Review
Changes in miRNA expression in solid tumors: An miRNA profiling in melanomas

https://doi.org/10.1016/j.semcancer.2008.01.001Get rights and content

Abstract

In this review, we briefly described microRNA biogenesis, function and the principal approaches for studying the function of microRNAs (miRNA) in solid cancers. There are currently hundreds of confirmed miRNAs in humans, and computational predictions suggest that the total count might be more than thousand. The regulatory nature of miRNAs combined with the large number of presumptive target genes suggests that they are essential regulators of a wide range of cellular processes. To illustrate the importance of miRNA-mediated regulation in solid cancer some confirmed interactions were collected. Their relevance is described in detail in melanomas from the aspect of diagnosis, the potential application of miRNAs as biomarkers and as potential therapeutic tools.

Introduction

Until recently, the non-coding RNAs and their functions were out of focus of investigations, primarily due to the fact that they are not converted into proteins and therefore the interpretation of their function is difficult. Now, the approach to non-protein-coding genomic sections changed fundamentally and investigations of small non-coding RNAs unfolded many, yet unpredictable, regulatory relationships.

Among non-protein-coding RNAs, the miRNA have been proven to play a key role in regulating gene expression by interacting with messenger RNA (mRNA)—either by inhibiting mRNA translation [1], [2], [3], [4] or by causing mRNA degradation [5], [6], [7]. Mature form of miRNAs are a class of conserved, approximately 21–25 nucleotides long RNAs. MiRNAs have been identified in both plants and animals, acting as key regulators of multicellular differentiation [8], [9], [10], [11]. In accordance to miRNAs control, a range of developmental events, such as timing of cell-fate decision, stem cell maintenance, apoptosis and organ morphogenesis, are suggested to play a role in the appropriate establishment of the tissue or cell type specific expression patterns along the development. Nevertheless, the majority of miRNAs expressed in many tissues, in more cases the highly tissue-specific suggested miRNAs latter proved to be expressed more broadly [12].

It is now already established that miRNAs contribute not only in developmental processes related functions, but also play an important role in the response of cells to outer signals and in adaptation to the changing environment (e.g. cellular stress [13], hypoxia [14]). Moreover, in a recent paper evidences are provided that miRNAs can be tools in the communication between different cell types. As part of the delivered “exosomal shuttled RNA”, miRNAs are present in exosomes secreted by mast cells. Through this newly discovered form of cell–cell communication, the donor cell may modulate the post-transcriptional system of target cells directly [15].

The range of different cellular pathways with miRNA-mediated regulation was estimated by Gaidatzis et al. [16]. Using bioinformatic tools a method was developed, which is able to mark significant association between a predicted miRNA target sets and their involvement in cellular pathways in human. The results confirmed the findings of other authors, that the miRNA target sites in the genes of ubiquitous, basic metabolic processes are relatively under-represented, while the genes involved in cell growth/death, development (especially in axon guidance pathway), transcriptional regulation, and intercellular communication are exposed to miRNA-driven control more frequently. Possibly, the miRNA-mediated regulation can be necessary in processes when beside the fundamental regulation, a fine balancing is also required for driving the cell to the most proper response for different signals.

Evidence is emerging that particular miRNAs may play a role in human cancer pathogenesis. The mutational and epigenetic changes in the genome leads stepwise to uncontrolled proliferation and cell death mechanisms in cancer. The dysregulation of cell proliferation with defects in differentiation of cancer cells, is a usual feature of carcinogenesis, often be accompanied the loss of tissue type-specific, unique miRNA profile. Little is known about the mechanisms underlying miRNA regulation in normal tissues and their deregulation in neoplastic processes. It remains also to be elucidated whether miRNA expression changes are the cause or the consequence of de-differentiated state. Further studies are also needed to clarify how to develop the altered miRNA fingerprint in cancer.

The estimated biological role of miRNA suggests that their expression may provide valuable diagnostic and prognostic indicators for human diseases, including solid tumors. miRNA expression changes have been described to correlate with the clinico-pathological features of the tumor in human cancers [17], [18], [19]. In classifying tumors and predicting their outcomes, the studies on miRNA-patterns are very promising. Understanding their function in gene regulation will help to develop biomarkers and new drug targets in cancer management.

Section snippets

miRNAs in the genome

The non-coding RNA represents a significant part of the genetic information in complex eukaryotes. According to the estimation, the non-protein–coding RNA can share 97–98% of the transcriptional output of a human cell. Certainly a part of these DNA segments which are transcribed but does not result protein-products belongs to intronic RNA, which constitutes 95% of the primary protein-coding transcripts (pre-mRNA) [20]. A recent paper with the purpose of finding direct experimental evidence on

miRNA processing

To understand the mechanism of miRNA-mediated silencing the basic step of their biogenesis has to be summarized. Briefly, miRNAs are a large family of endogenous, small regulatory RNAs that are generated by a two-step process from long primary miRNAs (pri-miRNAs) that are transcribed in the nucleus by the RNA polymerase II complex. At first it is processed by a complex comprised of the RNase III enzyme DROSHA and a double-stranded RNA binding domain possessing protein DGCR8 (DiGeorge syndrome

Range of methods available for measure expression of miRNAs

Different methodologies have been used to profile miRNA expression, including Northern blotting with radiolabeled probes [33], [34], oligonucleotide macroarrays [8], [35], quantitative PCR-based amplification of precursor or mature miRNAs [36], [37], [38], bead-based profiling methods [39], [40] and DNA microarrays [41], [42], [43], [44], [45], [12]. By contrast to mRNA profiling technologies, miRNA profiling must consider the short nature of microRNAs and should be able to distinguish between

Targets of miRNA

Beyond the knowledge of miRNA signature in different tumor types, it is necessary to uncover, how to act miRNAs with altered expression on their respective targets. The question is are there any pathways probably by the reason of altered miRNA expression over- or underrepresented in tumor cells, and in this way participate in manifestation of tumorous phenotype?

In accordance with the current model miRNAs affect the gene expression at the posttranscriptional level. Translational repression and

Altered expression of miRNAs in solid cancers

Although the biological functions and the target genes of miRNAs are poorly characterized, it has been confirmed that their pattern is changing during tumorigenesis. In tumor cells, both the levels of miRNA and their target gene mRNA expression are expressed differently. Conflicting reports have been published on whether the global amounts of miRNAs increase or decrease in cancers [40], [59]. Recent findings indicate the importance of the type and not the overall amount of altered miRNAs.

Unique

Lung cancer

In human lung cancers, reduced level of let-7 family was observed compared with levels in normal lung tissues. On the basis of expression of let-7 isoforms, the patients were classified into different outcome groups. In a lung cancer cell culture model was confirmed when levels of let-7a and let-7f were increased, then growth of the cancer cells was greatly reduced [71]. In Johnson's group was found that let-7 controls the activity of the critical human oncogene RAS. Accordingly, the lung tumor

Esophageal cancer

It has been shown that the miRNA processing enzyme RNASEN (an alias of Drosha, it cleaves pri-miRNA to pre-miRNA in nucleus) is overexpressed in a fraction of esophageal cancer compared to normal eosophagial epithelium. High levels of RNASEN found to associate with poor postoperative survival [78].

Hepatocellular cancer

MiR-21 is reported to be involved in the regulation of PTEN (phosphatase and tensin homolog) tumor suppressor is highly expressed in hepatocellular tumor samples and cell lines. Negative regulation of

Breast cancer

In breast cancer, the expression of various let-7 miRNAs is downregulated, which miRNA family were previously shown to control the level of RAS. Furthermore, downregulation of miR-20a, which regulates TGFBR2 was also described in breast cancer [59]. Tsuchiya and coworkers reported for the first time that miRNAs can regulate not only the essential genes for proliferation and apoptosis, but also drug metabolizing enzymes. They found an inverse correlation between miR-27b and CYP2B1. Since CYP2B1

Pituitary cancer

Bottoni and coworkers found that miR-15a and miR-16-1 are expressed at lower levels in pituitary adenomas as compared to normal pituitary tissue. Down-regulation of these miRNAs in pituitary adenomas correlates with a greater tumor diameter and a lower p43 secretion (as cofactor influence the activity of arginyl-tRNA-synthetase which is involved in inflammation and angiogenesis), suggesting that these genes may, at least in part, influence tumor growth [73].

Thyroid cancer

Kit is a tyrosine kinase receptor

Glioblastoma

Increased levels of the miR-21 have been found in glioblastomas compared with levels in normal brain tissue. Reducing the level of miR-21 in glioblastoma cells led to increased cell death in vitro. It appears that miR-21 can act as an anti-apoptoting factor by targeting the apoptosis-related genes, and in this way its overproduction could contribute to the maintenance of this tumor [87].

Oral squamous cell carcinoma

The increased expression of HMGA2 has been linked to epithelial-mesenchymal transition in oral squamous cell carcinoma. HMGA2 is a non-histone protein that bind through their AT binding motifs to the minor groove of AT-rich DNA strands. Although several proteins have been established as regulatory factors of HMGA2, Hebert and coworkers showed the upregulation of miRNA-98 under hypoxic condition and its role in the regulation of this protein which is critical in governing genotoxic response [88]

Melanoma: implication of miRNAs in diagnosis and treatment

Melanoma is one of the most aggressive cancer type in human. Melanoma transforms from melanocytes, the specialized pigment cells, which originate from neural crest. Most of melanomas arise within the epidermis where their progenitors are exposed to the UV radiation. Accordingly, the sunburn is high-ranked among the environmental risk factors. Notably, its incidence is progressively increasing in the past decades [90].

Besides the invasive growth the therapeutic resistance to available therapy

Concluding remarks, perspectives

The discovery of miRNAs and the perspectives of their regulatory potential revive a new layer in regulation of gene expression whereas many aspects of yet acquired ideas need to revaluate in cancer biology. The characteristic expression pattern observed in different tumor types and its prognostical value suggest miRNAs has a place sure enough in diagnosis and staging. The demand for reliable markers able to predict the prognosis is high, especially in cancer types such as melanoma. Otherwise,

Acknowledgement

This work was supported by grants of Hungarian Science Foundation (OTKA-67955).

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