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.
ReviewmicroRNAs in cancer management
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
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p38 MAPK/MK2-mediated induction of miR-34c following DNA damage prevents Myc-dependent DNA replication
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A variant in a microRNA complementary site in the 3′ UTR of the KIT oncogene increases risk of acral melanoma
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Cancer stem cells and cancer therapy
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These authors contributed equally