MicroRNA Signatures as Biomarkers in Cancer

Abstract

Microribonucleic acids (miRNAs) are a class of small noncoding RNAs that regulate gene expression posttranscriptionally and control many biological processes including tumourigenesis. Given that, miRNA levels are heavily dysregulated in tumour tissues, many of these RNAs have been identified as classifiers for particular cancer subtypes. In addition, miRNA gene signatures can provide prognostic value, are associated with tumourigenic processes such as metastasis and can identify certain tumour cell types including drug‐resistant and cancer stem cell populations. To gain a better molecular understanding of therapeutic response and disease relapse, there has been an impetus to develop miRNA biomarker profiles through less invasive strategies (i.e. from serum and other sources) rather than from repeated biopsy near the original tumour site. Through these techniques, miRNAs have been found to exist in cell‐free fractions, in exosomes and in circulating tumour cells. While it is still unclear about the mechanisms guiding the release of miRNAs into the serum and other sources, overall, miRNAs have the potential to be used in understanding the pathogenesis of disease prognosis and for diagnostic purposes and in the development of new therapeutic treatment regimens.

Key Concepts

  • MicroRNAs function as master regulators of gene expression at the posttranscriptional level.
  • MicroRNAs can function as oncogenes or tumour suppressors in a cell‐context‐dependent manner.
  • MicroRNAs are stable, found in serum and other biofluids and make good non‐invasive biomarkers.
  • MicroRNA profiles are associated with therapeutic treatments and disease outcomes.
  • MicroRNAs can themselves be therapeutic agents or therapeutic targets.

Keywords: microRNAs; cancer; biomarker; exosomes; stem cells; oncogene; tumour suppressor; therapeutics; serum; HDL

Figure 1. miRNA biogenesis. miRNAs are transcribed from RNA polymerase II promoters, can be expressed as single monocistronic or polycistronic miRNA clusters and are termed primary miRNAs (pri‐miRNAs). miRNAs can also be located within the introns of other genes and are therefore termed miRtrons. pri‐miRNAs have a characteristic hairpin structure that is recognised by DGCR8 and the RNase type III enzyme DROSHA to generate precursor miRNAs (pre‐miRNAs). These RNAs are exported into the cytoplasm by a Ran‐GTP/Exportin 5 complex where they are processed into miRNA duplexes via the RNase type III enzyme DICER (along with TRBP and PACT). The resultant miRNA duplexes are then incorporated into the RNA‐induced silencing complex (RISC), the major component of which is the Argonaute family proteins (depicted here as AGO2). Here, one strand is selected and processed into a mature miRNA molecule of ∼22 nt in length, which is then guided by AGO2 to the 3′‐UTR of target mRNAs. Full complementary of the miRNA:mRNA target interaction mediates direct cleavage and degradation, whereas imperfect base‐pairing facilitates translational repression owing to deadenylation, polysome stalling and addition mechanisms. In addition, RISC‐bound miRNA:mRNA complexes are stored in P‐bodies and are thought to be sites of storage and/or disintegration. Adapted with permission from Adams et al., (2014) ©Elsevier.
Figure 2. miRNAs in cancer stem cells. Cancer stem cells (CSCs) are a self‐renewing population of cells that differentiate into different tumour cell types, contributing to the overall heterogeneity within the tumour. CSCs also harbour unique properties that protect them from DNA damaging chemo‐ and radiation‐based therapies. In the left panel, a primary tumour is depicted, which is comprised both CSCs and bulk tumour cells, and is surrounded by a niche encompassing stromal cells and blood vessels. Microenvironmental signalling cues associated with hypoxia, and EMT helps cultivate CSC formation. Given CSCs are also slow‐cycling and quiescent in nature, these cells are intrinsically resistant to the effects of DNA damaging agents. Furthermore, CSCs have heightened DNA repair mechanisms, which remove DNA adducts generated by alkylating agents, and have higher levels of multidrug resistance channels that remove drugs from the cell before they are metabolised, all of which reduce the effectiveness of DNA damaging agents on this cell type (middle panel). Given that these mechanisms protect the CSC population, when relapse occurs (right panel), CSCs make up the bulk of the tumour, which is now refractory to various frontline chemotherapeutic regimens. Highlighted in red are some miRNAs known to regulate processes promoting CSC formation and maintenance.
Figure 3. miRNA as circulating biomarkers. miRNAs can be secreted in a regulated manner or passively shed into the extracellular space and possibly involved in cell–cell communication. Extracellular miRNAs are found to be in stable vesicles, such as exosomes and apoptotic bodies, bound to RNA‐binding proteins, such as AGO and HDL, or within CTCs shed from the primary tumour. Exosomes are built by inward budding of the cell membrane of the multivesicular body and by fusion with the plasma membrane. While unclear as to how pre‐ and mature miRNAs are sorted into exosomes, these circulating vesicles harbour‐specific RNA species involved in cell–cell communication (green box). During programmed cell death, cell remnants or apoptotic bodies are released and include various RNA transcripts including miRNAs. miRNAs are also found in a cell‐free or protein‐bound form (i.e. associated with AGO2 or HDL). The mechanisms guiding the release of pbmiRNAs are unclear, but it is most likely due to cell death by way of necrosis or by passive diffusion. Despite the numerous sources of circulating miRNAs, the ability to capture and detect the abundance of these small RNAs from a variety of biofluids is crucial to develop better cancer‐associated biomarker assays. Abbreviations: MVBs, multivesicular bodies; HDL, high‐density lipoprotein; CTCs, circulating tumour cells.
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Further Reading

Banzhaf‐Strathmann J and Edbauer D (2014) Good guy or bad guy: the opposing roles of microRNA 125b in cancer. Cell Communication and Signaling 12: 30. DOI: 10.1186/1478-811X-12-30.

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Khalyfa A and Gozal D (2014) Exosomal miRNAs as potential biomarkers of cardiovascular risk in children. Journal of Translational Medicine 12: 162. DOI: 10.1186/1479-5876-12-162.

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Adams, Brian D, and Slack, Frank J(Jun 2015) MicroRNA Signatures as Biomarkers in Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025346]