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Causes and consequences of microRNA dysregulation in cancer

Nature Reviews Genetics volume 10, pages 704–714 (2009)Cite this article

Key Points

  • This paper describes the alterations and mechanisms that are involved in microRNA (miRNA) dysregulation in human cancer and how such dysregulation is involved in cancer initiation and progression.

  • miRNA profiling can be used to assess which miRNAs are dysregulated in human cancer.

  • miRNAs acting as tumour suppressors target important oncogenes, such as B cell leukaemia/lymphoma 2 (BCL2), MYC and RAS.

  • miRNAs acting as oncogenes target important tumour suppressors, such as phosphatase and tensin homologue (PTEN), p27, p57 and tissue inhibitor of metalloproteinases 3 (TIMP3).

  • miRNA genes can be silenced by epigenetic changes and can cause epigenetic changes that result in the silencing of tumour suppressor genes; for example, loss of miR-29 family members results in the overexpression of DNA methyltransferases and the silencing of tumour suppressors. Reintroduction of miR-29 family members into tumour cells that have lost them results in the reactivation of silenced tumour suppressors and the suppression of tumorigenicity.

  • The same miRNAs are dysregulated in multiple human tumours, which suggests that they may be downstream targets of pathways that are commonly dysregulated in human cancer.

  • Dysregulated miRNAs could be targets for anticancer treatment.

Abstract

Over the past several years it has become clear that alterations in the expression of microRNA (miRNA) genes contribute to the pathogenesis of most — if not all — human malignancies. These alterations can be caused by various mechanisms, including deletions, amplifications or mutations involving miRNA loci, epigenetic silencing or the dysregulation of transcription factors that target specific miRNAs. Because malignant cells show dependence on the dysregulated expression of miRNA genes, which in turn control or are controlled by the dysregulation of multiple protein-coding oncogenes or tumour suppressor genes, these small RNAs provide important opportunities for the development of future miRNA-based therapies.

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Figure 1: MicroRNA genes map to chromosomal regions that are involved in alterations in human cancer.
Figure 2: Role of the miR-106b–25 and miR-17–92 clusters in the control of transforming growth factor-β signalling.

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Author information

Authors and Affiliations

  1. Department of Molecular Virology, Immunology and Medical Genetics, The Ohio State University Medical Center, 410 West 10th Avenue, Columbus, 43210, Ohio, USA

    Carlo M. Croce

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  1. Carlo M. Croce
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Related links

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DATABASES

miRBase

lin-4

miR-155

miR-15a

miR-15b

miR-16-1

miR-16-2

miR-17

miR-18a

miR-19a

miR-19b-1

miR-20a

miR-221

miR-222

miR-34a

miR-34b

miR-34c

miR-92a-1

Glossary

CpG island

A sequence of at least 200 bp with more CpG sites than would be expected for its GC content. These sequences are often GC rich, are typically undermethylated and are found upstream of many mammalian genes.

RNA-induced silencing complex

An Argonaute protein–small RNA complex that inhibits the translation of target RNAs through degradative or non-degradative mechanisms.

Indolent

In medical terms, slow to develop or heal.

Syngeneic mice

Mice that are genetically identical. Cells can be transferred between syngeneic mice without provoking an immune response.

Liposome

An artificial lipid vesicle. Liposomes fuse with the cell membrane to deliver their contents, such as DNA for gene therapy.

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Croce, C. Causes and consequences of microRNA dysregulation in cancer. Nat Rev Genet 10, 704–714 (2009). https://doi.org/10.1038/nrg2634

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