EPITHELIAL-MESENCHYMAL TRANSITION-ASSOCIATED MICRORNA/ MRNA SIGNATURE IS LINKED TO METASTASIS AND PROGNOSIS IN

Purpose:

The aim of our study was to identify an integrated microRNA/mRNA signature associated with metastasis and prognosis in clear-cell renal cell carcinoma (ccRCC) through targeted approach based on analysis of microRNAs/mRNAs associated with epithelialmesenchymal transition (EMT).

Experimental Design:

A cohort of 230 ccRCC was included in our study and further divided into discovery, training and validation cohorts. EMT markers (CDH1, CK18, CK19, VIM, S100A4) were evaluated in ccRCC tumor samples, which were grouped accordingly to EMT status, and large-scale miRNA/mRNA expression profiling was performed on exploratory cohorts to identify EMT-associated miRNAs/mRNAs. Diagnostic and prognostic potential of these miRNAs/mRNAs was evaluated on independent training and validation cohorts.

Results:

We identified miRNA/mRNA profiles 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 forwarded to validation phase, where 15 was confirmed to be significantly deregulated in tumor tissue (all p < 0.0001), 11 significantly differed in metastatic and non-metastatic tumors, 12 significantly correlated with clinical stage, 11 with Fuhrman grade and 9 with overall survival. Further, we have established an EMT-based stage-independent prognostic scoring system (miR-200a, miR-200b, miR-200c, miR-30a-3p, miR-429, CDH1, C3orf52 and PAPSS2) enabling identification of RCC patients at high-risk of cancer-related death (HR 3.63, 95% CI 1.69-7.81; p < 0.001). Finally, we confirmed functioning of miR-429 in EMT regulation in RCC cells in vitro.

Conclusion:

EMT-targeted approach enabled identification of novel miRNAs/mRNAs associated with metastasis and prognosis and development of stage-independent prognostic model in ccRCC.