miRNA-target network reveals miR-124as a key miRNA contributing to clear cell renal cell carcinoma aggressive behaviour by targeting CAV1 and FLOT1
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Henriett Butz1,2, Peter M. Szabó3, Heba W.Z. Khella1,2, Roy Nofech-Mozes1, Attila Patocs4 and George M. Yousef1,2
1 Department of Laboratory Medicine and The Keenan Research Centre for Biomedical Science of St. Michael’s Hospital, Toronto, Canada
2 Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada
3 Biometric Research Branch, Division of Cancer Treatment and Diagnosis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
4 HAS-SE “Lendulet” Hereditary Endocrine Tumors Research Group, Hungarian Academy of Sciences, Hungary
George M. Yousef, email:
Keywords: renal cell carcinoma, miR-124-3p, integrated analysis, CAV1, FLOT1
Received: February 18, 2015 Accepted: March 11, 2015 Published: April 14, 2015
Clear cell renal cell carcinoma (ccRCC) is an aggressive tumor with frequent metastatic rate and poor survival. Integrated analyses allow understanding the interplay between different levels of molecular alterations.
We integrated miRNA and gene expression data from 458 ccRCC and 254 normal kidney specimens to construct a miRNA-target interaction network.
We identified the downregulated miR-124-3p, -30a-5p and -200c-3p as the most influential miRNAs in RCC pathogenesis.miR-124-3p and miR-200c-3p expression showed association with patient survival, miR-30a-5p was downregulated in metastases compared to primary tumors. We used an independent set of 87 matched samples for validation. We confirmed the functional impact of these miRNAs by in vitro assays. Restoration of these miRNAs reduced migration, invasion and proliferation. miR-124-3p decreased the S phase of cell cycle, as well. We compared transcriptome profiling before and after miRNA overexpression, and validated CAV1 and FLOT1 as miR-124-3p targets. Patients with higher CAV1 and FLOT1 had lower miR-124-3p expression and shorter overall survival.
We hypothesize that these three miRNAs are fundamental contributing to ccRCC aggressive/metastatic behavior; and miR-124-3p especially has a key role through regulating CAV1 and FLOT1 expression. Restoration of the levels of these miRNAs could be considered as a potential therapeutic strategy for ccRCC.
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