Epithelial-mesenchymal transition-associated microRNA/mRNA signature is linked to metastasis and prognosis in clear-cell renal cell carcinoma.

Hana Mlcochova,Rostislav Vyzula,Marek Svoboda,Alexandr Poprach,Jan Dolezel,Anja Rabien,Katerina Slaba,Ondrej Slaby,Michal Stanik,Robert Iliev,Martina Redova-Lojova,Lenka Radova,Ergin Kilic,Klaus Jung,Tana Machackova,Pavel Fabian

doi:10.1038/srep31852

Abstract

Clear-cell renal cell carcinomas (ccRCCs) are genetically heterogeneous tumors presenting diverse clinical courses. Epithelial-mesenchymal transition (EMT) is a crucial process involved in initiation of metastatic cascade. The aim of our study was to identify an integrated miRNA/mRNA signature associated with metastasis and prognosis in ccRCC through targeted approach based on analysis of miRNAs/mRNAs associated with EMT. A cohort of 230 ccRCC was included in our study and further divided into discovery, training and validation cohorts. EMT markers were evaluated in ccRCC tumor samples, which were grouped accordingly to EMT status. By use of large-scale miRNA/mRNA expression profiling, we identified miRNA/mRNA with significantly different expression in EMT-positive tumors and selected 41 miRNAs/mRNAs for training phase of the study to evaluate their diagnostic and prognostic potential. Fifteen miRNAs/mRNAs were analyzed in the validation phase, where all evaluated miRNA/mRNA candidates were confirmed to be significantly deregulated in tumor tissue. Some of them significantly differed in metastatic tumors, correlated with clinical stage, with Fuhrman grade and with overall survival. Further, we established an EMT-based stage-independent prognostic scoring system enabling identification of ccRCC patients at high-risk of cancer-related death. Finally, we confirmed involvement of miR-429 in EMT regulation in RCC cells in vitro.

Highlights

Clear-cell renal cell carcinomas are genetically heterogeneous tumors presenting diverse clinical courses
We believe that a combinatorial approach based on evaluation of miRNAs and genes associated with Epithelial-mesenchymal transition (EMT) enables efficient identification of a metastatic phenotype in primary tumors and mainly prognosis prediction in RCC patients
EMT refers to a morphological transformation of cells that lose their epithelial features and acquire a mesenchymal phenotype

Summary

Introduction

Clear-cell renal cell carcinomas (ccRCCs) are genetically heterogeneous tumors presenting diverse clinical courses. A number of traditional clinicopathologic parameters (e.g. TNM stage, Fuhrman grading, performance status) are used in current clinical practice, the ability to predict the outcome after surgical or systemic therapy is still limited, underscoring the need for new approaches or novel prognostic markers to the management of RCC3,5. Epithelial-mesenchymal transition (EMT) is one of the key processes discussed in regards to progression and metastasis of a wide range of cancers, including RCC6. Loss or down-regulation of epithelial markers (e.g., E-cadherin, cytokeratins) and up-regulation of mesenchymal markers (e.g., N-cadherin, S100A4, vimentin) are presented as hallmarks of EMT These modulations result in increased motility, invasiveness and resistance to apoptosis of cancer cells[8]. This way, morphologically changed cells could get released from the primary tumor mass, enter the blood/lymph circulation and spread through the body

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