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Expression analysis and in silico characterization of intronic long noncoding RNAs in renal cell carcinoma: emerging functional associations

Angela A Fachel1, Ana C Tahira1, Santiago A Vilella-Arias1, Vinicius Maracaja-Coutinho1, Etel RP Gimba23, Giselle M Vignal3, Franz S Campos3, Eduardo M Reis14 and Sergio Verjovski-Almeida14*

Author Affiliations

1 Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, 05508-900 São Paulo, SP, Brazil

2 Departamento RIR, Instituto de Humanidades e Saúde, Universidade Federal Fluminense, 28880-000, Rio das Ostras, RJ, Brazil

3 Instituto Nacional de Câncer, 20231-050 Rio de Janeiro, RJ, Brazil

4 Instituto Nacional de Ciência e Tecnologia em Oncogenômica, São Paulo, SP, Brazil

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Molecular Cancer 2013, 12:140  doi:10.1186/1476-4598-12-140

Published: 15 November 2013

Abstract

Background

Intronic and intergenic long noncoding RNAs (lncRNAs) are emerging gene expression regulators. The molecular pathogenesis of renal cell carcinoma (RCC) is still poorly understood, and in particular, limited studies are available for intronic lncRNAs expressed in RCC.

Methods

Microarray experiments were performed with custom-designed arrays enriched with probes for lncRNAs mapping to intronic genomic regions. Samples from 18 primary RCC tumors and 11 nontumor adjacent matched tissues were analyzed. Meta-analyses were performed with microarray expression data from three additional human tissues (normal liver, prostate tumor and kidney nontumor samples), and with large-scale public data for epigenetic regulatory marks and for evolutionarily conserved sequences.

Results

A signature of 29 intronic lncRNAs differentially expressed between RCC and nontumor samples was obtained (false discovery rate (FDR) <5%). A signature of 26 intronic lncRNAs significantly correlated with the RCC five-year patient survival outcome was identified (FDR <5%, p-value ≤0.01). We identified 4303 intronic antisense lncRNAs expressed in RCC, of which 22% were significantly (p <0.05) cis correlated with the expression of the mRNA in the same locus across RCC and three other human tissues. Gene Ontology (GO) analysis of those loci pointed to 'regulation of biological processes’ as the main enriched category. A module map analysis of the protein-coding genes significantly (p <0.05) trans correlated with the 20% most abundant lncRNAs, identified 51 enriched GO terms (p <0.05). We determined that 60% of the expressed lncRNAs are evolutionarily conserved. At the genomic loci containing the intronic RCC-expressed lncRNAs, a strong association (p <0.001) was found between their transcription start sites and genomic marks such as CpG islands, RNA Pol II binding and histones methylation and acetylation.

Conclusion

Intronic antisense lncRNAs are widely expressed in RCC tumors. Some of them are significantly altered in RCC in comparison with nontumor samples. The majority of these lncRNAs is evolutionarily conserved and possibly modulated by epigenetic modifications. Our data suggest that these RCC lncRNAs may contribute to the complex network of regulatory RNAs playing a role in renal cell malignant transformation.

Keywords:
Renal cell carcinoma (RCC); Unspliced intronic long noncoding RNAs; Antisense lncRNAs; Microarray analysis; Molecular markers; Gene expression correlation; Histone methylation; Histone acetylation; Evolutionary lncRNA conservation