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MicroRNA biogenesis pathways in cancer

Key Points

  • MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate target gene expression through mRNA degradation or translational inhibition.

  • The miRNA biogenesis pathway is a multi-step process that has a crucial role in regulating miRNA maturation.

  • miRNAs can be oncogenes or tumour suppressors and are globally repressed in cancers.

  • Mutations in or dysregulation of components of the miRNA biogenesis pathway are frequently found in cancers and have important functions in oncogenesis.

  • Important oncogenic signalling proteins — such as LIN28A, LIN28B, epidermal growth factor receptor (EGFR) and Hippo — target miRNA biogenesis in cancers.

  • The targeting of abnormal miRNA biogenesis pathways is a novel, promising therapeutic strategy for cancers.

Abstract

MicroRNAs (miRNAs) are critical regulators of gene expression. Amplification and overexpression of individual 'oncomiRs' or genetic loss of tumour suppressor miRNAs are associated with human cancer and are sufficient to drive tumorigenesis in mouse models. Furthermore, global miRNA depletion caused by genetic and epigenetic alterations in components of the miRNA biogenesis machinery is oncogenic. This, together with the recent identification of novel miRNA regulatory factors and pathways, highlights the importance of miRNA dysregulation in cancer.

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Figure 1: Overview of miRNA biogenesis pathway.
Figure 2: Mutation of the miRNA biogenesis pathway in cancer.
Figure 3: Dysregulated miRNA biogenesis in cancer.

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Acknowledgements

S.L. is a Damon Runyon-Sohn Pediatric Cancer Research Fellow supported by the Damon Runyon Cancer Research Foundation (DRSG-7-13). R.I.G. is supported by grants from the US National Cancer Institute (NCI) (R01CA163467) and the American Cancer Society (121635-RSG-11-175-01-RMC).

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Glossary

3′ untranslated region

(3′ UTR). The non-coding region of mRNA between the translation termination codon and the poly(A) tail. The 3′ UTR often contains regulatory elements, such as miRNA binding sites, for post-transcriptional regulation of gene expression.

Ribonuclease III

(RNase III). Enzymes that can specifically recognize and cleave double-stranded RNA with their ribonuclease III domains.

Germline mutations

Heritable gene mutations that occur in germline tissues.

Somatic mutations

Gene mutations that occur in non-germline tissues that are not inherited.

Post-transcriptional gene silencing

A gene-silencing effect that controls gene expression after transcription, often mediated by small non-coding RNAs such as small interfering RNAs (siRNAs) and microRNAs (miRNAs).

Epithelial–mesenchymal transition

(EMT). A process that occurs during development or cancer progression in which the epithelial cells lose their cell polarity and cell–cell adhesion to become mesenchymal cells with migratory and invasive characteristics.

CpG islands

Genetic regions with high CpG content, often located at the gene promoter, that have important functions in regulating gene expression.

Microsatellite

Short (2–5 bp) tandem repeat of DNA that can be used as a genetic marker.

Loss of heterozygosity

(LOH). Deletion or mutation of the normal allele of a gene, of which the other allele is already deleted or inactivated, resulting in loss of both alleles of the gene.

Cold-shock domain

A protein domain of 70 amino acids that is often found in DNA- or RNA-binding proteins and that functions to protect cells during cold temperatures.

Cys-Cys-His-Cys (CCHC)-type zinc-fingers

Protein domains that are found in RNA-binding proteins or single-stranded DNA-binding proteins.

Terminal uridylyltransferases

(TUTases). Enzymes that catalyse the addition of one or more uridine monophosphate (UMP) molecules to the 3′ end of RNA.

Oncofetal genes

Genes that are typically highly expressed during fetal development and repressed in adult life, and reactivated in cancers.

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Lin, S., Gregory, R. MicroRNA biogenesis pathways in cancer. Nat Rev Cancer 15, 321–333 (2015). https://doi.org/10.1038/nrc3932

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