ZEB2 Represses the Epithelial Phenotype and Facilitates Metastasis in Ewing Sarcoma

Wiles, Elizabeth T.; Bell, Russell; Thomas, Dafydd G.; Beckerle, Mary C.; Lessnick, Stephen L.

doi:10.1177/1947601913506115

Cited by 47 publications

(52 citation statements)

References 80 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Unaffected expression levels of YAP1 and derepression of TAZ upon EWS-FLI1 silencing ( Fig. 6C, D) also supports the notion that both factors are maybe expressed in the cell of origin, as proposed for ZEB2, an EMT (epithelial-mesenchymal transition) inducer like YAP1 and TAZ [50].…”

Section: Discussionsupporting

confidence: 79%

Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma

Rodríguez‐Núñez

Romero‐Pérez

Amaral

et al. 2019

Preprint

View full text Add to dashboard Cite

YAP1 and TAZ (WWTR1) oncoproteins are the final transducers of Hippo tumor suppressor pathway.Deregulation of the pathway leads to YAP1/TAZ activation fostering tumorigenesis in multiple malignant tumor types, including sarcoma. However, oncogenic mutations within the core components of the Hippo pathway are uncommon. Ewing Sarcoma (EwS), a pediatric cancer with low mutation rate, is characterized by a canonical fusion involving EWSR1 gene, and FLI1 as the most common partner. The fusion protein is a potent driver of oncogenesis but secondary alterations are scarce, and little is known about other biological factors that determine the risk of relapse or progression. We have observed YAP1/TAZ expression and transcriptional activity in EwS cell lines. Analyses of 55 primary human EwS samples revealed that high YAP1/TAZ expression was associated with progression of the disease and predicted poorer outcome.We did not observe recurrent SNV or copy number gains/losses in Hippo pathway-related loci. However, differential CpG methylation of RASSF1 locus -a regulator of Hippo pathway-was observed in EwS cell lines compared with mesenchymal stem cells, the putative cell of origin of EwS. Hypermethylation of RASSF1 correlated with the transcriptional silencing of the tumor suppressor isoform RASFF1A, and transcriptional activation of the protumorigenic isoform RASSF1C promoting YAP1/TAZ activation. Knockdown of YAP1/TAZ decreased proliferation and invasion abilities of EwS cells, and revealed that YAP1/TAZ transcription activity is inversely correlated with the EWS-FLI1 transcriptional signature. This transcriptional antagonism could be partly explained by EWS-FLI1-mediated transcriptional repression of TAZ. Thus, YAP1/TAZ may override the transcriptional program induced by the fusion protein, contributing to the phenotypic plasticity determined by dynamic fluctuation of the fusion protein, a recently proposed model for disease dissemination in EwS.interplay between TAZ/YAP1 function with the fusion protein, which fits into a recent model concept for metastatic spreading in EwS based on fluctuations of the expression of the fusion protein [16]. MATERIALS AND METHODS Tumor samplesIn this study we analyzed 88 formalin-fixed paraffin-embedded (FFPE) samples from 68 Ewing sarcoma patients (55 samples corresponding to primary tumor). We also analyzed a subset of 21 frozen samples from the same series. Clinical diagnosis of all the samples was performed according to the World Health Organization (WHO) classification [17], performing fluorescence in situ hybridization (FISH) to assess the presence of EwS translocation in tissue sections, which validates the immunohistochemical diagnosis. The only selection criteria were the availability of pathological data and tissue for tissue microarray (TMA) construction. Medical records were retrospectively reviewed and clinicopathologic information for 55 patients with primary tumor material were retrieved for further analyses (summarized in Table 1). Tissue samples were obtained from the HU...

show abstract

Section: Discussionsupporting

confidence: 79%

Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma

Rodríguez‐Núñez

Romero‐Pérez

Amaral

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…EMT has been extensively studied in embryogenesis and cancer progression [10]. Transcription factors, such as TWIST1, SNAI1, ZEB1 and ZEB2, and cytokines, such as TGF-b and NF-kB, are known EMT inducers [11][12][13][14][15][16]. TGF-b is a multifunctional protein that acts as a tumour suppressor in early tumour development and as a tumour-growth promoter during later stages [17].…”

Section: Introductionmentioning

confidence: 99%

PRRX2 as a novel TGF‐β‐induced factor enhances invasion and migration in mammary epithelial cell and correlates with poor prognosis in breast cancer

Juang

Jeng

Chen

et al. 2016

Molecular Carcinogenesis

View full text Add to dashboard Cite

TGF-b and cancer progression share a multifaceted relationship. Despite the knowledge of TGF-b biology in the development of cancer, several factors that mediate the cancer-promoting role of TGF-b continue to be identified. This study aimed to identify and characterise novel factors potentially related to TGF-b-mediated tumour aggression in breast cells. We treated the human mammary epithelial cell line MCF10A with TGF-b and identified TGF-b-dependent upregulation of PRRX2, the gene encoding paired-related homeobox 2 transcription factor. Overexpression of PRRX2 enhanced migration, invasion and anchorage-independent growth of MCF10A cells and induced partial epithelial mesenchymal transition (EMT), as determined by partial fibroblastoid morphology of cells, upregulation of EMT markers and partially disrupted acinar structure in a three-dimensional culture. We further identified PLAT, the gene encoding tissue-type plasminogen activator (tPA), as the highest differentially expressed gene in PRRX2-overexpressing MCF10A cells, and demonstrated direct binding and transactivation of the PLAT promoter by PRRX2. Furthermore, PLAT knockdown inhibited PRRX2-mediated enhanced migration and invasion, suggesting that tPA may mediate PRRX2-induced migration and invasion. Finally, the significant correlation of PRRX2 expression with poor survival in 118 primary breast tumour samples (P ¼ 0.027) and the increased PRRX2 expression in metaplastic breast carcinoma samples, which is pathogenetically related to EMT, validated the biological importance of PRRX2-enhanced migration and invasion and PRRX2-induced EMT. Thus, our data suggest that upregulation of PRRX2 may be a mechanism contributing to TGF-binduced invasion and EMT in breast cancer.

show abstract

“…This is in contrast to certain carcinomas, such as colorectal cancer, where a slow progression and accumulation of mutations eventually leads to an invasive malignancy. A 'passive metastasis' model was recently proposed for Ewing's sarcoma dissemination to contrast the deliberate steps required in carcinoma metastasis (4). MET in sarcoma is represented by expression of epithelial-like markers, such as E-cadherin, whereas mesenchymal markers predominate in tumor cells.…”

Section: Introductionmentioning

confidence: 99%

Restoration of desmosomal junction protein expression and inhibition of H3K9-specific histone demethylase activity by cytostatic proline-rich polypeptide-1 leads to suppression of tumorigenic potential in human chondrosarcoma cells

Galoian

Qureshi

Wideroff

et al. 2014

Molecular and Clinical Oncology

View full text Add to dashboard Cite

Abstract. Disruption of cell-cell junctions and the concomitant loss of polarity, downregulation of tumor-suppressive adherens junctions and desmosomes represent hallmark phenotypes for several different cancer cells. Moreover, a variety of evidence supports the argument that these two common phenotypes of cancer cells directly contribute to tumorigenesis. In this study, we aimed to determine the status of intercellular junction proteins expression in JJ012 human malignant chondrosarcoma cells and investigate the effect of the antitumorigenic cytokine, proline-rich polypeptide-1 (PRP-1) on their expression. The cell junction pathway array data indicated downregulation of desmosomal proteins, such as desmoglein (1,428-fold), desmoplakin (620-fold) and plakoglobin (442-fold). The tight junction proteins claudin 11 and E-cadherin were also downregulated (399-and 52-fold, respectively). Among the upregulated proteins were the characteristic for tumors gap junction β-5 protein (connexin 31.1) and the pro-inflammatory pathway protein intercellular adhesion molecule (upregulated 129-and 43-fold, respectively). We demonstrated that PRP-1 restored the expression of the abovementioned downregulated in chondrosarcoma desmosomal proteins. PRP-1 inhibited H3K9-specific histone demethylase activity in chondrosarcoma cells in a dose-dependent manner (0.5 µg/ml PRP, 63%; 1 µg/ml PRP, 74%; and 10 µg/ml PRP, 91% inhibition). Members of the H3K9 family were shown to transcriptionally repress tumor suppressor genes and contribute to cancer progression. Our experimental data indicated that PRP-1 restores tumor suppressor desmosomal protein expression in JJ012 human chondrosarcoma cells and inhibits H3K9 demethylase activity, contributing to the suppression of tumorigenic potential in chondrosarcoma cells.

show abstract

ZEB2 Represses the Epithelial Phenotype and Facilitates Metastasis in Ewing Sarcoma

Cited by 47 publications

References 80 publications

Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma

Hippo pathway effectors YAP1/TAZ induce a EWS-FLI1-opposing gene signature and associate with disease progression in Ewing Sarcoma

PRRX2 as a novel TGF‐β‐induced factor enhances invasion and migration in mammary epithelial cell and correlates with poor prognosis in breast cancer

Restoration of desmosomal junction protein expression and inhibition of H3K9-specific histone demethylase activity by cytostatic proline-rich polypeptide-1 leads to suppression of tumorigenic potential in human chondrosarcoma cells

Contact Info

Product

Resources

About