Abstract
MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate gene expression post-transcriptionally through complementary base pairing with thousands of messenger RNAs. Although the precise biological functions of individual miRNAs are still unknown, miRNAs are speculated to play important roles in diverse biological processes through fine regulation of their target gene expression. A growing body of data indicates the deregulation of miRNAs during hepatocarcinogenesis. In this review, we summarize recent findings regarding deregulated miRNA expression and their possible target genes in hepatocarcinogenesis, with emphasis on inflammation-related hepatocarcinogenesis. Because miRNA-based strategies are being applied to clinical therapeutics, precise knowledge of miRNA functions is crucial both scientifically and clinically. We discuss the current open questions from these points of view, which must be clarified in the near future.
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Introduction
MicroRNAs (miRNAs) are short, single-stranded, non-coding RNAs, which are expressed in most organisms, from plants to vertebrates [1]. Since the discovery of the miRNA lin-4 in Caenorhabditis elegans [2, 3], 1,872 miRNA precursors and 2,578 mature miRNA sequences in humans have been deposited in miRBase, a public repository hosted by the Sanger Institute, as of November 2013 [4]. Bioinformatic predictions suggest that miRNAs regulate more than 30 % of human protein-coding genes [5–7]. Through the regulation of gene expression, miRNAs are involved in various physiological and pathological processes, including cell proliferation, apoptosis, differentiation, metabolism, oncogenesis and oncogenic suppression [8, 9]. Thus, it is not surprising that deregulation of miRNAs is linked closely to various human pathological conditions. In this review, we will describe the crucial role of miRNAs in liver carcinogenesis, especially inflammation-related hepatocarcinogenesis.
Biogenesis and functions of miRNAs
Transcription is the first step in miRNA expression (Fig. 1). Similar to most protein-coding genes, transcriptional factors, enhancers and silencers are involved in miRNA transcription [10–12]. Epigenetic mechanisms, such as promoter methylation or histone modification, also regulate miRNA transcription, and it was shown that histone deacetylase (HDAC) inhibition results in transcriptional changes in ~40 % of miRNAs [13].
Biogenesis of miRNAs. The primary miRNA transcript (pri-miRNA) is transcribed from the genome by RNA polymerase II or III. The microprocessor complex Drosha–DGCR8 cleaves the pri-miRNA into the precursor hairpin, pre-miRNA in the nucleus. The pre-miRNA is exported from the nucleus by exportin-5–Ran-GTP. In the cytoplasm, the RNase Dicer in complex with the double-stranded RNA-binding protein, TRBP, cleaves the pre-miRNA hairpin to its mature length. The functional strand of the mature miRNA is loaded together with Argonaute (Ago2) proteins into the RNA-induced silencing complex (RISC), where it guides RISC to silence target mRNAs through mRNA cleavage or translational repression. The passenger strand (black) is degraded
Primary miRNAs, which possess stem-loop structures, are transcribed by RNA polymerase II [8]. These pri-miRNAs are processed by a microprocessor complex comprising Drosha (RNAase III) [14] and DGCR8/Pasha [15] in the nucleus [16]. The processed products are approximately 65-nucleotide hairpin-shaped precursors (pre-miRNAs) that are transported to the cytoplasm via exportin-5 [17, 18]. Pre-miRNAs are further cleaved into mature miRNAs by Drosha and Dicer RNA polymerase III. Mature miRNA duplexes are loaded onto an RNA-induced silencing complex (RISC) and are unwound into the single-stranded mature form [19–21]. The resulting co-complex directly targets the 3′-untranslated regions (3′-UTRs) of target mRNAs, depending on the sequence similarities, to negatively regulate their expression by enhancing mRNA cleavage or inhibiting translation (Fig. 1) [8, 22]. Because most miRNAs guide the recognition of imperfect matches of target mRNAs, individual miRNAs have multiple (probably hundreds) of mRNA targets. In addition, multiple miRNAs can cooperate to regulate the expression of the same transcript [6]. Thus, depending upon the identity of the target mRNAs, miRNAs play roles as “fine-tuners of gene expression” in the control of various biological functions.
Identifying functionally important miRNA target genes is crucial for understanding the impact of specific miRNAs on cellular function. However, this is challenging because miRNAs usually have imperfect complementarity with their targets [22]. In mammals, the most consistent requirement for miRNA-target interaction, although not always essential, is a contiguous and perfect pairing of the miRNA (nt 2–8), representing the “seed” sequence [22]. In many cases, the seed sequences determine this recognition, but in other cases, additional determinants are required, such as reasonable complementarity to the miRNA 3′ half to stabilize the interaction. In addition, target pairing to the center of some miRNAs has also been reported [23]. Although public miRNA target prediction algorithms, such as TargetScan [24] and PicTar [25], have facilitated the rapid identification of miRNA target genes [22], candidates should be validated experimentally.
miRNAs and cancer
The involvement of miRNAs in cancer pathogenesis is well established. miRNAs can affect six hallmarks of malignant cells, which are (1) self-sufficiency in growth signals, (2) insensitivity to anti-growth signals, (3) evasion of apoptosis, (4) limitless replicative potential, (5) angiogenesis, and (6) invasion and metastasis [26]. miRNAs are frequently up- or downregulated in malignant tissues and can be considered oncogenes or tumor suppressors, respectively. However, it is essential to test experimentally whether the deregulated miRNAs are actually causative to carcinogenesis, since miRNAs have a very restricted tissue-specific expression and the apparent miRNA modulation in cancer tissues may only reflect the different constituents of a cell population as compared to normal tissues. Extensive analyses have confirmed the causative roles of miRNAs in cancer by using either human cancer cells or genetically engineered animal models, such as transgenic expression of miR-155, miR-21 and miR-15-a/16-1, which are sufficient to initiate lymphomagenesis in mice [27–29]. These results suggest the potential role of miRNAs in the pathogenesis of carcinogenesis and as therapeutic targets.
miRNAs and hepatocarcinogenesis
Numerous reports regarding the deregulated expression of miRNAs in human hepatocellular carcinoma (HCC) are extant. Most studies compared the miRNA expression levels between cancer tissues and background non-tumorous tissues, selected candidate miRNA(s) and revealed their target genes, which may be involved in carcinogenesis. As shown in Tables 1 and 2, many miRNAs have been identified as downregulated or upregulated in recent studies (Tables 1, 2). However, these numerous results are not always superimposable due to the large variances in the results. These significant differences may be due to several reasons, such as the use of different techniques or different samples as controls, normal liver tissues versus peritumoral non-neoplastic tissues. In addition, one may need to take into consideration the fact that HCCs arise in background livers with different etiologies, such as hepatitis B, hepatitis C or steatohepatitis, and also the age or sex of the tissue-derived patients and background liver condition, such as fibrosis staging or inflammation activity, which may result in differences in the expression status of miRNAs. Despite these considerable limitations, the list suggests that diverse miRNAs play crucial roles in hepatocarcinogenesis. We will briefly describe some of them below.
The expression levels of miRNAs have restricted tissue specificities. In the liver, miR-122, miR-192 and miR-199a/b-3p are the three most expressed miRNAs, accounting for 52, 17 and 5 % of all mRNAs in the tissues, respectively [30]. The tumorigenic role of the loss of miR-122 was confirmed in gene-knockout mice [31, 32] and its expression is indeed decreased in half of the HCCs, especially non-viral HCCs [30]. We also reported that decreased expression of miR-122 is linked with poor prognosis of HCC [33]. While miR-192 does not appear to be deregulated in HCC samples in previous studies, miR-199a/b-3p is decreased with high frequency in HCC, which is closely linked to a poor prognosis of HCC [30]. In contrast, miR-21, whose expression is increased following rat hepatectomy [34], is upregulated as a known oncomiRNA and represses PTEN signaling, resulting in promotion of HCC development [35]. Although individual miRNAs may be involved in hepatocarcinogenesis, because miRNAs often function co-operatively, the extent of their involvement remains to be determined.
As described above, miRNAs usually have multiple mRNA targets. Thus, it is not practical to describe only a few genes as being responsible for the phenotypes by deregulation of specific miRNAs, while many studies identify specific genes as targets of specific miRNAs. Nonetheless, the identified targeted genes are generally related to at least one of the hallmarks of cancer, such as cell growth, apoptosis, invasion, and so on. These results suggest that the deregulation of miRNA expression might mediate hepatocarcinogenesis through deregulating the expression of their target genes.
The miRNAs identified as deregulated in hepatocarcinogenesis may be useful as diagnostic and prognostic markers [36], because miRNAs in the circulation are reported to be relatively stable [37]. Also, deregulated miRNAs may be candidate therapeutic and preventive targets against HCC. However, to include the obtained results in clinical interventional applications, it is necessary to confirm if the deregulated miRNAs are truly drivers or are simply passive in hepatocarcinogenesis. To this end, genetically modified mice may provide some information. In addition, to correctly interpret the data, a standard method of normalizing the microRNAome data between studies may also be crucial. Since there are multiple target genes of miRNAs and, conversely, one transcript can be targeted by multiple miRNAs, a more systematic comparison using miRNA data, transcriptome data and proteome data would increase our understanding of the consequences of the deregulation of miRNAs during hepatocarcinogenesis. From this point of view, systematic and comprehensive target gene analyses for in silico systems biology models may be one option to resolve these issues.
miRNAs linked to inflammation-mediated hepatocarcinogenesis
Inflammation is considered to be a major cause of cancer [38, 39]. In the liver, hepatocarcinogenesis frequently occurs in persistently inflamed liver tissues caused by chronic hepatitis viral infection or non-alcoholic steatohepatitis. However, the molecular linkage between chronic inflammation and carcinogenesis is not well characterized. miRNAs, as a new class of gene expression regulators, may be involved in chronic inflammation-induced carcinogenesis and, in fact, several studies have clarified one such linkage, in which miRNAs may serve as a bridge between continuous inflammation and carcinogenesis.
A flagship report addresses a positive feedback loop of an inflammatory response mediated by NF-κB that activates Lin28B transcription (Fig. 2) [40]. LIN28B, which is an inhibitor of miRNA processing, reduces let-7 levels. Let-7 inhibits IL-6 expression, resulting in higher levels of IL-6 than achieved by NF-κB activation. IL-6-mediated STAT3 activation is necessary for transformation and IL-6 activates NF-κB, completing a positive feedback loop. Although the experiments mainly used MCF10A cells (breast cancer cells), a similar feedback loop was observed in HCC tissues. The authors termed these mechanisms an “epigenetic switch” because the loop maintains the epigenetic transformed state even in the absence of induction by inflammation (Fig. 2).
A model bridging chronic inflammation and transformation by miRNA. Inflammation triggers activation of NF-κB, which leads to transcription of LIN28B. LIN28B inhibits the production of Let-7. Let-7 normally inhibits IL-6 expression, resulting in higher levels of IL-6 than are achieved by NF-κB activation. IL-6 mediated STAT3 activation is necessary for transformation and IL-6 activates NF-κB, completing a positive feedback loop
Another report addressed hepatocarcinogenesis induced by transient inhibition of HNF4α (Fig. 3) [41]. HNF4α was reported to be involved in liver oncogenesis, although discrepant reports have also been published [42–44]. In that report, transient HNF4α silencing was sufficient to maintain cell transformation. Through a miRNA library screen, miR-24 and miR-629 were identified to target HNF4α. Interestingly, both miRNAs were induced following HNF4α silencing, supporting their involvement in the HNF4α-dependent feedback loop. miR-24 and miR-629 contain the STAT3-binding motif in their promoter region. The authors showed that in response to IL-6, STAT3 binding to their promoters increased, resulting in miRNA expression. They also identified miR-124, whose promoter region contains HNF4α binding sites. miR-124 targets IL-6R and, thus, HNF4α silencing results in reduced expression of miR-124 and enhanced expression of IL-6R and activation of STAT3. The importance of these feedback loops was confirmed in vivo using a mouse HCC model induced by diethylnitrosamine. miR-124 delivery by cationic liposomes prevented tumor development. Thus, these microRNA feedback-inflammatory loops are important and can be a therapeutic target for liver cancer (Fig. 3) [41].
A model describing a positive feedback loop mediated by miRNAs from transient HNF4α inhibition to transformation. Transient silencing of HNF4α is mediated by miR-24 and miR-629, both of which are induced by STAT3 activation following IL-6 stimulation. miR-124, whose promoter region contains HNF4α-binding sites, targets IL-6R and, thus, HNF4α silencing results in reduced expression of miR-124 and enhanced expression of IL-6R and activation of STAT3, which induces miR-24 and miR-629. This microRNA feedback-inflammatory loop is thought to be crucial in IL-6-mediated liver cancer
A recent paper reported a similar but distinct observation (Fig. 4). The authors found that when using DEN-induced foci of altered hepatocytes (FAH), LIN28-expressing cells are present in FAH, in which let-7 is down-regulated, resulting in the enhanced expression of IL-6, mediating the progression of malignancies from progenitors. An important difference between the cells in FAH and those in early hepatocarcinogenesis is that IL-6 signaling is autocrine, being mediated by reduced let-7 due to upregulation of LIN28B in FAH cells. This mechanism may contribute to malignant progression from HCC progenitor cells (Fig. 4) [45].
A model bridging the malignant transformation of precursor cells and autocrine-mediated inflammation by microRNA. LIN28-expressing cells exist in the foci of altered hepatocytes, in which let-7 is downregulated, resulting in enhanced IL-6 expression, which mediates the progression of malignancies from progenitor cells
These three reports are from related research groups, and rely on the hypothesis that the IL-6-STAT3 pathway is crucial for hepatocarcinogenesis. Although IL-6 has been implicated as a growth factor in various epithelial cancers [46, 47], its relevance in hepatocarcinogenesis needs to be confirmed to determine the applicability and reproducibility of these findings to the clinical setting.
miRNAs as therapeutic targets in the liver
Recently, miravirsen, a LNA-modified DNA phosphorothioate antisense oligonucleotide against miR-122, became the first miRNA-targeting drug for clinical use [48]. It was developed to target HCV, as the stability and propagation of this virus is dependent on a functional interaction between the HCV genome and miR-122 [49, 50]. No harmful events were observed in Phase I studies in healthy volunteers, and Phase II studies proceeded to evaluate the safety and efficacy of miravirsen in 36 patients with chronic HCV genotype 1 infection. The patients were randomly assigned to receive 5 weeks of subcutaneous miravirsen injections at 3, 5 or 7 mg per kg body weight or a placebo over a 29-day period. Miravirsen resulted in a dose-dependent reduction in HCV levels, without major adverse events and with no escape mutations in the miR-122 binding sites of the HCV genome [48]. The success of miravirsen is promising, not only as a novel anti-HCV drug, but also as the first trial of miRNA-targeting therapy.
In addition to miravirsen, a clinical trial of MRX34 as a mimic of miR-34 is underway. MRX34 is a liposome-formulated mimic of the tumor suppressor miR-34 (Mirna Therapeutics, Austin, TX, USA). Further study of MRX34 is being conducted by Mirna Therapeutics, which initiated a Phase I study in May 2013 to examine the effects of MRX34 on unresectable primary liver cancer or advanced or metastatic cancer with liver involvement (ClinicalTrials.gov Identifier: NCT01829971). If these oligonucleotide therapies are successful, therapeutic options based on the numerous miRNAs deregulated during hepatocarcinogenesis appear promising [51].
Issues to be resolved in miRNA involvement in hepatocarcinogenesis
As described above, along with recent discoveries of the diverse effects of miRNAs in hepatocarcinogenesis, miRNA-mediated intervention is promising for the development of new diagnostic, preventive and therapeutic tools. However, the data obtained to date are far from complete. The following are some of the critical issues that we believe need to be resolved.
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1.
The reason for the non-reproducible results among studies should be determined to utilize the available data more reasonably and efficiently.
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2.
Identification of crucial driver miRNAs among the diverse deregulated miRNAs is critical to develop useful therapeutics in clinics, although even passive miRNAs may be utilized as markers for diagnosis or prediction of prognosis.
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3.
Comprehensive target gene analyses using in silico systems biology models should be applied.
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4.
For effective interventions using miRNA, the delivery method, improved oligonucleotide modification and safety must be further considered. Since miRNAs generally have diverse effects due to targeting multiple mRNAs, undesired outcomes, so called off-target effects, may be encountered, even when a specific miRNA is targeted.
Finding solutions to these issues should be considered as critically important for the near future in order to understand more fully the physiological function of miRNAs in hepatocarcinogenesis and utilize this knowledge in translational research.
Conclusions
The discovery of miRNA has, without doubt, opened up new possibilities for understanding the molecular mechanisms of gene regulation. As numerous findings regarding miRNA, from diverse perspectives, have been reported, the speed of discovery in this field is astonishing. In fact, novel therapeutics targeting miRNAs have already been successfully applied in clinical trials. Some miRNAs may be useful as novel biomarkers. Additionally, the discovery of novel concepts in the pathogenesis of hepatocarcinogenesis frequently involves miRNA. On the other hand, several important issues remain to be resolved in this field. Thus, continuous research in this field is still necessary to develop truly innovative concepts in our understanding of pathogenesis related to miRNA and to transform the obtained knowledge into real clinical applications.
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Otsuka, M., Kishikawa, T., Yoshikawa, T. et al. The role of microRNAs in hepatocarcinogenesis: current knowledge and future prospects. J Gastroenterol 49, 173–184 (2014). https://doi.org/10.1007/s00535-013-0909-8
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DOI: https://doi.org/10.1007/s00535-013-0909-8