Pleiotropic action of renal cell carcinoma-dysregulated miRNAs on hypoxia-related signaling pathways.
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.
Department of Laboratory Medicine, Keenan Research Centre in the Li Ka Shing Knowledge Institute St. Michael's Hospital, Toronto, Ontario, Canada.
Zsuzsanna
Z
Lichner
Salvador
S
Mejia-Guerrero
Monika
M
Ignacak
Adriana
A
Krizova
Tian Tian
TT
Bao
Andrew H F
AH
Girgis
Yousef M
YM
Youssef
George M
GM
Yousef
D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D058685:Genetic Pleiotropy / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D007680:Kidney Neoplasms / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D051902:Smad5 Protein / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C524941:MIRN17 microRNA, human; C546140:MIRN224 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; C497796:SMAD4 protein, human; C497797:SMAD5 protein, human; D051901:Smad4 Protein; D051902:Smad5 Protein; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C497446:VHL protein, human