Recently published data in our laboratory have established a link between hypoxia and specific microRNAs, thereby revealing a novel molecular pathway in the response to low oxygen.

MicroRNAs represent approximately 1%–2% of the eukaryotic transcriptome and have been shown to play critical roles in the coordination of cell differentiation, proliferation, death, metabolism. and more recently in tumorigenesis. Indeed, a significant percentage of microRNAs-encoding genes are located at fragile sites, minimal loss of heterozygosity regions, minimal regions of amplification, or common break-point regions in cancers. Moreover, global microRNA expression changes have been described in human cancers and in some cases shown to correlate with the clinico-pathological features of the tumor. However, no mechanism has been proposed to date for these profile alterations.

Despite of this wealth of data, relatively little is known about microRNA regulation and their response to microenvironmental factors. One mechanism involves activation of specific signal transduction pathways that in turn promote transcription of certain microRNAs. For example, it was reported that the miR-1 genes are targets of serum response factor, a converging downstream effector for a variety of oncoproteins and growth factors. Another transcription factor, the c-myc oncogene product was also found to activate the expression of a microRNA cluster.

Hypoxia is an essential feature of the neoplastic microenvironment. Tumors with widespread low oxygenation tend to exhibit increased invasion and resistance to conventional therapy. The molecular mechanisms responsible for the hypoxic survival of neoplastic cells are not fully characterized, and a better understanding of this process may lead to novel strategies for pharmacological intervention. 

Our data indicate that hypoxia leaves a specific mark on microRNA profiles in a variety of cell types, including lines derived from breast and colon cancer. Indeed, a specific spectrum of microRNAs (including miR-23, 24, 26, 27, 103, 107, 181, 210 and 213) is induced in response to low oxygen, with a critical contribution of the hypoxia inducible factor (HIF) at least in some cases. Moreover, at least miR-210, 107, and 26 seem to play a role in cell survival in a low oxygen environment.

Finally, by comparing hypoxia-associated microRNA spectra with published data from a large number of tumors (Volinia S. et al 2006), we propose that cancer-associated microRNA profiles exhibit a hypoxic signature.