Proteomic approach to ETV5 during endometrial carcinoma invasion reveals a link to oxidative stress

Monge, Marta; Colás, Eva; Doll, Andreas; Gil‐Moreno, Antonio; Castellví, Josep; Díaz, Belén Muñoz; González, Marta; López‐López, Rafael; Xercavins, Jordi; Carreras, Ramón; Alameda, Francesc; Canals, Françesc; Gabrielli, Franco; Reventós, Jaume; Abal, Miguel

doi:10.1093/carcin/bgp119

Cited by 51 publications

(45 citation statements)

References 30 publications

(40 reference statements)

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“…ETV5 has been identified in a gene expression profiling analysis as specifically upregulated in invasive ECs, 17 associated with its capability to regulate mediators of the myometrial infiltrative process. 21,22 The findings presented here emphasize its critical role in the early stages of invasion of EC, as we now describe a principal function for ETV5 transcription factor in the promotion of EMT. We first characterized at the molecular level the alterations associated with the acquisition of a mesenchymal phenotype, and depicted a main regulatory effect of ETV5 by modulating E-Cadherin repression.…”

Section: Discussionsupporting

confidence: 57%

“…22 Image analysis and statistical quantification of relative protein abundances were performed using DeCyder V. 6.0 software (GE Healthcare, Waukesha, WI, USA). Protein features were selected by presenting t-test values p0.05, when comparing five invasive stage IB EC tissues (former IC stage) with four stage IA EC tissues, together with a fold-change 4 ± 1.3.…”

Section: Two-dimensional Differential In Gel Electrophoresismentioning

confidence: 99%

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ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas

et al. 2012

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Endometrial carcinoma (EC) is the most frequent among infiltrating tumors of the female genital tract, with myometrial invasion representing an increase in the rate of recurrences and a decrease in survival. We have previously described ETV5 transcription factor associated with myometrial infiltration in human ECs. In this work, we further investigated ETV5 orchestrating downstream effects to confer the tumor the invasive capabilities needed to disseminate in the early stages of EC dissemination. Molecular profiling evidenced ETV5 having a direct role on epithelial-to-mesenchymal transition (EMT). In particular, ETV5 modulated Zeb1 expression and E-Cadherin repression leading to a complete reorganization of cell --cell and cell --substrate contacts. ETV5-promoted EMT resulted in the acquisition of migratory and invasive capabilities in endometrial cell lines. Furthermore, we identified the lipoma-preferred partner protein as a regulatory partner of ETV5, acting as a sensor for extracellular signals promoting tumor invasion. All together, we propose ETV5-transcriptional regulation of the EMT process through a crosstalk with the tumor surrounding microenvironment, as a principal event initiating EC invasion.

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Section: Discussionsupporting

confidence: 57%

Section: Two-dimensional Differential In Gel Electrophoresismentioning

confidence: 99%

ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas

et al. 2012

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“…Despite the characterization of molecular events associated with the development of type I and type II endometrial carcinoma such as alterations in PTEN, b-catenin, KRAS, p53, or HER-2/neu, the molecular pathology of myometrial infiltration that defines the initial steps of invasion in endometrial carcinoma is almost unknown (12,22,23). Thus, an important clinical impact would be associated with discovering genes or canonical pathways associated with advanced endometrial carcinomas, unmasking the principal common mechanisms of tumor aggressiveness, providing novel markers and developing rational therapies.…”

Section: Discussionmentioning

confidence: 99%

High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

Muinelo‐Romay

Colás

Barbazán

et al. 2011

Molecular Cancer Therapeutics

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Endometrial cancer is among the three most common cancers in females in industrialized countries. In the majority of cases, the tumor is confined to the uterus at the time of diagnosis and presents a good prognosis. However, after primary surgery, 15% to 20% of these tumors recur and have limited response to systemic therapy. We carried out gene expression profiling of high-risk recurrence endometrial cancers to identify new therapeutic approaches targeting the molecular pathways involved in the acquisition of an aggressive tumor phenotype. A microarray gene-expression analysis on a total of 51 human endometrial carcinomas revealed 77 genes specifically altered in high-risk recurrence tumors (P < 0.001). The bioinformatics analysis of gene-gene interactions and molecular relationships among these genes pointed to a prominent role for TGFb1 signaling in the acquisition of an aggressive phenotype. We further showed that TGF-b1 has a principal role at the initiation of endometrial carcinoma invasion through the promotion of the epithelial to mesenchymal transition that leads to the acquisition of an invasive phenotype in HEC-1A and RL95-2 cells. Impairment of this initial step with SB-431542, a specific TGF-b1 inhibitor, precluded further persistent endometrial carcinoma invasion. In conclusion, we showed that the characterization of the molecular changes associated with the acquisition of an aggressive phenotype represents a realistic strategy for the rational identification and characterization of new potential therapeutic targets in an effort to improve the clinical management and the outcome of high-risk endometrial cancer patients. Mol Cancer Ther; 10(8); 1357-66. '2011 AACR.

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“…Prolonged TGFB3 treatment disrupted epithelial cell morphology, promoted cell motility and induced upregulation of SNAIL, vimentin, ZEB1 and N-cadherin, and downregulation of claudin-1 and E-cadherin. Monge et al (2009) linked the TGFB1 pathway with increased invasive ability promoted by ETV5 transcription factor during the initial steps of EC dissemination.…”

Section: Cell Signaling Pathwaysmentioning

confidence: 99%

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

Makker

Goel

2015

Endocrine-Related Cancer

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Endometrioid endometrial carcinoma (EEC), also known as type 1 endometrial cancer (EC), accounts for over 70-80% of all cases that are usually associated with estrogen stimulation and often develops in a background of atypical endometrial hyperplasia. The increased incidence of EC is mainly confined to this type of cancer. Most EEC patients present at an early stage and generally have a favorable prognosis; however, up to 30% of EEC present as high risk tumors, which have invaded deep into the myometrium at diagnosis and progressively lead to local or extra pelvic metastasis. The poor survival of advanced EC is related to the lack of effective therapies, which can be attributed to poor understanding of the molecular mechanisms underlying the progression of disease toward invasion and metastasis. Multiple lines of evidence illustrate that epithelial-mesenchymal transition (EMT)-like events are central to tumor progression and malignant transformation, endowing the incipient cancer cell with invasive and metastatic properties. The aim of this review is to summarize the current knowledge on molecular events associated with EMT in progression, invasion, and metastasis of EEC. Further, the role of epigenetic modifications and microRNA regulation, tumor microenvironment, and microcystic elongated and fragmented glands like invasion pattern have been discussed. We believe this article may perhaps stimulate further research in this field that may aid in identifying high risk patients within this clinically challenging patient group and also lead to the recognition of novel targets for the prevention of metastasis -the most fatal consequence of endometrial carcinogenesis.

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Proteomic approach to ETV5 during endometrial carcinoma invasion reveals a link to oxidative stress

Cited by 51 publications

References 30 publications

ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas

ETV5 cooperates with LPP as a sensor of extracellular signals and promotes EMT in endometrial carcinomas

High-Risk Endometrial Carcinoma Profiling Identifies TGF-β1 as a Key Factor in the Initiation of Tumor Invasion

Tumor progression, metastasis, and modulators of epithelial–mesenchymal transition in endometrioid endometrial carcinoma: an update

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