A MicroRNA Signature of Hypoxia

Abstract

Recent research has identified critical roles for microRNAs in a large number of cellular processes, including tumorigenic transformation. While significant progress has been made towards understanding the mechanisms of gene regulation by microRNAs, much less is known about factors affecting the expression of these noncoding transcripts. Here, we demonstrate for the first time a functional link between hypoxia, a welldocumented tumor microenvironment factor, and microRNA expression. Microarray-based expression profiles revealed that a specific spectrum of microRNAs (including miR-23, -24, -26, -27, -103, -107, -181, -210, and -213) is induced in response to low oxygen, at least some via a hypoxia-inducible-factor-dependent mechanism. Select members of this group (miR-26, -107, and -210) decrease proapoptotic signaling in a hypoxic environment, suggesting an impact of these transcripts on tumor formation. Interestingly, the vast majority of hypoxiainduced microRNAs are also overexpressed in a variety of human tumors.

A microRNA component of the hypoxic response

“…The HRM group includes: miR-21, 23a, 23b, 24, 26a, 26b, 27a, 30b, 93, 103, 103, 106a, 107, 125b, 181a, 181b, 181c, 192, 195, 210 and 213, which were consistently induced in response to hypoxia in the breast and colon cancer cells tested. 21 Our study selected only microRNAs exhibiting consistent upregulation in at least two cell lines and at several time points in hypoxia, potentially increasing the stringency of the screen. Three additional articles reported microRNAs that respond to low oxygen with some notable similarities, including miR-210, miR-30b, 93 and 181b.…”

“…[22][23][24] It is also true, however, that a significant number of microRNAs differed between the studies, which is not necessarily surprising, given the differences in the cellular backgrounds and technology employed, both being a recognized source of variability. An additional difference was in the experimental conditions employed by the different groups: hypoxia mimetics, 22 versus 1% oxygen for 1 h, 23 versus 5% oxygen for 8 h, 23 versus 0.2% for various periods of time from 8-48 h. 21 In addition to the microRNAs that respond to hypoxia by upregulation, a set of microRNAs were identified as downregulated in hypoxic cells, including miR-15b, 16, 19a, 20a, 20b, 29b, 30b, 30e-5p, 101, 141, 122a, 186, 320 and 197. [22][23][24] In our study, we have also detected microRNAs that exhibited downregulation at the level of microarrays (miR-126, 128, 138, 323, 326); however, the changes seemed restricted to one cell line and were not pursued at this stage (R Kulshreshtha et al, unpublished).…”

“…The strategy employed a combination of HIF transduction, chromatin immunoprecipitation and luciferase-based reporters driven by fragments of select HRM promoters. 21 Delineating the promoter regions of microRNAs, where relevant transcription factors such as HIF bind, is a necessary step for an expanded understanding of microRNA expression control. The main challenge comes from the fact that only few microRNA promoters have been identified experimentally.…”

“…[25][26][27] In a preliminary analysis of the promoters of all known and predicted microRNAs, we predicted HIF-binding sites by position weight matrix approach. 21 While our methodology analyzed the 5 kb promoter region of all the microRNAs, the promoter regions can span much longer regions. The analysis, performed separately for individual types of HIFbinding consensuses (V$HIF_Q3 and V$HIF_Q5) revealed that the HRMs (as a group) contains significantly more microRNAs with at least one HIF site than the average random 23 microRNAs.…”

Hypoxia and chronic lung disease

“…Recent evidence indicates that hypoxia induces the synthesis of microRNAs (MIRs), which add additional levels of complexity in the regulation of gene expression under hypoxia [3,4]. MIRs, a group of small RNAs with approximately 22 nucleotides in length, have important roles in the regulation of gene expression.…”