Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma

Montserrat, Núria; Mozos, Anna; Llobet, David; Dolcet, Xavier; Pons, Cristina; Herreros, Antonio Garcı́a de; Matías‐Guiu, Xavier; Prat, Jaime

doi:10.1016/j.humpath.2011.06.021

Cited by 72 publications

(55 citation statements)

References 34 publications

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“…[26][27][28] After validation by RT-qPCR of miRNA selected from the previous step, we found that miR-34b-5p, miR-34c-5p, miR-34c-3p, miR-375, and miR-184 emerged as being particularly relevant to determine positive or negative LN metastatic status in women with grade 1-2 early-stage EC. Furthermore, miR34b-5p, miR-34c-5p, miR-34c-3p, and miR-184 dominated the first principal component of the principal component analysis.…”

Section: Discussionmentioning

confidence: 97%

Identification of microRNA expression profile related to lymph node status in women with early-stage grade 1–2 endometrial cancer

et al. 2016

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Conventional methods used for histologic classification and grading of endometrial cancer (EC) are not sufficient to predict lymph node metastases. microRNA signatures have recently been related to EC pathologic characteristics or prognosis. The aim of this study was to evaluate whether microRNA profiles of grade 1-2 endometrioid adenocarcinomas can be related to nodal status and used as a tool to adapt surgical staging in early-stage EC. microRNA expression was assessed in nine formalin-fixed paraffin-embedded (FFPE) EC primary tumors with positive lymph node and in 27 FFPE EC primary tumors with negative lymph node, matched for grade, stage, and lymphovascular space involvement status. A microarray analysis showed that there was more than a twofold significant difference in the expression of 12 microRNAs between the two groups. A quantitative reverse transcriptase-PCR assay was used to confirm these results: the expression levels of five microRNAs (microRNA-34c-5p, -375, -184, -34c-3p, and -34b-5p) were significantly lower in the EC primary tumor with positive lymph node compared with those with negative lymph node. A minimal P-value approach revealed that women with a microRNA-375-fold change o 0.30 were more likely to have positive lymph node (n = 8; 53.3%) compared with those with a microRNA-375-fold change 40.30 (n = 1; 4.8%), P = 0.001. Furthermore, women with a microRNA 184-fold change o0.30 were more likely to have positive lymph node (n = 6; 60.0%) compared with those with a microRNA 184-fold change 40.30 (n = 3; 11.5%), P = 0.006. This is the first study investigating the relative expression of mature microRNA genes in early-stage grade 1-2 EC primary tumors according to the nodal status. This microRNA expression profile provides a potential basis for further study of the microRNA function in EC and could be used as a diagnostic tool for nodal status.

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Section: Discussionmentioning

confidence: 97%

Identification of microRNA expression profile related to lymph node status in women with early-stage grade 1–2 endometrial cancer

et al. 2016

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“…[36][37][38] As cancer cells shift towards a mesenchymal phenotype, they demonstrate lower levels of proteins such as E-cadherin and γ-catenin that promote cell-to-cell adhesion and higher levels of vimentin and N-cadherin. 35,[39][40][41][42] Expression of these mesenchymal markers increases the migratory capability and invasive potential of the cells. [43][44][45] Interestingly, pancreatic cell lines resistant to gemcitabine also showed EMT characteristics, and re-expression of the miR-200 family resulted in a decrease in Zeb1, Slug, and vimentin, consistent with a reversal of EMT.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA Profile to Predict Gemcitabine Resistance in Bladder Carcinoma Cell Lines

et al. 2013

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MicroRNAs (miRNA) are small, noncoding RNAs with important regulatory roles in development, differentiation, cell proliferation, and death as well as the complex process of acquired drug resistance. The goal of this study was to identify specific miRNAs and their potential protein targets that confer acquired resistance to gemcitabine in urothelial carcinoma of the bladder (UCB) cell lines. Gemcitabine-resistant cells were established from 6 cell lines following exposure to escalating concentrations of the drug and by passaging cells in the presence of the drug over a 2-to 3-month period. Differential miRNA expression was identified in a microarray format comparing untreated controls with resistant cell lines, representing the maximum tolerated concentration, and results were validated via qRT-PCR. The involvement of specific miRNAs in chemoresistance was confirmed with transfection experiments, followed by clonogenic assays and Western blot analysis. Gemcitabine resistance was generated in 6 UCB cell lines. Microarray analysis comparing miRNA expression between gemcitabine-resistant and parental cells identified the differential expression of 66 miRNAs. Confirmation of differential expression was recorded via qRT-PCR in a subset of these miRNAs. Within this group, let-7b and let-7i exhibited decreased expression, while miR-1290 and miR-138 displayed increased expression levels in gemcitabine-resistant cells. Transfection of pre-miR-138 and pre-miR-1290 into parental cells attenuated cell death after exposure to gemcitabine, while transfection of pre-miR-let-7b and pre-miR-let-7i into the resistant cells augmented cell death. Mucin-4 was up-regulated in gemcitabine-resistant cells. Ectopic expression of let-7i and let-7b in the resistant cells resulted in the down-regulation of mucin-4. These results suggest a role for miRNAs 1290, 138, let-7i, and let-7b in imparting resistance to gemcitabine in UCB cell lines in part through the modulation of mucin-4. Alterations in these miRNAs and/or mucin-4 may constitute a potential therapeutic strategy for improving the efficacy of gemcitabine in UCB.

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“…The authors observed an increase in SNAIL protein expression and its inverse correlation with E-cadherin expression in both primary tumors and metastasis of EEC. Montserrat et al (2011) investigated the activation status of EMT program in early stages of EEC and observed SNAIL upregulation in noninvasive (stage IA) and myoinvasive (stages IB and IC) tumors. As compared to normal endometrium, stage IC tumors overexpressed the whole set of E-cadherin repressors viz.…”

Section: Emt Effectors and Core Regulators In Eec Progression And Metmentioning

confidence: 99%

“…Pertinently an extensive myometrial invasion may be a progeny of EMT which has been implicated in invasive characteristics of endometrial tumors (Montserrat et al 2011).…”

Section: Steroid Hormones and Their Receptorsmentioning

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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Epithelial to mesenchymal transition in early stage endometrioid endometrial carcinoma

Cited by 72 publications

References 34 publications

Identification of microRNA expression profile related to lymph node status in women with early-stage grade 1–2 endometrial cancer

Identification of microRNA expression profile related to lymph node status in women with early-stage grade 1–2 endometrial cancer

MicroRNA Profile to Predict Gemcitabine Resistance in Bladder Carcinoma Cell Lines

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

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