Elsevier

The Lancet Oncology

Volume 13, Issue 6, June 2012, Pages e249-e258
The Lancet Oncology

Review
microRNAs in cancer management

https://doi.org/10.1016/S1470-2045(12)70073-6Get rights and content

Summary

Since the identification of microRNAs (miRNAs) in 1993, and the subsequent discovery of their highly conserved nature in 2000, the amount of research into their function—particularly how they contribute to malignancy—has greatly increased. This class of small RNA molecules control gene expression and provide a previously unknown control mechanism for protein synthesis. As such, it is unsurprising that miRNAs are now known to play an essential part in malignancy, functioning as tumour suppressors and oncogenes. This Review summarises the present understanding of how miRNAs operate at the molecular level; how their dysregulation is a crucial part of tumour formation, maintenance, and metastasis; how they can be used as biomarkers for disease type and grade; and how miRNA-based treatments could be used for diverse types of malignancies.

Introduction

MicroRNAs (miRNAs) are small non-coding RNAs (21–23 nucleotides) encoded in the genome of plants, invertebrates, and vertebrates. These small molecules mainly bind imperfectly to the 3′ untranslated region of target messenger RNAs (mRNAs).1 They negatively regulate gene expression post-transcriptionally by inhibiting translation and causing degradation of target mRNA. More than a thousand miRNAs exist in the human genome and each one can potentially regulate hundreds of mRNAs. miRNAs play an important part in many cellular processes, such as differentiation, proliferation, apoptosis, and stress response. Additionally, they are key regulators in many diseases—eg, neurological disorders, heart disease, vascular diseases, viral infection, and cancer.1

The discovery of miRNAs led to a worldwide research effort to establish their roles in cancer. The results have been impressive, collectively showing that miRNAs form central nodal points in cancer development pathways. miRNAs regulate molecular pathways in cancer by targeting various oncogenes and tumour suppressors,1 and have a role in cancer-stem-cell biology, angiogenesis, the epithelial–mesenchymal transition, metastasis, and drug resistance. Loss of one miRNA can have substantial effects; dysregulation can cause tumorigenesis (figure 1). Because miRNA-based regulation is dependent on expression of its mRNA targets, which are not always ubiquitously expressed, an miRNA can have effects specific to cells types and conditions.

Researchers are beginning to uncover the complex role that miRNAs have in malignant disease. However, little detailed, in-vivo work has been reported. An improved understanding of miRNA mechanisms in tumorigenesis and cancer maintenance would thus provide invaluable information about key cancer pathways, cancer diagnostics, and disease prognosis. Importantly, this knowledge could be used in the development of anticancer therapies.

Section snippets

Gene regulation and mutations

In 2002, the first report about the role of miRNAs in cancer established that the gene cluster containing the miRNAs miR-15 and miR-16 is deleted in most people with chronic lymphocytic leukaemia (CLL).2 Further studies have shown that miR-15 and miR-16 act as tumour suppressors by targeting the oncogene BCL2, which encodes a protein involved in cell survival.3

Conversely, miR-21 is an excellent example of an oncogenic miRNA (a so-called oncomir). It is overexpressed in most cancers—eg, breast

Diagnosis and classification

The development of cytogenetic, immunological, and molecular methods to supplement the traditional morphological classification systems has refined the identification of cancer subtypes.37 For instance, transcriptome profiling studies of different cancer types with large-scale genomic approaches showed that a 97-gene expression profile is better for classification of breast cancer histological grade than are lymph-node status and tumour size.37 Gene-expression profiling has also led to

miRNAs as cancer treatment

The development of new treatments has contributed substantially to increased 5-year survival and the reduction in overall mortality rates.62, 69 However, although the classification of cancers has become increasingly diversified, the variety and specificity of treatment options has lagged behind. The same treatment is indicated for cancers with similar clinical phenotypes, even though substantial variation exists in the molecular phenotype that will affect treatment success. With the progress

Conclusion

The discovery of miRNAs has changed the way control of gene expression is thought about and, perhaps more importantly, has set a precedent for the development of new diagnostic methods and treatments of diseases, including malignancies. In the short term, the validation of prognostic and diagnostic miRNA panels in large cohort studies would enable their introduction into the clinic setting. Tailoring of treatment regimens to specific cancers would maximise the likelihood of success. In the long

Search strategy and selection criteria

Data for this Review were identified by searches of PubMed with the term “microRNA” in combination with “cancer”, “in vivo”, “circulating”, “systemic delivery”, “therapeutics”, or “LNA”. Reference lists of reports identified were also searched. Only articles published in English and relevant to the Review were included. We used no date restrictions.

References (87)

  • JA Freudenberg et al.

    The role of HER2 in early breast cancer metastasis and the origins of resistance to HER2-targeted therapies

    Exp Mol Pathol

    (2009)
  • M Hanke et al.

    A robust methodology to study urine microRNA as tumor marker: microRNA-126 and microRNA-182 are related to urinary bladder cancer

    Urol Oncol

    (2010)
  • F Berrino et al.

    Survival for eight major cancers and all cancers combined for European adults diagnosed in 1995–99: results of the EUROCARE-4 study

    Lancet Oncol

    (2007)
  • P Trang et al.

    Systemic delivery of tumor suppressor microRNA mimics using a neutral lipid emulsion inhibits lung tumors in mice

    Mol Ther

    (2011)
  • K Nishina et al.

    Efficient in vivo delivery of siRNA to the liver by conjugation of alpha-tocopherol

    Mol Ther

    (2008)
  • H Maeda et al.

    Vascular permeability enhancement in solid tumor: various factors, mechanisms involved and its implications

    Int Immunopharmacol

    (2003)
  • L Brannon-Peppas et al.

    Nanoparticle and targeted systems for cancer therapy

    Adv Drug Deliv Rev

    (2004)
  • DL Nida et al.

    Fluorescent nanocrystals for use in early cervical cancer detection

    Gynecol Oncol

    (2005)
  • F Takeshita et al.

    Systemic delivery of synthetic microRNA-16 inhibits the growth of metastatic prostate tumors via downregulation of multiple cell-cycle genes

    Mol Ther

    (2010)
  • GA Calin et al.

    Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia

    Proc Natl Acad Sci USA

    (2002)
  • A Cimmino et al.

    miR-15 and miR-16 induce apoptosis by targeting BCL2

    Proc Natl Acad Sci USA

    (2005)
  • ML Si et al.

    miR-21-mediated tumor growth

    Oncogene

    (2007)
  • MV Iorio et al.

    MicroRNA gene expression deregulation in human breast cancer

    Cancer Res

    (2005)
  • JA Chan et al.

    MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells

    Cancer Res

    (2005)
  • AJ Schetter et al.

    MicroRNA expression profiles associated with prognosis and therapeutic outcome in colon adenocarcinoma

    JAMA

    (2008)
  • PP Medina et al.

    OncomiR addiction in an in vivo model of microRNA-21-induced pre-B-cell lymphoma

    Nature

    (2010)
  • G Gabriely et al.

    MicroRNA 21 promotes glioma invasion by targeting matrix metalloproteinase regulators

    Mol Cell Biol

    (2008)
  • J Sarkar et al.

    MicroRNA-21 plays a role in hypoxia-mediated pulmonary artery smooth muscle cell proliferation and migration

    Am J Physiol Lung Cell Mol Physiol

    (2010)
  • KA O'Donnell et al.

    c-Myc-regulated microRNAs modulate E2F1 expression

    Nature

    (2005)
  • V Olive et al.

    miR-19 is a key oncogenic component of mir-17-92

    Genes Dev

    (2009)
  • TC Chang et al.

    Lin-28B transactivation is necessary for Myc-mediated let-7 repression and proliferation

    Proc Natl Acad Sci USA

    (2009)
  • B Boyerinas et al.

    The role of let-7 in cell differentiation and cancer

    Endocr Relat Cancer

    (2010)
  • DC Corney et al.

    MicroRNA-34b and microRNA-34c are targets of p53 and cooperate in control of cell proliferation and adhesion-independent growth

    Cancer Res

    (2007)
  • A Watahiki et al.

    MicroRNAs associated with metastatic prostate cancer

    PLoS One

    (2011)
  • C Liu et al.

    The microRNA miR-34a inhibits prostate cancer stem cells and metastasis by directly repressing CD44

    Nat Med

    (2011)
  • M Toyota et al.

    Epigenetic silencing of microRNA-34b/c and B-cell translocation gene 4 is associated with CpG island methylation in colorectal cancer

    Cancer Res

    (2008)
  • IG Cannell et al.

    p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication

    Proc Natl Acad Sci USA

    (2010)
  • LJ Chin et al.

    A SNP in a let-7 microRNA complementary site in the KRAS 3′ untranslated region increases non-small cell lung cancer risk

    Cancer Res

    (2008)
  • SE Godshalk et al.

    A variant in a microRNA complementary site in the 3′ UTR of the KIT oncogene increases risk of acral melanoma

    Oncogene

    (2011)
  • S Soltanian et al.

    Cancer stem cells and cancer therapy

    Tumour Biol

    (2011)
  • N Takebe et al.

    Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways

    Nat Rev Clin Oncol

    (2011)
  • F Yu et al.

    Mir-30 reduction maintains self-renewal and inhibits apoptosis in breast tumor-initiating cells

    Oncogene

    (2010)
  • Z Hua et al.

    MiRNA-directed regulation of VEGF and other angiogenic factors under hypoxia

    PLoS One

    (2006)
  • Cited by (678)

    View all citing articles on Scopus

    These authors contributed equally

    View full text