Printer Friendly

MicroRNAs regulate expression of oncogenes.

Featured Article: Johnson SM, Grosshans H, Shingara J, Byrom M, Jarvis R, Cheng A, Labourier E, et al. RAS is regulated by the let-7 microRNA family. Cell 2005;120:635-47. (2)

Today, we fully appreciate that microRNAs (miRNAs) (3) represent a paradigm shift in our understanding of gene expression and disease, but it was not always this way. miRNAs are small noncoding RNAs belonging to a novel class of regulatory molecules in plants and animals that control the expression of hundreds of target mRNA transcripts. Thousands of known miRNAs regulate gene expression by binding to imperfect complementary sites within the 3' untranslated regions (UTRs) of their target protein-coding mRNAs and repressing the expression of these genes at the level of mRNA stability and translation (1). Recent progress has revealed that miRNAs are involved in the regulation of most biological functions, including development, life span, and metabolism, and their dysregulation contributes, not surprisingly, to many types of disease, notably cancer (2). For example, certain miRNAs regulate processes important for cell growth, division, differentiation, survival, and migration--all processes that go awry in cancer. In addition, several key miRNA genes known to be amplified, deleted, or misexpressed in cancer (3) act in pathways important for cancer progression and metastasis. We now know that miRNAs in fact act as oncogenes and tumor suppressors.

let-7 was the first known human miRNA (4).In 2005, when our Cell report was published, it was known that let-7 was required for the normal cell differentiation of stem cells in the model organism Caenorhabditis elegans (5) and that multiple human genes encoding let-7 family members mapped to regions of the genome with known deletions in cancer, especially lung and breast cancer (3). This finding suggested that let-7 might be a tumor suppressor, but there was no mechanism of action for this miRNA (or any other) in cancer.

The results published in our Cell report, in collaboration with David Brown's group at Ambion, showed for the first time that miRNAs could regulate cellular oncogene mRNAs. We showed initially in C. elegans and subsequently in human cells that let-7 regulates the RAS oncogenes through complementary sites in their RNAs' 3' UTRs. In C. elegans, we showed genetically that loss of RAS suppressed let-7 [4] mutant phenotypes in the skin and vulval stem cells. The RAS 3' UTR contained multiple let-7-complementary sites and restricted reporter gene expression in a let-7-dependent manner. We found that miR-84, a let-7 family member, was largely absent in the primitive primary vulval precursor cell at the time that RAS specified the primary vulval fate in that cell, and that miR-84 overproduction suppressed the multivulva phenotype of activating RAS mutations. Remarkably, the 3' UTRs of the 3 human RAS genes [HRAS (v-Ha-ras Harvey rat sarcoma viral oncogene homolog), KRAS (v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog), and NRAS (neuroblastoma RAS viral (v-ras) oncogene homolog)] contained multiple let-7--complementary sites, allowing let-7 to regulate RAS expression. We also showed that let-7 was produced at low concentrations in lung tumor samples relative to those of normal lung tissue from the same patient, whereas the concentration of RAS protein was significantly higher in lung tumors. These results provided a likely mechanism for let-7 to function as a tumor suppressor in cancer via negative regulation of RAS oncogenes.

Subsequent work revealed that let-7 regulates a number of other oncogenes, including CCND2 (cyclin D2), CDK6 (cyclin-dependent kinase 6), CDC25 [cell division cycle 25 homolog C (S. pombe)], and MYC [v-myc myelocytomatosis viral oncogene homolog (avian)], and the gene encoding let-7 is expressed at low levels in multiple different cancers, such as breast cancers and in breast cancer stem cells. Its misexpression patterns have also been shown to act as biomarkers of cancer outcome.

I believe this publication is highly cited for several reasons. First, it introduced a number of useful tools for miRNA studies, including premiRs (miRNA mimics used to increase miRNA function) and antimiRs (antisense molecules designed to inhibit miRNA function). Second, it popularized the use of 3' UTR reporter gene fusions for studying miRNA activity at 3' UTRs. Third, and most importantly, it showed for the first time that miRNAs regulate important cancer genes and fit within cancer pathways. Consequently, this publication was partly responsible for launching a new field of cancer biology and cancer therapeutics that has culminated in the use of let-7 as a novel, natural anticancer agent (6).

Author Contributions: All authors confirmed they have contributed to the intellectual content of this paper and have met the following 3 requirements: (a) significant contributions to the conception and design, acquisition of data, or analysis and interpretation of data; (b) drafting or revising the article for intellectual content; and (c) final approval of the published article.

Authors' Disclosures or Potential Conflicts of Interest: Upon manuscript submission, all authors completed the author disclosure form. Disclosures and/or potential conflicts of interest:

Employment or Leadership: None declared.

Consultant or Advisory Role: F.J. Slack, Mira Dx and Mirna Rx.

Stock Ownership: F.J. Slack, Mira Dx and Mirna Rx.

Honoraria: None declared.

Research Funding: F.J. Slack, NIH (grant nos. GM062594 and CA157749).

Expert Testimony: None declared.

Other Remuneration: F.J. Slack is an inventor on patents (US 07893034/US 07741306) that describe the use of technology derived from this publication.

References

(1.) Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004;116:281-97.

(2.) Esquela-Kerscher A, Slack FJ. Oncomirs--microRNAs with a role in cancer. Nat Rev Cancer 2006;6:259-69.

(3.) Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, et al. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A 2004;101:2999-3004.

(4.) Pasquinelli AE, Reinhart BJ, Slack F, Martindale MQ, Kuroda MI, Maller B, et al. Conservation of the sequence and temporal expression of let-7 hetero chronic regulatory RNA. Nature 2000;408:86-9.

(5.) Reinhart BJ, Slack FJ, Basson M, Pasquinelli AE, Bettinger JC, Rougvie AE, et al. The 21-nucleotide let-7 RNA regulates developmental timing in Caenorhabditis elegans. Nature 2000;403:901-6.

(6.) Esquela-Kerscher A, Trang P, Wiggins JF, Patrawala L, Cheng A, Ford L, et al. The let-7 microRNA reduces tumor growth in mouse models of lung cancer. Cell Cycle 2008;7:759-64.

Frank J. Slack [1] *

[1] Department of Molecular, Cellular and Developmental Biology, Yale University, New Haven, CT.

* Address correspondence to the author at: Department of Molecular, Cellular and Developmental Biology, Yale University, P.O. Box 208103, New Haven, CT 06520. E-mail frank.slack@yale.edu.

[2] This article has been cited more than 1370 times since publication.

[3] Nonstandard abbreviations: miRNA, microRNA; UTR, untranslated region; premiR, miRNA mimic used to increase miRNA function; antimiR, antisense molecule designed to inhibit miRNA function.

[4] Genes: let-7; HRAS, v-Ha-ras Harvey rat sarcoma viral oncogene homolog; KRAS, v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog; NRAS, neuroblastoma RAS viral (v-ras) oncogene homolog; CCND2, cyclin D2; CDK6, cyclin-dependent kinase 6; CDC25, cell division cycle 25 homolog C (S. pombe); MYC, v-myc myelocytomatosis viral oncogene homolog (avian).

Received March 26, 2012; accepted April 9, 2012.

Previously published online at DOI: 10.1373/clinchem.2011.181016
COPYRIGHT 2013 American Association for Clinical Chemistry, Inc.
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2013 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:Citation Classic
Author:Slack, Frank J.
Publication:Clinical Chemistry
Article Type:Report
Geographic Code:1USA
Date:Jan 1, 2013
Words:1190
Previous Article:Integrated analyses of proteins and their glycans in a magnetic bead-based multiplex assay format.
Next Article:Cardiac and inflammation biomarker profile after initiation of adjuvant trastuzumab therapy.
Topics:

Terms of use | Copyright © 2018 Farlex, Inc. | Feedback | For webmasters