Review
MiR-210 – micromanager of the hypoxia pathway

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Hypoxia inducible factors (HIFs) regulate a variety of genes to prepare cells to adapt and survive under a hypoxic environment. Recently, microRNAs (miRNAs) have emerged as a new class of genes regulated by HIFs in response to hypoxia, of which miR-210 is the most consistently and predominantly upregulated miRNA. Functional studies have demonstrated that miR-210 is a versatile gene that regulates many aspects of hypoxia pathways, both in physiological and malignant conditions. Here, we summarize recent findings on the mechanism of hypoxia regulation of miR-210 expression and its multifaceted biological functions in normal physiological and malignant conditions, and discuss the challenges we face in elucidating the biological functions of miR-210 and exploring its potential use for therapeutics.

Section snippets

Introduction of hypoxia and microRNA

MiRNAs are a class of single-stranded noncoding RNAs 21–22 nucleotides in length. Genes encoding miRNAs are initially transcribed as part of much longer primary transcripts (pri-miRNAs) [1]. In the nucleus, these primary transcripts are first processed by the type III RNA endonuclease Drosha into pre-miRNAs that are 60–70 nucleotides in length and form a stem–loop structure [2]. The subsequent transport of pre-miRNAs into the cytoplasm by exportin-5 results in further processing by another type

Regulation of miR-210 expression by hypoxia

The hypoxic regulation of miR-210 was first identified by miRNA microarray in 2007 [18]. The stem–loop of miR-210 is located in an intron of a noncoding RNA, which is transcribed from AK123483 on chromosome 11p15.5. The boundary and length of human pri-miR-210 is predicted with high confidence based on expressed sequence tags, gene expression analysis using the captured 5′ 7-methylguanosine cap of mRNA, the location of the transcription start site (TSS), CpG islands and polyadenylation site [19]

Angiogenesis

Virtually all solid tumors contain hypoxic regions that stimulate angiogenesis to sustain tumor growth. One of the major regulators of tumor angiogenesis is vascular endothelial growth factor (VEGF), a gene regulated by hypoxia [26]. Although the increased expression of VEGF promotes angiogenesis, miR-210 might also be involved [25]. MiR-210 targets the receptor tyrosine kinase ligand Ephrin-A3 (EFNA3) (which is one of the most consistently reported miR-210 target genes 17, 25, 27, 28),

MiR-210 in cancer

MiR-210 is frequently elevated in cancer, including glioblastoma [59], melanoma 20, 60, clear cell renal cell carcinoma [61] and lung 62, 63, 64, 65, 66, pancreatic [28] and breast cancer 21, 29, 65, which is consistent with miR-210 promoting cell cycle progression [20]. However, because miR-210 is the most robustly induced miRNA under hypoxia [17], it is possible that elevated miR-210 expression only reflects the in vivo status of tumor hypoxia. Even under nonmalignant physiological conditions

Future challenges

Although much progress has been made since the first report of hypoxic regulation of miRNA three years ago [18], tremendous challenges still lie ahead (Box 1). One challenge common to the entire miRNA research field is the accurate identification of miRNA targets, because ultimately miRNA exerts its biological function by regulating cellular protein levels. The computational prediction of miRNA targets is based on the complementarity of target gene 3′ UTR sequence to the “seed region” sequence

Acknowledgements

This work is supported by NIH grants P01-CA67166 (QTL, AJG) and R01-CA118582 (QTL) and funding from Magee-Womens Research Institute (XH).

Glossary

Locked nucleic acid (LNA)
LNA is a modified nucleotide with an extra bridge connecting the 2’ oxygen and 4’ carbon on the ribose moiety. The locked ribose confirmation significantly increases the thermal stability of oligonucleotides where LNA is incorporated. Because of the short target sequence (∼22 nucleotides) of mature miRNA, the LNA nucleotide is usually incorporated into the antisense RNA oligonucleotide for efficient miRNA knockdown.
MiRNA sponge
a competitive miRNA inhibitor composed of

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