RNA in cancer

Abstract

While the processing of mRNA is essential for gene expression, recent findings have highlighted that RNA processing is systematically altered in cancer. Mutations in RNA splicing factor genes and the shortening of 3′ untranslated regions are widely observed. Moreover, evidence is accumulating that other types of RNAs, including circular RNAs, can contribute to tumorigenesis. In this Review, we highlight how altered processing or activity of coding and non-coding RNAs contributes to cancer. We introduce the regulation of gene expression by coding and non-coding RNA and discuss both established roles (microRNAs and long non-coding RNAs) and emerging roles (selective mRNA processing and circular RNAs) for RNAs, highlighting the potential mechanisms by which these RNA subtypes contribute to cancer. The widespread alteration of coding and non-coding RNA demonstrates that altered RNA biogenesis contributes to multiple hallmarks of cancer.

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Fig. 1: Processing and nuclear export of mRNA.
Fig. 2: Formation and functions of miRNAs.
Fig. 3: lncRNAs and their effects in cancers.
Fig. 4: Formation and functions of circRNAs.
Fig. 5: RNA splicing in cancer.
Fig. 6: Polyadenylation and mRNA export in cancer.

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Acknowledgements

The authors thank W. Filipowicz and P. Gregory for critically reading the manuscript. They gratefully acknowledge funding from the Australian National Health and Medical Research Council (GNT1127745 to V.O.W, and GNT1126711 and research fellowship GNT1118170 to GJG). V.O.W. is supported by an innovation fellowship from veski and a mid-career fellowship from the Victorian Cancer Agency.

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Correspondence to Gregory J. Goodall or Vihandha O. Wickramasinghe.

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Glossary

Spliceosome

Executes RNA splicing reactions and is composed of a number of distinct small nuclear ribonucleoprotein complexes containing proteins that are stably bound to uridine-rich small nuclear RNA molecules. It is dynamically remodelled during the splicing reaction.

Genomic instability

An underlying hallmark of cancers is their genomic instability, which is associated with a greater tendency to accumulate DNA damage. Genomic instability and mutation are an enabling characteristic driving tumour progression.

TREX and TREX2

Export of mRNA from the nucleus to the cytoplasm requires the transcription–export complexes TREX and TREX2, which recognize mRNAs during their biogenesis. Cargo mRNAs are transferred to the transport factors NXF1 and p15 for transit through nuclear pores. Expression of TREX components such as ALYREF and THOC1 and the TREX2 component GANP is altered in cancer.

Epithelial-to-mesenchymal transition

(EMT). A change in cell phenotype that normally occurs during embryogenesis as part of tissue remodelling, and during wound healing, but can also be recapitulated by cancers. EMT confers on cancer cells the ability to invade and metastasize, and also contributes to chemoresistance.

M1 macrophage

A proinflammatory macrophage that secretes inflammatory cytokines such as IL-1, IL-6, IL-12 and tumour necrosis factor (TNF).

Genotoxic stress

Cellular exposure to DNA-damaging agents, which elicits biochemical responses to repair DNA damage, enhancing cell survival or leading to cell death.

Nucleators

Molecules that nucleate complex formation by binding to multiple binding partners.

3′ end processing complex

Interacts with sequence motifs in nascent RNAs to determine the site of cleavage and polyadenylation and comprising a number of subcomplexes (cleavage and polyadenylation factor, cleavage factors 1 and 2 and cleavage stimulation factor). Following endonucleolytic cleavage, the poly(A) tail is synthesized on the 3′ end of the cleaved product by poly(A) polymerase.

Nuclear pore complexes

Proteins and RNA molecules are transported between the nucleus and cytoplasm through nuclear pore complexes. They are ~110-MDa macromolecular complexes with an overall octagonal symmetry and consist of several copies of ~30 proteins called ‘nucleoporins’. mRNA export factors such as NXF1 directly interact with nucleoporins, which have regions rich in phenylalanine–glycine repeats (FG nucleoporins) that line the inner part of the channel and help to move the cargo through the pore.

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Goodall, G.J., Wickramasinghe, V.O. RNA in cancer. Nat Rev Cancer (2020). https://doi.org/10.1038/s41568-020-00306-0

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