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MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy

Nature Reviews Cancer volume 11, pages 849–864 (2011)Cite this article

Subjects

Key Points

  • Recently generated germline transgenic and knockout mice have provided a detailed view of the implication of the gain or loss of individual microRNAs (miRNAs), miRNA clusters and the miRNA processing machinery in cancer. These have been classified as oncogenic (such as miR-155, miR-21 and miR-17∼92), tumour-suppressive (such as miR-15∼16, LIN28, DICER) or context-dependent (such as miR-146 and miR-29).

  • miRNAs and the miRNA processing machinery are involved in all stages of metastatic disease. Some — such as miR-200, the LIN28–let-7 interaction and DICER — contribute to both metastasis and primary tumour development, whereas others, such as miR-31 and miR-10b, are unique to metastasis.

  • Studies uncovering miRNA function have led to their therapeutic application. Delivering tumour-suppressive miRNAs and silencing oncogenic miRNAs with antagomirs has been successful in various mouse models. Many of these studies began with overexpression and knockdown strategies and have since progressed to delivering miRNA-based molecules intranasally, intratumorally or systemically.

  • Expanding on their therapeutic application, miRNAs are also being evaluated for their ability to sensitize cancers to chemotherapeutics. Much of this work is being accomplished in cell culture, with the hope that it will soon transition into preclinical model systems.

Abstract

In normal cells multiple microRNAs (miRNAs) converge to maintain a proper balance of various processes, including proliferation, differentiation and cell death. miRNA dysregulation can have profound cellular consequences, especially because individual miRNAs can bind to and regulate multiple mRNAs. In cancer, the loss of tumour-suppressive miRNAs enhances the expression of target oncogenes, whereas increased expression of oncogenic miRNAs (known as oncomirs) can repress target tumour suppressor genes. This realization has resulted in a quest to understand the pathways that are regulated by these miRNAs using in vivo model systems, and to comprehend the feasibility of targeting oncogenic miRNAs and restoring tumour-suppressive miRNAs for cancer therapy. Here we discuss progress in using mouse models to understand the roles of miRNAs in cancer and the potential for manipulating miRNAs for cancer therapy as these molecules make their way towards clinical trials.

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Figure 1: Opposing roles of miRNAs in cancer.
Figure 2: RNAs are subject to genomic, transcriptional and post-transcriptional modes of regulation.
Figure 3: RNA expression patterns dictate miRNA repressibility in cells.
Figure 4: miRNAs that contribute to metastasis.

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Acknowledgements

A.L.K. was supported by a US National Institutes of Health (NIH) grant (1F32CA153885-01) and an American Cancer Society Postdoctoral Fellowship (120,766-PF-11-244-01-TBG). F.J.S. was supported by a grant from the US National Cancer Institute (NCI) (1R01CA131301).

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  1. Department of Molecular, Cellular and Developmental Biology, Yale University, PO BOX 208103, New Haven, 06520, Connecticut, USA

    Andrea L. Kasinski & Frank J. Slack

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  1. Andrea L. Kasinski
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Correspondence to Frank J. Slack.

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F.J.S. is a consultant to Mirna Therapeutics, Inc. and Mira Dx, Inc. A.L.K. declares no competing financial interests.

Related links

Glossary

miR-17∼92

This is a cluster of miRNAs containing miR-17, miR-20a, miR-18a, miR-19a, miR-19b and miR-92a. Clusters are expressed as a polycistronic message from a single promoter; this is indicated in the text by a tilde (∼).

Paralogues

Genes that are derived from the same ancestral gene but that reside in different locations in the same genome.

DICER

An endoribonuclease that cleaves precursor microRNAs (pre-miRNAs) into 20–25 nucleotide double-stranded RNAs.

Adaptive immune response

The adaptive immune response — also known as specific or acquired immunity — is mediated by antigen-specific lymphocytes and antibodies.

Innate immune response

The innate immune system provides an immediate, non-specific defence against pathogens until an adaptive, pathogen-specific immune response is able to develop.

Nestin promoter

This promoter drives the expression of genes in the central and peripheral nervous system and in myogenic and other tissues.

DMBA–TPA model

A two-stage chemical skin carcinogenesis model using a single dose of the genotoxic carcinogen, 7,12-dimethylbenz(a) anthracene (DMBA), followed by multiple doses of a non-genotoxic tumour-promoter, 12-O-tetradecanoylphorbol-13-acetate (TPA).

Papillomas

Benign tumours of epithelial origin that grow outwards.

Polycistronic

A single transcript that carries the information of several genes.

Fragile site

A site in a chromosome that is susceptible to chromosome breakage and fusion with other chromosomes.

Host gene

A gene containing another gene (such as a microRNA within an intron of a protein-coding gene).

Seed region

Nucleotides 2–7 of the microRNA, typically having 100% complementarity with the target gene.

Xenografts

Grafts of cells or tissues that are transplanted from one species to another.

Haploinsufficient

A phenotype that arises in diploid organisms owing to the loss of only one allele.

Hemizygous

A state of having a single copy of a gene (in a diploid organism).

Epithelial to mesenchymal transition

(EMT). The conversion of polarized, immotile epithelial cells to motile mesenchymal cells. It is characterized by the loss of adhesion, the repression of E-cadherin, the expression of mesenchymal markers and increased cell motility.

Adjuvant

Treatment given in addition to the primary therapy. For cancer treatment, this typically refers to the therapy given after the surgical resection of a tumour.

Antagomirs

Chemically engineered, cholesterol-conjugated single-stranded RNA oligonucleotides that are complementary to microRNAs.

Autochthonous

Formed from endogenous tissue in the correct anatomical location.

Orthotopic

Transplanted into the correct anatomical location.

Silent information regulator 1

(SIRT1). A class-III histone deacetylase that regulates apoptosis in response to genotoxic and oxidative stress.

star strand

(miRNA*). The passenger strand of the mature microRNA (miRNA), originally thought not to be involved in miRNA-induced silencing; however, deep sequencing followed by functional studies have determined that the some of the miRNA* products are abundant and functional.

Selective oestrogen receptor modulator

(SERM). An agent that targets the oestrogen receptors, ERα and ERβ, which are often upregulated in breast cancer.

Docetaxel

A cytotoxic antimicrotubule agent that is used to treat breast, ovarian, prostate and non-small-cell lung cancer.

Gemcitabine

A nucleoside analogue that is used to treat multiple forms of cancer.

Cisplatin

A platinum-containing cytotoxic cancer drug.

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Kasinski, A., Slack, F. MicroRNAs en route to the clinic: progress in validating and targeting microRNAs for cancer therapy. Nat Rev Cancer 11, 849–864 (2011). https://doi.org/10.1038/nrc3166

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