Review
MicroRNAs: Predictors and modifiers of chemo- and radiotherapy in different tumour types

https://doi.org/10.1016/j.ejca.2009.10.027Get rights and content

Abstract

MicroRNAs (miRNAs) represent a class of naturally occurring small non-coding RNA molecules. They regulate gene expression at the post-transcriptional level and control thereby cellular mechanisms including developmental transitions, organ morphology, apoptosis and cell proliferation. As might be expected from molecules with these roles, miRNAs are involved in cancer development, and deregulation of several miRNAs has been found in various cancer types. Some miRNAs modulate expression of known oncogenes or tumour suppressor genes whereas others function as so called onco-miRs or tumour-suppressor-miRs. Recently, miRNAs have been studied as potential diagnostic or therapeutic targets in cancer treatment. There is increasing interest in an association between miRNA expression in tumours and chemo- and radiosensitivity, both with regards to predicting or modulating sensitivity. And indeed, different miRNAs have been found to predict sensitivity to anticancer treatment: miR-30c, miR-130a and miR-335 are downregulated in various chemoresistant cell lines, hsa-Let-7g and hsa-miR-181b are strongly associated with response to 5-fluorouracil-based antimetabolite S-1. In addition, several miRNAs were shown to influence sensitivity to chemo- or radiotherapy: miRNAs of the Let-7 family induced radiosensitivity in vitro/in vivo, inhibition of miR-21 and miR-200b increased sensitivity to gemcitabine in cholangiocarcinoma cell lines, and restoration of miR-34 in p53-deficient human gastric cancer cells induced chemosensitisation. This article summarises the current literature describing the impact of miRNAs on prediction and modification of anticancer treatment including the possible intracellular pathways involved in these processes.

Introduction

Epigenetic changes are defined as heritable changes in gene expression that occur without alteration of DNA sequences. The two widely recognised epigenetic modifications are DNA cytosine methylation and the post-translational modification of histones. These changes play key roles in biological processes such as gene regulation, development and carcinogenesis.1, 2, 3, 4, 5, 6, 7

MicroRNAs (miRNAs, miRs) represent a class of naturally occurring, small (19 to 25-nucleotides), non-coding RNA molecules. They can be included among the components of the ‘epigenetic machinery’ with a profound effect on the modulation of gene expression.8 Today more than 1500 miRNA genes in over 50 species have been identified, over 600 of these miRNAs were identified in humans (for further detailed information see miRBase (http://microrna.sanger.ac.uk/)).9 However, these numbers are rapidly increasing with improvements in miRNA detection and prediction approaches.

MiRNAs are encoded in the genome. Their biogenesis has been investigated by many authors.6, 10, 11, 12 The final step of this biogenesis involves incorporation of the mature miRNA into an effector complex, called RNA-induced silencing complex (RISC). In animals, single-stranded miRNA binds through partial or complete sequence homology to the 3′ untranslated region of target mRNAs and causes either block of translation or, less frequently, mRNA degradation.

MiRNAs can regulate gene expression at the post-transcriptional level and thereby control fundamental cellular aspects as developmental transitions, organ morphology, bilateral asymmetry, stress response, metabolism, cell proliferation and apoptosis.13 Their major impact is the direct interaction with the mRNA via the described RISC. It is postulated that each miRNA regulates up to 100 different mRNAs and that more than 10,000 mRNAs appear to be directly regulated by miRNAs.14, 15, 16, 17 Furthermore, miRNAs seems to affect gene expression in close cooperation with epigenetic changes. There is an increasing understanding of the interaction between miRNAs and DNA cytosine methylation or the post-translational modification of histones: miRNAs are involved in establishing DNA methylation and can probably also affect histone modifications. Furthermore, epigenetic mechanisms have been shown to influence miRNA expression.6, 18, 19

Calin and colleagues described in 2004 that probably more than 50% of miRNA genes are located in cancer associated genomic regions or in fragile sites.20 Subsequently, recent research has revealed strong evidence for the role of miRNAs in the initiation and progression of cancer. Alterations in miRNA levels are associated with dysplasia and cancer, and the expression of miRNAs has been clearly linked to cancer development.10, 11, 21, 22, 23 MiRNA profiles can be used to classify human cancers. In different tumour tissues, miRNA expression profiling has been shown to provide more accurate classification of tissue and tumour types than global messenger RNA expression profiles.6, 24 In addition to these findings, evidence for regulation of angiogenesis by miRNAs has been obtained for several miRNAs (e.g. miR-221, miR-222, miR-17-92 and miR-27b) including anti-angiogenic as well as pro-angiogenic effects.25 Distinct miRNA expression profiles are also associated with prognosis/disease progression and with well defined clinico-pathological features of human cancer24 and are able to predict outcome.10, 26

Recent studies have focused on the intracellular mechanisms by which miRNAs are involved in the initiation and progression of cancer, especially on possible functions and pathways regulated by miRNAs. Different miRNAs were demonstrated to regulate known oncogenes.27, 28 Recently, Lu and colleagues demonstrated that the translation of the tumour suppressor gene PDCD4 is negatively regulated by the miRNA miR-21 in different tumour cell lines.29 Furthermore, several pathways which modulate cell proliferation and apoptosis have been directly linked to miRNA alterations. So, miRNAs can either regulate known oncogenes or tumour suppressor genes at the post-transcriptional level or act themselves as oncogenes or tumour suppressor genes, so called onco-miRs and suppressor-miRs.10, 11, 14, 23

With increasing knowledge about the function of miRNAs, their possible diagnostic and, more important, therapeutic associations gained in attention. Due to the interaction of miRNAs with different oncogenes and tumour suppressor genes one potential aim could be to modulate these oncogenes and tumour suppressor genes by up- or downregulation of the involved miRNA. Another feasible approach would be to address intracellular pathways which are directly controlled by onco-miRs and suppressor-miRs in the same manner.

Hence, the most promising application of miRNAs might lie in estimation of outcome and modification of response in known and well established anti-tumour therapies such as radiation and chemotherapy. For example, alterations in miRNA expression profiles could provide information about sensitivity or resistance of certain tumour types to different treatments before starting any therapy (‘response prediction’); alternatively or in addition, changes in expression during a therapy might offer a tool for control of success of treatment (‘response control’). Last but not least, modification of miRNA expression by up- or downregulation may possibly enhance sensitivity to the applied chemo- or radiotherapy (‘response modulation’). In fact, Blower and colleagues demonstrated significant correlations between microRNA expression patterns and compound potency patterns, suggesting that miRNAs may play a role in chemoresistance.30

This review article summarises the results of current literature regarding the impact of miRNAs on prediction and modification of anticancer treatment including the possible intracellular pathways involved in these processes.

Section snippets

Methods

We performed a PubMed search with various combinations of the following keywords: chemoresistance, chemosensitivity, radioresistance, radiosensitivity, chemotherapy, radiotherapy, exosomal, circulating, miRNA, microRNA. The following number of articles (in brackets) were identified to meet the criteria: miRNA and radiotherapy (9), microRNA and radiotherapy (10), miRNA and radioresistance (1), microRNA and radioresistance (1), miRNA and radiosensitivity (3), microRNA and radiosensitivity (3),

Response prediction

Advances in detection techniques of miRNAs led to the development of microarrays. By enabling screening of tissue samples for several miRNAs simultaneously this approach revealed convincing evidence that a large number of miRNAs are deregulated in drug resistant or sensitive cancer cell lines. For example, Kovalchuk and colleagues31 found 137 differentially regulated miRNA genes (63 upregulated and 75 downregulated) when comparing doxorubicine-resistant and -sensitive breast cancer cell lines.

Summary and future expectations

MiRNAs represent a recently identified class of small, non-coding RNA molecules which control gene expression at post-transcriptional levels. The growing knowledge about their impact on several aspects of carcinogenesis and their meaning for therapeutic usage implicates miRNAs to be promising candidates for response prediction, control and modification of conventional and/or new developed anticancer treatments. It has been shown that alterations in miRNA expression profiles can be used to

Conflict of interest statement

None declared.

Acknowledgement

This work was supported by a Research Fellowship of the German Research Foundation (DFG) to R.H. (Hu 1763/1-1).

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