Abstract
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.
Highlights
Kidney cancer is a common urologic malignancy and its incidence has been steadily rising by 2–4% each year [1]
AHRR, Caveolin 1 (CAV1), DRAM1, GAS2L1, GNA13, PPM1F, SLC1A4 the top three networks to obtain a 133-node miRNA network including 20 miRNAs and renal cell carcinomas (RCC)-associated genes using Ingenuity Pathway Analysis Software.The network structure is formed of basic elements and the connections representing miRNA-target interactions (Figure 1)
We investigated the association between patient survival and CAV1, Flotillin 1 (FLOT1) expression
Summary
Kidney cancer is a common urologic malignancy and its incidence has been steadily rising by 2–4% each year [1]. The vast majority of adult kidney cancers are renal cell carcinomas (RCC), and 70-85% of those are clear cell subtype (ccRCC) [2]. Around 30% patients are already at metastatic stage at the time of diagnosis even in the absence of symptoms [1]. Patients with metastatic disease have 13 months median survival and the 5 year survival rate under 10% [3]. MicroRNAs (miRNAs) are small, protein non-coding RNA molecules which posttranscriptionally regulate protein expression. Their role have been broadly investigated and demonstrated in several cancers including ccRCC [4]
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