A MicroRNA Signature of Hypoxia<sup><a href="#fn1" rid="fn1" class=" fn">†</a></sup> <sup><a href="#fn2" rid="fn2" class=" fn">▿</a></sup>

Ritu Kulshreshtha

Manuela Ferracin

Sylwia Wojcik

Ramiro Garzon

Hansjuerg Alder

Francisco Agosto-Perez

Ramana Davuluri

Chang Liu

Carlo Croce+3 authors

Molecular Oncology Research Institute, Tufts-New England Medical Center, Boston, Massachusetts 02111,^{Department of Experimental and Diagnostic Medicine and Interdepartmental Center for Cancer Research, University of Ferrara, Ferrara 44100, Italy,}^{Comprehensive Cancer Center, Ohio State University, Columbus, Ohio 43210}³

^{Corresponding author. Mailing address: 750 Washington Street, Box 5609, Boston, MA 02111. Phone: (617) 636-7514. Fax: (617) 636-6127. E-mail:}gro.cmen-stfut@navim.

Received 2006 Jul 28; Revised 2006 Aug 28; Accepted 2006 Dec 10.

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 well-documented 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 hypoxia-induced microRNAs are also overexpressed in a variety of human tumors.

Abstract

MicroRNAs represent approximately 1% to 2% of the eukaryotic transcriptome and have been shown to play critical roles in the coordination of cell differentiation, proliferation, death, and metabolism (1, 3, 6, 7, 17, 24) and more recently in tumorigenesis (2, 5, 6, 10, 13, 20, 21). Indeed, a significant percentage of microRNA-encoding genes are located at fragile sites, minimal loss-of-heterozygosity regions, minimal regions of amplification, or common breakpoint regions in cancers.

Moreover, global microRNA expression changes have been described to occur in human cancers and in some cases shown to correlate with the clinico-pathological features of the tumor (2, 13, 29). However, no mechanism has been proposed to date for these profile alterations.

Despite this wealth of data, relatively little is known about microRNA regulation and response to microenvironmental factors. One mechanism involves the activation of specific signal transduction pathways that in turn promote the 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 (30). Another transcription factor, the c-myc oncogene product, was also found to activate the expression of a microRNA cluster (25).

Hypoxia is an essential feature of the neoplastic microenvironment. Tumors with widespread low oxygenation tend to exhibit increased invasion and resistance to conventional therapy (9). 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, with a critical contribution of the hypoxia-inducible factor (HIF). Moreover, at least a subgroup of these hypoxia-regulated microRNAs (HRMs) 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 (28), we propose that cancer-associated microRNA profiles exhibit a hypoxic signature.

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Acknowledgments

This work was supported by NIH grant P30 DK-34928 and an AACR/PanCan career development award to M.I.; a Kimmel Scholar award to G.A.C.; grants from the Italian Ministry of Public Health, the Italian Association for Cancer Research (AIRC), and Comitato Sostenitori Progetto CAN-2006 to M.N.; and grants from the National Cancer Institute to C.M.C. M.F. is a recipient of a fellowship from Fondazione Italiana per la Ricerca sul Cancro (FIRC).

We declare that we have no competing financial interests.

Acknowledgments

Footnotes

^{Supplemental material for this article may be found at}http://mcb.asm.org/.

^{Published ahead of print on 28 December 2006.}

Footnotes

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