Genomic and Epigenomic Biomarkers of Toxicology and Disease. Группа авторов

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5 MicroRNA Biomarkers of Malignant Mesothelioma

       Lijin Zhu, Fangfang Zhang, Min Zhang, Hailing Xia, Xiuyuan Yuan, and Yanan Gao

       Hangzhou Medical College

      Pleural malignant mesothelioma (MM), which arises from the cells that line the lung and the chest cavity (pleura), is a highly aggressive tumor with a high recurrence rate after surgical resection, and is insensitive to chemotherapy and radiotherapy. The median survival time commonly does not exceed 12–18 months after diagnosis (Wright et al. 2013). Therefore biomarkers for early detection are imperative even for experienced pathologists (Wu et al. 2013; Zhang et al. 2014). Approximately 80% of the cases of pleural MM are attributed to asbestos exposure, and the latency after exposure could be 20–60 years (Rascoe et al. 2012). Asbestos exposure, a genetic basis, and other factors are likely to contribute to the etiology of pleural MM (Robinson and Lake 2005).

      MicroRNA (miRNA) is a kind of highly conserved, non-coding, single-stranded small RNA with a length of 18–25 nucleotides (Kirschner et al. 2011). About 35,828 mature miRNAs have been found in human genome, which can be divided into 223 species; these miRNAs regulate one third of human genes. The same miRNA can regulate single or multiple target genes and, in turn, the same gene can be regulated by multiple miRNAs (Luo et al. 2010) . Here mature miRNAs bind to untranslated sequences at the 3ʹ-end of the target mRNA through base complementary pairing, to inhibit mRNA translation or degradation, thereby regulating gene expression and playing a role in promoting or inhibiting cancer.

      During the two decades since Calin et al. (2002) first discovered two miRNAs (miR-15 and miR-16) closely related to the occurrence of chronic lymphoblastic leukemia, miRNAs have been proved to play a key role in cancer progression, treatment response, and diagnosis (Berindan-Neagoe et al. 2014; Hata and Lieberman 2015). The tumor-promoting or tumor-suppressing effects of miRNAs in various cancers depend on their expression levels. More and more researchers have applied miRNAs to the diagnosis and treatment of malignant tumors—for example the miR-200 family, miR-9, miR-34, miR-21, and miR-340 in the prognosis of pancreatic cancer (Zöller 2013) and miR-140 and miR-145 in the diagnosis and treatment of ovarian cancer (Banno et al., 2014).

The earliest study on miRNA in relation to MM began with Guled’s research in 2009 (Guled et al. 2009). In this study, the miRNA expression profiles of seventeen freshly frozen MM tissue samples and normal pericardium were analyzed using miRNA microarray, and multiple differentially expressed miRNAs between MM tissues and adjacent tissues were found. Moreover, different tissue subtypes of MM expressed specific miRNAs: for example, epithelial MM expressed miR-135b, miR-181a-2*, miR-499-5p, miR-517b, miR-519d, miR-615-5p, and miR-624, biphasic MM expressed miR-218-2*, miR-346, miR-377*, miR-485-5p, and miR-525-3p, and sarcomatous MM expressed miR-301b, miR-433, and miR-543. In this study, patients’ exposure to smoking and asbestos were also considered, and some miRNAs were specifically expressed in smoking patients (miR-379, miR-301a, miR-299-3p, miR-455-3p, and miR-127-3p); No miRNAs specifically expressed in asbestos exposure samples were found, but this absence may be related to different methods of asbestos exposure assessment. Other study found that most of these miRNAs were located in abnormal chromosomal positions of MM patients and that their target genes, such as CDKN2A, NF2, JUN, HGF, and PDGFA, were most likely to affect the occurrence and development of MM. This pioneering research has opened up a new kind of approach in the field. Since its publication in 2009, more studies have discussed the role of miRNA in MM in detail (Truini et al. 2014).

      Methods for Detecting the Expression of miRNAs

      As a biomarker of human diseases, ideally the detection method of miRNA should not need expensive reagents and instruments and be easy to operate. Such a method should have good specificity for distinguishing miRNAs with similar sequences. At the same time, it should have sufficient sensitivity for quantitative analysis, even for micro clinical samples, and it should be able to detect multiple samples in parallel (de Planell-Saguer and Rodicio 2011; Van Roosbroeck, Pollet, and Calin 2013).

      The Gold Standard Conference believes that the method for meeting these requirements and for detecting miRNA in clinical laboratories is quantitative reverse transcription polymerase chain reaction (PCR) (qRT-PCR). miRNA microarray is more expensive than qRT-PCR and is normally used in the discovery stage of biomarkers.

      However, these methods all need to extract miRNAs from tumor samples of patients, which include non-tumor matrix and inflammatory cells in addition to malignant tumor cells. If the goal is to detect the specific expression of miRNA in malignant tumor cells, it is recommended to use flow cytometry to sort liquid tumors or laser capture microscopy to cut solid tumors. In situ hybridization technology (Sempere and Korc 2013) can also be used; it can detect target miRNA in different types of cells (malignant tumor cells or microenvironment cells) that constitute tumors. This method provides additional miRNA subcellular localization information. At present, the latest method for detecting miRNA expression is next-generation sequencing. This technique is highly sensitive and specific, can be used for high-throughput analysis, and can discover new miRNAs. Next-generation sequencing produces a large amount of complex data, which need to be analyzed by a trained bioinformatician; besides, the cost of single RNA sequencing is too high, so this method is not suitable for diagnosis but can still be considered as a screening method for miRNAs of interest (Berindan-Neagoe et al. 2014).

      Early Screening for Malignant Mesothelioma

      In view of the high degree of malignancy and difficult treatment of MM, early screening is particularly important in the prevention and treatment of the disease. At present, there have been studies designed to improve the detection rate of early MM patients by identifying the expression level of specific miRNAs in serum or plasma (Mujoomdar et al. 2010).

Santarelli et al. (2011) found that miR-126 is downregulated in the tissues of MM patients. They noticed that one of the target genes of miR-126 is vascular endothelial growth factor (VEGF), which encodes a protein that stimulates angiogenesis and increases the VEGF content in the serum of MM patients. СКАЧАТЬ