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

Abstract

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.

The epigenetic landscape of renal cancer

“…pVHL decreases HIF1α and HIF2α protein levels 22 and induces the expression of miR-30c-2-3p and miR-30a-3p, which target HIF2α transcripts for degradation. Loss of pVHL, therefore, increases HIF1α and HIF2α protein levels and promotes HIF2α transcription through the loss of miR-30c-2-3p and miR-30a-3p 192 . Patients with RCC who have reduced levels of these mi RNAs have reduced survival 192 .…”

“…Loss of pVHL, therefore, increases HIF1α and HIF2α protein levels and promotes HIF2α transcription through the loss of miR-30c-2-3p and miR-30a-3p 192 . Patients with RCC who have reduced levels of these mi RNAs have reduced survival 192 . Both HIF1α and HIF2α upregulate the expression of miR-210 (REF.…”

Original article Differential expression of microRNA-210 in gliomas of variable cell origin and correlation between increased expression levels and disease progression in astrocytic tumours

“…A number of targets of miR-210 have been reported, such as vacuole membrane protein 1 (VMP1), enzyme glycerol-3-phosphate dehydrogenase 1-like (GPD1L), iron-sulfur cluster scaffold homolog (ISCU), succinate dehydrogenase complex subunit D (SDHD) and MNT [15,19,25,42,45].…”

“…Preventing degradation of HIF-1α leads to induction of a wide variety of genes including those involved in energy metabolism, angiogenesis, cell proliferation and survival [15]. In addition, HIF-1α stability leads to further up-regulation of miR-210 [15,19].…”

“…ISCU is repressed in the presence of miR-210 leading to a decrease in Krebs cycle enzyme activity and mitochondrial function, providing a mechanism for handling increases in free radical production and a switch to glycolysis affecting cell growth and survival under hypoxic conditions. A decrease in ISCU in cancer patients has been associated with a worse prognosis and is therefore important as a clinicopathological prognostic factor [7,19]. MiR-210's induction of mitochondrial dysfunction under hypoxia is further supported by down-regulation of SDHD in the presence of miR-210, which leads to an increase in HIF-1 stability in lung tumour cells, A549 [25].…”