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Vav proteins maintain epithelial traits in breast cancer cells using miR-200c-dependent and independent mechanisms.

ABSTRACT: The bidirectional regulation of epithelial-mesenchymal transitions (EMT) is key in tumorigenesis. Rho GTPases regulate this process via canonical pathways that impinge on the stability of cell-to-cell contacts, cytoskeletal dynamics, and cell invasiveness. Here, we report that the Rho GTPase activators Vav2 and Vav3 utilize a new Rac1-dependent and miR-200c-dependent mechanism that maintains the epithelial state by limiting the abundance of the Zeb2 transcriptional repressor in breast cancer cells. In parallel, Vav proteins engage a mir-200c-independent expression prometastatic program that maintains epithelial cell traits only under 3D culture conditions. Consistent with this, the depletion of endogenous Vav proteins triggers mesenchymal features in epithelioid breast cancer cells. Conversely, the ectopic expression of an active version of Vav2 promotes mesenchymal-epithelial transitions using E-cadherin-dependent and independent mechanisms depending on the mesenchymal breast cancer cell line used. In silico analyses suggest that the negative Vav anti-EMT pathway is operative in luminal breast tumors. Gene signatures from the Vav-associated proepithelial and prometastatic programs have prognostic value in breast cancer patients.

SUBMITTER: Lorenzo-Martin LF

PROVIDER: S-EPMC6230471 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Vav proteins maintain epithelial traits in breast cancer cells using miR-200c-dependent and independent mechanisms

Project description:Here, we report that the Rho GTPase activators Vav2 and Vav3 utilize a new, miR-200c-dependent mechanism that maintains the epithelial state by limiting the abundance of the Zeb2 transcriptional repressor in breast cancer cells. In parallel, Vav proteins engage an expression program that maintains epithelial cell traits in 3D culture. Depletion of Vav proteins triggers EMT in epithelioid breast cancer cells and, conversely, expression of constitutively active Vav2 restores both miR-200c expression and epithelial traits in mesenchymal breast cancer cells. In silico analyses suggest that the negative Vav-Zeb2 axis is operative in human luminal breast tumors.

2018-09-21 | GSE97385 | GEO

MiR-200c-3p Modulates Cisplatin Resistance in Biliary Tract Cancer by ZEB1-Independent Mechanisms.

Project description:Biliary tract cancer is a major global health issue in cancer-related mortality. Therapeutic options are limited, and cisplatin-based treatment schedules represent the mainstay of first-line therapeutic strategies. Although the gain of survival by the addition of cisplatin to gemcitabine is moderate, acquired cisplatin resistance frequently leads to treatment failures with mechanisms that are still poorly understood. Epithelial-mesenchymal transition (EMT) is a dynamic process that changes the shape, function, and gene expression pattern of biliary tract cancer cells. In this study, we explored the influence of the EMT-regulating miR-200c-3p on cisplatin sensitivity in biliary tract cancer cells. Using gain of function experiments, we demonstrated that miR-200c-3p regulates epithelial cell markers through the downregulation of the transcription factor ZEB1. MiR-200c-3p upregulation led to a decreased sensitivity against cisplatin, as observed in transient overexpression models as well as in cell lines stably overexpressing miR-200c-3p. The underlying mechanism seems to be independent of miR-200c-3p's influence on ZEB1 expression, as ZEB1 knockdown resulted in the opposite effect on cisplatin resistance, which was abolished when ZEB1 knockdown and miR-200c-3p overexpression occurred in parallel. Using a gene panel of 40 genes that were previously associated with cisplatin resistance, two (Dual Specificity Phosphatase 16 (DUSP16) and Stratifin (SFN)) were identified as significantly (>2 fold, p-value < 0.05) up-regulated in miR-200c-3p overexpressing cells. In conclusion, miR-200c-3p might be an important contributor to cisplatin resistance in biliary tract cancer, independently of its interaction with ZEB1.

| S-EPMC8392278 | biostudies-literature

Tamoxifen reverses epithelial-mesenchymal transition by demethylating miR-200c in triple-negative breast cancer cells.

Project description:BackgroundAlthough the efficacy of tamoxifen (TAM) for breast cancer has been attributed to inducing cell cycle arrest and apoptosis by inhibiting estrogen receptor (ER) signaling, recent evidence indicates that TAM also possesses ER-independent antitumor activity through an unclear mechanism. The present study investigated the anti-tumor mechanism of TAM on mesenchymal triple-negative breast cancer (TNBC).MethodsThe inhibitory effect of TAM on tumor migration and metastasis was analyzed by transwell chamber in vitro and by murine xenograft model in vivo. The promoter sequence of miR-200c was predicted by an online CpG island predictor. Relative expression of miR-200c was measured by quantitative real-time PCR.ResultsAfter treatment with TAM, mesenchymal TNBC cells (MCF-7/ADR and MDA-MB-231) morphologically changed from mesenchymal to epithelial types. Meanwhile, cell migration ability was also significantly decreased in ER-positive breast cancer cells after exposure to TAM. Consistent with these in-vitro results, TAM significantly suppressed lung metastasis rate of mesenchymal TNBC cells in murine xenograft tumors. miRNA array analysis of two types of breast cancer cells showed that miR-200c expression was inhibited in mesenchymal TNBC cells, but increased after TAM treatment due to demethylation of miR-200c promoters.ConclusionsOur results indicate that TAM inhibits cell migration and enhances chemosensitivity of mesenchymal TNBC cells by reversing their EMT-like property; and that this EMT-reversal effect results from upregulation of miR-200c through demethylating its promoter. To our knowledge, this is the first explanation of a non-ER-related mechanism for the effect of TAM on mesenchymal TNBC cells.

| S-EPMC5518097 | biostudies-literature

miR-200c inhibits breast cancer proliferation by targeting KRAS.

Project description:The microRNA, miR-200c, is involved in the tumorigenesis and progression of a variety of cancers. The purpose of this study was to investigate the expression, mechanism and prognostic roles of miR-200c in breast cancer. We found that miR-200c was downregulated in both breast cancer tissue and cell lines using quantitative real-time PCR (qRT-PCR). In situ hybridization (ISH) and microarrays showed that low miR-200c expression was associated with poor patient overall survival (OS) and disease free survival (DFS). We used luciferase reporter plasmids to find that miR-200c inhibited the AKT and ERK pathways by directly targeting KRAS. Repression of KRAS by miR-200c suppressed the proliferation and survival of breast cancer cells in vitro and in vivo. miR-200c also had an anti-tumor effect by negatively regulating KRAS in a xenograft mouse model. Our findings provide clues regarding the role of miR-200c as a tumor suppressor in breast cancer through the inhibition of KRAS translation both in vitro and in vivo. miR-200c could be a potential therapeutic target in breast cancer.

| S-EPMC4741502 | biostudies-literature

Circulating miR-200c and miR-141 and outcomes in patients with breast cancer.

Project description:BackgroundThe deregulation of microRNAs in both tumours and blood has led to the search for microRNAs to indicate the presence of cancer and predict prognosis. We hypothesize the deregulation of miR-200c/miR-141 in the whole blood can identify breast cancer (BC), and could be developed into a prognostic signature.MethodsThe expression of miR-200c and miR-141 were examined in bloods (57 stage I-IV BC patients and 20 age-matched controls) by quantitative reverse-transcription PCR. The associations of circulating microRNAs with clinic and pathological characteristics were analysed. Their effects on survival were analysed by the Kaplan-Meier method and Cox regressions.ResultsMiR-200c was down regulated (P < 0.0001) in the blood of BC patients, yielded an area under the ROC curve of 0.79 (90% sensitivity, 70.2% specificity) in discriminating BC from controls. Circulating miR-141 was not discriminating. MiR-200c and miR-141 in the blood of BC patients were inversely correlated (P = 0.019). The miR-200c levels were numerically higher in stage IV and tumours with lower MIB-1. MiR-141 was significantly higher in the blood of patients with stage I-III, lymph node metastasis, and HER2 negative tumours. High blood expression of miR-200c and/or low expression of miR-141 was associated with unfavourable overall survival (hazard ratio, 3.89; [95% CI: 1.28-11.85]) and progression-free survival (3.79 [1.41-10.16]) independent of age, stage and hormonal receptors.ConclusionsCirculating miR-200c and miR-141 were deregulated in BC comparing with controls. Furthermore, miR-200c and miR-141 were independent prognostic factors and associated with distinct outcomes of BC patients.

| S-EPMC4405843 | biostudies-literature

Differential expression of miR-200c in breast cancer stem cells.

Project description:Breast cancer has become the most popular malignant tumors in females. Breast cancer stem cells (BCSCs) play an important role in metastasis and recurrence. Previous study showed close correlation between miR-200c and behavioral regulation of breast cancer stem cells. This study aimed to investigate differential expression of miR-200c in breast cancer stem cells, and its role in regulation tumor formation property. DNA microchip assay and qRT-PCR analyzed differential expression of microRNA between BCSCs and non-tumor formation NTG cells. Bioinformatics and luciferase reporter gene assay determined targeted site of miR-200c. MiR mimic and inhibitor were transfected to change miR-200c expression level, followed by Western Blot for detecting BMI1 gene expression. Cell clonal assay determined cell proliferation, whilst tumor xenograft was performed to analyze tumor formation potency. MiR-200c was down-regulated in BCSCs compared to NTG cells (P<0.05). Bioinformatics and luciferase reporter gene assay attributed BMI1 gene as targeting site of miR-200c. Transfection of miR-200c and inhibitor altered miR-200c expression. Results showed that miR-200c could suppress BMI1 expression, and suppressed proliferation and tumor formation rate (P<0.05). Compared to NTG cells, BCSCs has significantly down-regulated expression of miR-200c. BCSCs facilitate BMI1 gene expression via inhibiting miR-200c expression, further elevating BCSCs proliferation and tumor formation potency.

| S-EPMC6965978 | biostudies-literature

Circular RNA hsa_circ_001783 regulates breast cancer progression via sponging miR-200c-3p.

Project description:Increasing evidence suggests circular RNAs (circRNAs) exert critical functions in tumor progression via sponging miRNAs (microRNAs). However, the role of circRNAs in breast cancer remains unclear. Here we systematically analyzed the circular RNAs in breast cancer based on their characteristic in sponging disease-specific miRNAs and identified hsa_circ_001783 as a top ranked circRNA in our computation and verified its high expression in both breast cancer cells and cancer tissue. A higher level of hsa_circ_001783 was significantly correlated with heavier tumor burden and poorer prognosis of patients with breast cancer. Knockdown of this circRNA remarkably inhibited the proliferation and invasion of breast cancer cells. Importantly, hsa_circ_001783 promoted progression of breast cancer cells via sponging miR-200c-3p. Taken together, hsa_circ_001783 may serve as a novel prognostic and therapeutic target for breast cancer.

| S-EPMC6343010 | biostudies-literature

Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer.

Project description:Exosomes are membrane vesicles that mediate intercellular communication by transporting their molecular cargo from cell to cell. We investigated whether serum levels of exosomal miR-373, miR-200a, miR-200b and miR-200c and circulating exosomes have diagnostic and prognostic relevance in a cohort of 163 epithelial ovarian cancer (EOC) patients using TaqMan MicroRNA assays and ELISA. The serum concentrations of exosomal miR-373 (p = 0.0001), miR-200a (p = 0.0001), miR-200b (p = 0.0001) and miR-200c (p = 0.028) were significantly higher in EOC patients than healthy women. The levels of miR-200a (p = 0.0001), miR-200b (p = 0.0001) and miR-200c (p = 0.019) could distinguish between malignant and benign ovarian tumors. While the levels of miR-373 and miR-200a were increased in all FIGO/lymph node stages (p = 0.0001), the levels of miR-200b and miR-200c were higher in patients with FIGO stage III-IV (p = 0.0001, p = 0.008, respectively) including lymph node metastasis (p = 0.0001, p = 0.004, respectively) than FIGO stages I-II. The increased levels of miR-200b and miR-200c were also associated with CA125 values (p = 0.0001, p = 0.0001, respectively) and a shorter overall survival (p = 0.007, p = 0.017, respectively). The levels of exosomes were excessively elevated in EOC patients (p = 0.0001). In all three cohorts, they were positively associated with the serum levels of exosomal miR-373 (p = 0.004), miR-200a (p = 0.0001), miR-200b (p = 0.0001) and miR-200c (p = 0.008). In conclusion, the increased levels of exosomal miR-200b and miR-200c mainly observed in advanced EOC suggest that these microRNAs may be involved in tumor progression. The high concentrations of exosomes in EOC patients imply an excessive, active exosomal secretion in EOC.

| S-EPMC4941360 | biostudies-literature

miR-200c-driven Mesenchymal-To-Epithelial Transition is a Therapeutic Target in Uterine Carcinosarcomas.

Project description:Uterine carcinosarcomas (UCSs) are highly aggressive malignancies associated with poor prognoses and limited treatment options. These tumors are hypothesized to develop from the endometrial adenocarcinoma (EAC) through epithelial-mesenchymal transition (EMT). We test this long-standing hypothesis by depleting miR-200, a family of microRNAs critical for EMT, in EAC cell lines. Our data suggest that UCSs do not develop from EACs via EMT. Clinically more relevant, we show that miR-200 expression in UCS cells induces a robust mesenchymal-epithelial transition (MET). Using in vitro and murine xenograft models, we demonstrate decreased growth and aggressiveness of miR-200-overexpressing UCS cell lines. Whole transcriptome analysis confirmed changes consistent with an MET and also revealed changes in angiogenic genes expression. Finally, by treatment of UCS-xenografted mice with miR-200c incorporated in DOPC nanoliposomes, we demonstrate anti-tumor activities. These findings suggest that ectopic miR-200 expression using advanced microRNA therapeutics may be a potential treatment approach for patients with UCS.

| S-EPMC5472620 | biostudies-literature

Curcumin Modifies Epithelial-Mesenchymal Transition in Colorectal Cancer Through Regulation of miR-200c/EPM5.

Project description:BackgroundThe serious side effect of current conventional treatments for patients with metastatic colorectal cancer (CRC) highlights the requirement of an alternative treatment strategy. Natural compounds, such as curcumin, have been gained much attention due to its low toxicity and anti-tumor effect.MethodsqPCR and Western blot were used to measure the molecular changes induced by curcumin. Wound-healing assay and transwell assay were conducted to study the effect on cell migration and invasion. RT1 PCR array was performed to identify the miRNAs involved in curcumin-repressed EMT. Three algorithms and luciferase reporter assay were used to identify EPM5 as a target of miR-200c. The bioinformatical analysis of TCGA-COAD and other CRC cohorts were used to examine the association of EPM5 with EMT signatures and clinical relevance. The ectopic expression or siRNA-mediated knockdown of EPM5 was applied to study the role of EPM5 in CRC.ResultsTreatment with curcumin changed the epithelial-mesenchymal transition (EMT)-related gene expression, repressed cell migration and invasion in CRC cells. Its anti-tumor capability required the upregulation of miR-200c. EPM5 was a direct target of miR-200c and enriched in the consensus molecular subtype (CMS) 4 of CRC. Ectopic expression of EPM5 alone was sufficient to induce EMT in CRC. Downregulation of EPM5 was necessary for curcumin-repressed EMT, migration, and invasion. Higher expression of EPM5 was associated with the advanced TNM stages and poor survival in CRC.ConclusionOur data provide the first evidence that the curcumin inhibits EMT in CRC by upregulation of miR-200c and downregulation of EPM5, and the use of curcumin might be able to prevent or delay CRC progression.

| S-EPMC7534868 | biostudies-literature

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