Regulation of Hypoxia Responses by MicroRNA Expression

© 2014 by John Wiley & Sons, Inc. All rights reserved. Hypoxia in solid tumors may confer resistance to conventional therapies and is associated with a poorer prognosis. Hypoxia leads to changes in the transcription of many genes participating in processes such as glucose metabolism, cell proliferation and survival, pH regulation, migration, and angiogenesis. This transcriptional regulation, which allows cells to adapt to this new condition, is orchestrated by the family of hypoxia inducible factors (HIFs). MicroRNAs (miRNAs) are also regulated by hypoxia, and some of them are directly regulated by HIFs. In this chapter, we will consider the effect of hypoxia on the regulation of miRNAs with particular focus on miR-210, a HIF-induced miRNA that is associated with cancer. Indeed, high levels of miR-210 have been correlated with poor prognosis in breast, head and neck, and pancreatic cancers. We will discuss the functional role of miR-210 in hypoxia and cancer through the regulation of its target genes, which are involved in processes such as mitochondrial function, DNA repair, cell cycle, and apoptosis among others. We will then contemplate the ability of miRNAs to regulate HIF function. These include miRNAs regulated directly by HIFs, regulated by hypoxia in a HIF-independent manner, and also those not regulated by hypoxia. The implications of regulatory levels will be discussed, revealing the complexity of miRNA-associated regulation under hypoxia.