MicroRNA: a prognostic biomarker and a possible druggable target for circumventing multidrug resistance in cancer chemotherapy

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Abstract

Multidrug resistance (MDR) is a major obstacle to successful cancer treatment. It is often associated with an increased efflux of a variety of structurally unrelated anticancer drugs by ATP-binding cassette (ABC) transporters including P-gp, ABCG2 and MRP1. MicroRNAs (miRNAs) are small non-coding RNAs that govern posttranscriptional regulation of target genes by interacting with specific sequences in their 3′ untranslated region (3′UTR), thereby promoting mRNA degradation or suppressing translation. Accumulating evidence suggests that alterations in miRNAs contribute to resistance to anticancer drugs. While miRNAs are well-known to be dysregulated in cancer, recent literature revealed that miRNA levels in biological samples may be correlated with chemotherapy response. This review summarized the coordinated network by which miRNA regulated MDR transporters. The usefulness of miRNAs as prognostic biomarkers for predicting chemotherapeutic outcome is discussed. MiRNAs may also represent druggable targets for circumvention of MDR.

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Most cited references 93

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Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.

Xiaohui Xie, Jun Lu, E J Kulbokas … (2005)

Comprehensive identification of all functional elements encoded in the human genome is a fundamental need in biomedical research. Here, we present a comparative analysis of the human, mouse, rat and dog genomes to create a systematic catalogue of common regulatory motifs in promoters and 3' untranslated regions (3' UTRs). The promoter analysis yields 174 candidate motifs, including most previously known transcription-factor binding sites and 105 new motifs. The 3'-UTR analysis yields 106 motifs likely to be involved in post-transcriptional regulation. Nearly one-half are associated with microRNAs (miRNAs), leading to the discovery of many new miRNA genes and their likely target genes. Our results suggest that previous estimates of the number of human miRNA genes were low, and that miRNAs regulate at least 20% of human genes. The overall results provide a systematic view of gene regulation in the human, which will be refined as additional mammalian genomes become available.

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A large-scale analysis of mRNA polyadenylation of human and mouse genes

Bin Tian, Jun Hu, Haibo Zhang … (2005)

mRNA polyadenylation is a critical cellular process in eukaryotes. It involves 3′ end cleavage of nascent mRNAs and addition of the poly(A) tail, which plays important roles in many aspects of the cellular metabolism of mRNA. The process is controlled by various cis-acting elements surrounding the cleavage site, and their binding factors. In this study, we surveyed genome regions containing cleavage sites [herein called poly(A) sites], for 13 942 human and 11 155 mouse genes. We found that a great proportion of human and mouse genes have alternative polyadenylation (∼54 and 32%, respectively). The conservation of alternative polyadenylation type or polyadenylation configuration between human and mouse orthologs is statistically significant, indicating that alternative polyadenylation is widely employed by these two species to produce alternative gene transcripts. Genes belonging to several functional groups, indicated by their Gene Ontology annotations, are biased with respect to polyadenylation configuration. Many poly(A) sites harbor multiple cleavage sites (51.25% human and 46.97% mouse sites), leading to heterogeneous 3′ end formation for transcripts. This implies that the cleavage process of polyadenylation is largely imprecise. Different types of poly(A) sites, with regard to their relative locations in a gene, are found to have distinct nucleotide composition in surrounding genomic regions. This large-scale study provides important insights into the mechanism of polyadenylation in mammalian species and represents a genomic view of the regulation of gene expression by alternative polyadenylation.

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miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation.

Michela Garofalo, Gianpiero Di Leva, Giulia Romano … (2009)

Lung and liver cancers are among the most deadly types of cancer. Despite improvements in treatment over the past few decades, patient survival remains poor, underlining the need for development of targeted therapies. MicroRNAs represent a class of small RNAs frequently deregulated in human malignancies. We now report that miR-221&222 are overexpressed in aggressive non-small cell lung cancer and hepatocarcinoma cells, as compared with less invasive and/or normal lung and liver cells. We show that miR-221&222, by targeting PTEN and TIMP3 tumor suppressors, induce TRAIL resistance and enhance cellular migration through the activation of the AKT pathway and metallopeptidases. Finally, we demonstrate that the MET oncogene is involved in miR-221&222 activation through the c-Jun transcription factor.

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Author and article information

Journal

Journal ID (nlm-ta): J Biomed Sci

Journal ID (iso-abbrev): J. Biomed. Sci

Title: Journal of Biomedical Science

Publisher: BioMed Central

ISSN (Print): 1021-7770

ISSN (Electronic): 1423-0127

Publication date Collection: 2013

Publication date (Electronic): 20 December 2013

Volume: 20

Issue: 1

Page: 99

Affiliations

[1 ]School of Pharmacy, Room 801 N, Lo Kwee-Seong Integrated Biomedical Sciences Building, Faculty of Medicine, The Chinese University of Hong Kong, Area 39, Shatin, New Territories, Hong Kong SAR, China

Article

Publisher ID: 1423-0127-20-99

DOI: 10.1186/1423-0127-20-99

PMC ID: 3878201

PubMed ID: 24358977

SO-VID: 853b81fe-96ee-41ba-933c-e5b4c7b99def

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This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

MicroRNA: a prognostic biomarker and a possible druggable target for circumventing multidrug resistance in cancer chemotherapy

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Cancer Immunotherapy

Most cited references 93

Systematic discovery of regulatory motifs in human promoters and 3' UTRs by comparison of several mammals.

A large-scale analysis of mRNA polyadenylation of human and mouse genes

miR-221&222 regulate TRAIL resistance and enhance tumorigenicity through PTEN and TIMP3 downregulation.

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