MicroRNAs May Affect Cell Survival after Chemotherapy

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Molecular Cancer Therapeutics 7, 1-9, January 1, 2008. Published

Online First January 9, 2008;

doi: 10.1158/1535-7163.MCT-07-0573

© 2008 American Association for Cancer Research

Spotlight on Molecular Profiling

MicroRNAs modulate the chemosensitivity of tumor cells

E. Blower1, Ji-Hyun Chung1, ph S. Verducci2,3, Shili Lin2,3,

Jong-Kook Park4, Zunyan Dai1, Chang-Gong Liu5, D. Schmittgen4,

C. Reinhold6, Carlo M. Croce5, N. Weinstein6 and Wolfgang

Sadee1

1 Program of Pharmacogenomics, Department of Pharmacology and the

Comprehensive Cancer Center, College of Medicine, 2 Department of

Statistics, 3 Mathematical Biosciences Institute, 4 College of

Pharmacy, and 5 Department of Molecular Virology, Immunology and

Medical Genetics, Comprehensive Cancer Center, The Ohio State

University, Columbus, Ohio; and 6 Genomics and Bioinformatics Group,

Laboratory of Molecular Pharmacology, Center for Cancer Research,

National Cancer Institute, Bethesda, land

Abstract

MicroRNAs are strongly implicated in such processes as development,

carcinogenesis, cell survival, and apoptosis. It is likely, therefore,

that they can also modulate sensitivity and resistance to anticancer

drugs in substantial ways.

To test this hypothesis, we studied the pharmacologic roles of three

microRNAs previously implicated in cancer biology (let-7i, mir-16, and

mir-21) and also used in silico methods to test pharmacologic microRNA

effects more broadly. In the experimental system, we increased the

expression of individual microRNAs by transfecting their precursors

(which are active) or suppressed the expression by transfection of

antisense oligomers.

In three NCI-60 human cancer cell lines, a panel of 60 lines used for

anticancer drug discovery, we assessed the growth-inhibitory potencies

of 14 structurally diverse compounds with known anticancer activities.

Changing the cellular levels of let-7i, mir-16, and mir-21 affected

the potencies of a number of the anticancer agents by up to 4-fold.

The effect was most prominent with mir-21, with 10 of 28 cell-compound

pairs showing significant shifts in growth-inhibitory activity.

Varying mir-21 levels changed potencies in opposite directions

depending on compound class; indicating that different mechanisms

determine toxic and protective effects.

In silico comparison of drug potencies with microRNA expression

profiles across the entire NCI-60 panel revealed that ~30 microRNAs,

including mir-21, show highly significant correlations with numerous

anticancer agents. Ten of those microRNAs have already been implicated

in cancer biology.

Our results support a substantial role for microRNAs in anticancer

drug response, suggesting novel potential approaches to the

improvement of chemotherapy. [Mol Cancer Ther 2008;7(1):1–9]