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Am J Pathol ; 180(4): 1675-87, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-22326755

RESUMO

The von Hippel-Lindau (VHL) gene is lost in ≈ 70% of all renal cell carcinomas (RCCs); however, increasing evidence supports the involvement of alternative mechanisms in the regulation of VHL expression, including suppression by microRNAs (miRNAs). miRNAs are small, noncoding RNA molecules that regulate gene expression through binding to target mRNAs. In this study, we found that miRNAs, which are dysregulated in cases of RCC, can target multiple members of RCC-related signaling pathways. Importantly, both VHL and the hypoxia-inducible factor 1-α gene are experimentally validated and are likely direct targets of miR-17-5p and miR-224, as shown by both luciferase assay and Western blot analysis. We found a negative correlation between miR-17-5p and its two predicted targets, VEGF-A and EGLN3, and between miR-224 and its targets SMAD4 and SMAD5 in RCC specimens, suggesting that downstream signaling pathways are also modulated by clear cell RCC-dysregulated miRs. Results from our bioinformatics analysis show that a single miRNA molecule can target multiple components of the same pathway and that multiple miRNAs can target the same molecule. Our results also indicate that miRNAs represent a mechanism for the inactivation of VHL in cases of RCC and can elucidate a new dimension in cancer pathogenesis. As such, miRNAs exemplify new potential therapeutic targets with a significant effect on both tumor growth and metastatic potential.


Assuntos
Carcinoma de Células Renais/genética , Pleiotropia Genética/genética , Neoplasias Renais/genética , MicroRNAs/genética , Carcinoma de Células Renais/metabolismo , Hipóxia Celular/genética , Hipóxia Celular/fisiologia , Regulação Neoplásica da Expressão Gênica/fisiologia , Pleiotropia Genética/fisiologia , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/metabolismo , Neoplasias Renais/metabolismo , PTEN Fosfo-Hidrolase/genética , PTEN Fosfo-Hidrolase/metabolismo , RNA Mensageiro/genética , Transdução de Sinais/genética , Transdução de Sinais/fisiologia , Proteína Smad4/genética , Proteína Smad4/metabolismo , Proteína Smad5/genética , Proteína Smad5/metabolismo , Células Tumorais Cultivadas , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Proteína Supressora de Tumor Von Hippel-Lindau/genética , Proteína Supressora de Tumor Von Hippel-Lindau/metabolismo
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