miR-210 is a target of hypoxia-inducible factors 1 and 2 in renal cancer, regulates ISCU and correlates with good prognosis

• Published in: British journal of cancer Vol. 108; no. 5; pp. 1133 - 1142
• Main Authors: McCormick, R I, Blick, C, Ragoussis, J, Schoedel, J, Mole, D R, Young, A C, Selby, P J, Banks, R E, Harris, A L
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19-03-2013; Nature Publishing Group
• Subjects: 631/337/384/331; 692/699/67/589/1588; 692/700/1750; Adult; Aged; Aged, 80 and over; Basic Helix-Loop-Helix Transcription Factors - metabolism; Biobanks; Biological and medical sciences; Biomedical and Life Sciences; Biomedicine; Cancer Research; Carcinoma, Renal Cell - genetics; Carcinoma, Renal Cell - metabolism; Cell Line, Tumor; Drug Resistance; Epidemiology; Female; Gene Expression Regulation, Neoplastic; Genes; Humans; Hypoxia; Hypoxia-Inducible Factor 1 - metabolism; Iron-Sulfur Proteins - metabolism; Kidney cancer; Kidney Neoplasms - genetics; Kidney Neoplasms - metabolism; Kidneys; Male; Medical prognosis; Medical research; Medical sciences; MicroRNAs; MicroRNAs - genetics; Middle Aged; Molecular Diagnostics; Molecular Medicine; Mutation; Nephrology. Urinary tract diseases; Oncology; Prognosis; Tumors; Tumors of the urinary system; Up-Regulation; Von Hippel-Lindau Tumor Suppressor Protein - genetics; United Kingdom > UK; United States > US; hypoxia; renal cancer; miRNA; VHL; HIF; prognosis; Kidney disease; Oxygen; Urinary system disease; RNA interference; Prognosis; Targeting; Micro RNA; Malignant tumor; Gene silencing; Target; Regulation(control); Cancerology; Kidney cancer; Hypoxia; Transcription factor HIF1; Cancer
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2013.56

Background:
Clear cell renal cancer frequently harbours von Hippel–Lindau (VHL) gene mutations, leading to stabilisation of the hypoxia-inducible factors (HIFs) and expression of their target genes. We investigated HIF-1 and HIF-2 in the regulation of microRNA-210 (miR-210), and its clinical relevance in renal tumours.
Methods:
RCC4 and 786-O renal cancer cell lines transfected with either an empty vector or functional VHL and incubated in normoxia or hypoxia were examined for miR-210 expression. Hypoxia-inducible factor siRNAs were used to examine their regulation of miR-210. Seventy-one clear cell renal tumours were sequenced for VHL mutations. Expression of miR-210, VHL, CA9, ISCU and Ki-67 were determined by immunohistochemistry and qRT–PCR.
Results:
In addition to HIF-1 regulating miR-210 in renal cancer, HIF-2 can regulate this microRNA in the absence of HIF-1. MicroRNA-210 is upregulated in renal cancer compared with normal renal cortex tissue. MicroRNA-210 correlates negatively with its gene target ISCU at the protein and mRNA level. MicroRNA-210 correlated with positive outcome variables and negatively with Ki-67.
Conclusion:
We provide further evidence of miR-210 activity
in vivo
, and show that high miR-210 expression is associated with better clinico-pathological prognostic factors.