal Transition in Breast Cancer Cells by Cell Contact and Adhesion

Cancer Informatics ◽

10.4137/cin.s18965 ◽

2015 ◽

Vol 14s3 ◽

pp. CIN.S18965 ◽

Cited By ~ 9

Author(s):

Magdalena A. Cichon ◽

Celeste M. Nelson ◽

Derek C. Radisky

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Rna Splicing ◽

Epithelial Mesenchymal Transition ◽

Mammary Epithelial Cells ◽

Mammary Epithelial ◽

Cell Contact ◽

Mesenchymal Transition ◽

Matrix Metalloproteinase 3 ◽

Expression Of Genes

Epithelial-mesenchymal transition (EMT) is a physiological program that is activated during cancer cell invasion and metastasis. We show here that EMT-related processes are linked to a broad and conserved program of transcriptional alterations that are influenced by cell contact and adhesion. Using cultured human breast cancer and mouse mammary epithelial cells, we find that reduced cell density, conditions under which cell contact is reduced, leads to reduced expression of genes associated with mammary epithelial cell differentiation and increased expression of genes associated with breast cancer. We further find that treatment of cells with matrix metalloproteinase-3 (MMP-3), an inducer of EMT, interrupts a defined subset of cell contact-regulated genes, including genes encoding a variety of RNA splicing proteins known to regulate the expression of Rac1b, an activated splice isoform of Rac1 known to be a key mediator of MMP-3-induced EMT in breast, lung, and pancreas. These results provide new insights into how MMPs act in cancer progression and how loss of cell-cell interactions is a key step in the earliest stages of cancer development.

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Extensive lymphatic spread of papillary thyroid microcarcinoma is associated with an increase in expression of genes involved in epithelial‐mesenchymal transition and cancer stem cell‐like properties

Cancer Medicine ◽

10.1002/cam4.2544 ◽

2019 ◽

Vol 8 (15) ◽

pp. 6528-6537 ◽

Cited By ~ 3

Author(s):

Sohee Lee ◽

Ja Seong Bae ◽

Chan Kwon Jung ◽

Woong Youn Chung

Keyword(s):

Stem Cell ◽

Cancer Stem Cell ◽

Epithelial Mesenchymal Transition ◽

Lymphatic Spread ◽

Papillary Thyroid Microcarcinoma ◽

Papillary Thyroid ◽

Mesenchymal Transition ◽

Thyroid Microcarcinoma ◽

Expression Of Genes

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Exploiting Current Understanding of Hypoxia Mediated Tumour Progression for Nanotherapeutic Development

Cancers ◽

10.3390/cancers11121989 ◽

2019 ◽

Vol 11 (12) ◽

pp. 1989 ◽

Cited By ~ 7

Author(s):

Jie Feng ◽

Niall M. Byrne ◽

Wafa Al Jamal ◽

Jonathan A. Coulter

Keyword(s):

Epithelial Mesenchymal Transition ◽

Tumour Progression ◽

Metabolic Reprogramming ◽

Therapeutic Window ◽

Malignant Tumours ◽

Independent Manner ◽

Mesenchymal Transition ◽

Expression Of Genes ◽

Signalling Network ◽

The Impact

Hypoxia is one of the most common phenotypes of malignant tumours. Hypoxia leads to the increased activity of hypoxia-inducible factors (HIFs), which regulate the expression of genes controlling a raft of pro-tumour phenotypes. These include maintenance of the cancer stem cell compartment, epithelial-mesenchymal transition (EMT), angiogenesis, immunosuppression, and metabolic reprogramming. Hypoxia can also contribute to the tumour progression in a HIF-independent manner via the activation of a complex signalling network pathway, including JAK-STAT, RhoA/ROCK, NF-κB and PI3/AKT. Recent studies suggest that nanotherapeutics offer a unique opportunity to target the hypoxic microenvironment, enhancing the therapeutic window of conventional therapeutics. In this review, we summarise recent advances in understanding the impact of hypoxia on tumour progression, while outlining possible nanotherapeutic approaches for overcoming hypoxia-mediated resistance.

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The Most Common VHL Point Mutation R167Q in Hereditary VHL Disease Interferes with Cell Plasticity Regulation

Cancers ◽

10.3390/cancers13153897 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3897

Author(s):

Stéphanie Buart ◽

Stéphane Terry ◽

M’boyba Khadija Diop ◽

Philippe Dessen ◽

Sophie Couvé ◽

...

Keyword(s):

Point Mutation ◽

Epithelial Mesenchymal Transition ◽

Suppressor Gene ◽

Phenotypic Switching ◽

Mesenchymal Transition ◽

Von Hippel Lindau ◽

Expression Of Genes ◽

Tumor Plasticity ◽

Vhl Disease ◽

Hypoxic State

Von Hippel–Lindau disease (VHL) is a rare hereditary syndrome due to mutations of the VHL tumor suppressor gene. Patients harboring the R167Q mutation of the VHL gene have a high risk of developing ccRCCs. We asked whether the R167Q mutation with critical aspects of pseudo-hypoxia interferes with tumor plasticity. For this purpose, we used wild-type VHL (WT-VHL) and VHL-R167Q reconstituted cells. We showed that WT-VHL and VHL-R167Q expression had a similar effect on cell morphology and colony formation. However, cells transfected with VHL-R167Q display an intermediate, HIF2-dependent, epithelial–mesenchymal phenotype. Using RNA sequencing, we showed that this mutation upregulates the expression of genes involved in the hypoxia pathway, indicating that such mutation is conferring an enhanced pseudo-hypoxic state. Importantly, this hypoxic state correlates with the induction of genes belonging to epithelial–mesenchymal transition (EMT) and stemness pathways, as revealed by GSEA TCGA analysis. Moreover, among these deregulated genes, we identified nine genes specifically associated with a poor patient survival in the TCGA KIRC dataset. Together, these observations support the hypothesis that a discrete VHL point mutation interferes with tumor plasticity and may impact cell behavior by exacerbating phenotypic switching. A better understanding of the role of this mutation might guide the search for more effective treatments to combat ccRCCs.

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The Bladder Microbiome Is Associated with Epithelial–Mesenchymal Transition in Muscle Invasive Urothelial Bladder Carcinoma

Cancers ◽

10.3390/cancers13153649 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3649

Author(s):

Wei Tse Li ◽

Anjali S. Iyangar ◽

Rohan Reddy ◽

Jaideep Chakladar ◽

Valmik Bhargava ◽

...

Keyword(s):

Bladder Carcinoma ◽

Epithelial Mesenchymal Transition ◽

Clinical Prognosis ◽

Mesenchymal Transition ◽

E Coli ◽

Urothelial Bladder Carcinoma ◽

Expression Of Genes ◽

Urothelial Bladder ◽

Muscle Invasive ◽

The Relationship

The intra-tumor microbiome has recently been linked to epithelial–mesenchymal transition (EMT) in a number of cancers. However, the relationship between EMT and microbes in bladder cancer has not been explored. In this study, we profiled the abundance of individual microbe species in the tumor samples of over 400 muscle invasive bladder carcinoma (MIBC) patients. We then correlated microbe abundance to the expression of EMT-associated genes and genes in the extracellular matrix (ECM), which are key players in EMT. We discovered that a variety of microbes, including E. coli, butyrate-producing bacterium SM4/1, and a species of Oscillatoria, were associated with expression of classical EMT-associated genes, including E-cadherin, vimentin, SNAI2, SNAI3, and TWIST1. We also found significant correlations between microbial abundance and the expression of genes in the ECM, specifically collagens and elastin. Lastly, we found that a large number of microbes exhibiting significant correlations to EMT are also associated with clinical prognosis and outcomes. We further determined that the microbes we profiled were likely not environmental contaminants. In conclusion, we discovered that the intra-tumoral microbiome could potentially play a significant role in the regulation of EMT in MIBC.

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MicroRNA-361-Mediated Inhibition of HSP90 Expression and EMT in Cervical Cancer Is Counteracted by Oncogenic lncRNA NEAT1

Cells ◽

10.3390/cells9030632 ◽

2020 ◽

Vol 9 (3) ◽

pp. 632 ◽

Cited By ~ 2

Author(s):

Daozhi Xu ◽

Peixin Dong ◽

Ying Xiong ◽

Junming Yue ◽

Yosuke Konno ◽

...

Keyword(s):

Cervical Cancer ◽

Epithelial Mesenchymal Transition ◽

Potential Interaction ◽

High Expression ◽

Luciferase Reporter ◽

Mesenchymal Transition ◽

Normal Tissues ◽

Expression Of Genes ◽

Sphere Formation ◽

Lncrna Neat1

Epithelial-mesenchymal transition (EMT) is a key process contributing to cervical cancer (CC) metastasis, and microRNAs (miRNAs) modulate the expression of genes implicated in EMT. However, the accurate role of miR-361 in CC-associated EMT and the mechanisms underlying its function in CC remains largely unknown. The functional roles of miR-361 in CC cells were explored by a series of cell functional assays. Luciferase reporter assays were used to demonstrate the potential interaction between miR-361, HSP90, and long non-coding RNA (lncRNA) NEAT1. We detected a reduction of miR-361 expression in CC tissues compared with normal tissues, and miR-361 overexpression inhibited invasion and EMT phenotypes of CC cells by directly targeting a key EMT activator HSP90. Additionally, we detected significantly higher levels of HSP90 in CC tissues compared with normal tissues, and high expression of HSP90 predicted a poorer prognosis. We further identified NEAT1 as a significantly upregulated lncRNA in CC tissues and high expression of NEAT1 was associated with worse survival in CC patients. NEAT1 directly repressed miR-361 expression and played an oncogenic role in CC cell invasion and sphere formation. Conclusions: These results demonstrated that miR-361 directly targets HSP90 to inhibit the invasion and EMT features, and NEAT1 functions as an oncogenic lncRNA that suppresses miR-361 expression and induces EMT and sphere formation in CC cells, thus providing critical insights into the molecular pathways operating in this malignancy.

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CBD Reverts the Mesenchymal Invasive Phenotype of Breast Cancer Cells Induced by the Inflammatory Cytokine IL-1β

International Journal of Molecular Sciences ◽

10.3390/ijms21072429 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2429

Author(s):

Lázaro García-Morales ◽

Aída M Castillo ◽

José Tapia Ramírez ◽

Horacio Zamudio-Meza ◽

Ma del Carmen Domínguez-Robles ◽

...

Keyword(s):

Breast Cancer ◽

Nuclear Translocation ◽

Epithelial Mesenchymal Transition ◽

Cell System ◽

Invasive Phenotype ◽

Mesenchymal Transition ◽

Akt Activation ◽

Non Invasive ◽

Inflammatory Conditions ◽

Expression Of Genes

Cannabidiol (CBD) has been used to treat a variety of cancers and inflammatory conditions with controversial results. In previous work, we have shown that breast cancer MCF-7 cells, selected by their response to inflammatory IL-1β cytokine, acquire a malignant phenotype (6D cells) through an epithelial–mesenchymal transition (EMT). We evaluated CBD as a potential inhibitor of this transition and inducer of reversion to a non-invasive phenotype. It decreased 6D cell viability, downregulating expression of receptor CB1. The CBD blocked migration and progression of the IL-1β-induced signaling pathway IL-1β/IL-1RI/β-catenin, the driver of EMT. Cannabidiol reestablished the epithelial organization lost by dispersion of the cells and re-localized E-cadherin and β-catenin at the adherens junctions. It also prevented β-catenin nuclear translocation and decreased over-expression of genes for ∆Np63α, BIRC3, and ID1 proteins, induced by IL-1β for acquisition of malignant features. Cannabidiol inhibited the protein kinase B (AKT) activation, a crucial effector in the IL-1β/IL-1RI/β-catenin pathway, indicating that at this point there is crosstalk between IL-1β and CBD signaling which results in phenotype reversion. Our 6D cell system allowed step-by-step analysis of the phenotype transition and better understanding of mechanisms by which CBD blocks and reverts the effects of inflammatory IL-1β in the EMT.

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TET3- and OGT-Dependent Expression of Genes Involved in Epithelial-Mesenchymal Transition in Endometrial Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms222413239 ◽

2021 ◽

Vol 22 (24) ◽

pp. 13239

Author(s):

Piotr Ciesielski ◽

Paweł Jóźwiak ◽

Ewa Forma ◽

Anna Krześlak

Keyword(s):

Endometrial Cancer ◽

Cancer Progression ◽

Epithelial To Mesenchymal Transition ◽

Epithelial Mesenchymal Transition ◽

Cancer Tissue ◽

Gene Expressions ◽

Tissue Samples ◽

Mesenchymal Transition ◽

Expression Of Genes ◽

Ishikawa Cells

TET3 is a member of the TET (ten-eleven translocation) proteins family that catalyzes the conversion of the 5-methylcytosine into 5-hydroxymethylcytosine. TET proteins can also affect chromatin modifications and gene expression independently of their enzymatic activity via interactions with other proteins. O-GlcNAc transferase (OGT), the enzyme responsible for modification of proteins via binding of N-acetylglucosamine residues, is one of the proteins whose action may be dependent on TET3. Here, we demonstrated that in endometrial cancer cells both TET3 and OGT affected the expression of genes involved in epithelial to mesenchymal transition (EMT), i.e., FOXC1, TWIST1, and ZEB1. OGT overexpression was caused by an increase in TWIST1 and ZEB1 levels in HEC-1A and Ishikawa cells, which was associated with increased O-GlcNAcylation of histone H2B and trimethylation of H3K4. The TET3 had the opposite effect on gene expressions and histone modifications. OGT and TET3 differently affected FOXC1 expression and the migratory potential of HEC-1A and Ishikawa cells. Analysis of gene expressions in cancer tissue samples from endometrial cancer patients confirmed the association between OGT or TET3 and EMT genes. Our results contribute to the knowledge of the role of the TET3/OGT relationship in the complex mechanism supporting endometrial cancer progression.

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