Genomic and Epigenomic Biomarkers of Toxicology and Disease. Группа авторов
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MM cell line MSTO-211H for migration and invasion experiments, and found that overexpression of miR-205 can inhibit the migration and invasion of tumor cells. Similarly, an in vitro chemotaxis test—a Boyden chamber assay—has been used to detect that the migration and invasion ability of LP-9 cells transfected with miR-34 inhibitor is significantly enhanced (Tanaka et al. 2013); but some tumor cell lines (H28, H290 and H2052) have increased their cell migration and invasion ability after miR-34 methylation (Muraoka et al. 2013). When miR-34b/c is transfected into tumor cell lines, the ability of tumor cells to form clones is obviously weakened, and the migration and invasion ability of cells is also obviously inhibited (Santarelli et al. 2011). However, through the transwell cell migration test and the cell scratch test, the migration ability of MSTO-211H and NCI-H2052 cell lines transfected with miR-145 analogue was compared with that of non-transfected miR-145 analogue cells, and it was found that migration was significantly weakened in the transfected group and was not found at all in the NCI-H28 cell line (Cioce et al. 2014).
Apoptosis-related miRNAs
In the process of tumor formation and malignant transformation, tumor cells escape the monitoring system by avoiding apoptosis and survive in the microenvironment of tumor growth. Studies have found that miRNA may play a role in inducing apoptosis. The expression levels of miR-1(Kirschner et al. 2012) and miR-34b/c(Kubo et al. 2011) decreased in MM cell lines. After transfection of miR-1 and adenovirus carrying miR-34b/c into tumor cell lines, the number of early and late apoptosis of tumor cells increased significantly. It indicated that miR-1 and miR-34b/c could promote the apoptosis of MM cell.
Inhibition of miRNAs Associated with Explant Tumor
Apart from the experimental studies in vitro already mentioned, there are also many in vivo experimental studies that demonstrate the role of miRNA in the treatment of MM. Ueno et al. (2014) injected adenovirus-carried miR-34b/c into explants of MM tissues from mice and found that the expression of miR-34b/c in tumor cells increased. When compared with the lentivirus-carried luciferase treatment, the volume of tumor did not change for six to ten days after injection, which indicated that miR-34b/c has a certain inhibitory effect on tumor growth. Another study transplanted tumors in nude mice, and then injected into these mice, intravenously, micro cells containing miR-16 analogues. It was found that the degree of inhibition of tumor growth became more obvious as the dose increased; and DNA fragment analysis found that miR-16 analogues also damaged intracellular DNA. When MSTO-211H or MM 05 cell line is transfected with miR-16 analogue, the sensitivity of tumor cells to chemotherapy drugs increases and the efficacy of these drugs is enhanced (Reid et al. 2013). Cioce et al. (2014) inoculated the experimental mice with MSTO-211H. The results showed that eight out of eight mice in the positive control group that were not transfected with miR-145 analogues had solid tumors, while only two out of eight mice in the experimental group that were transfected with miR-145 analogues had tumors; and the tumor volume in the experimental group was significantly smaller than in the positive control group. These experimental results on animals provide more powerful evidence for the usefulness of miRNA in the treatment of MM.
miRNA is able not only to regulate cell cycle, proliferation, clone formation, migration, invasion ability, and apoptosis or inhibit the growth of explant tumors, but also to improve the sensitivity of tumor cells to traditional radiotherapy by regulating the expression level of some miRNAs in cells. Increased expression of miR-34b/c in tumor cells can destroy DNA double-strand damage repair and inhibit the expression of tumor cell growth-related proteins. It can also enhance the sensitivity of MM cells to radiation, which indicates that the combination of increased expression level of miR-34b/c in cells and radiotherapy may be used for the treatment of MM (Maki et al. 2012). At present, on the basis of this research, the application of miRNA to the treatment of MM produces the following three ideas. First, miRNA antagonist is used to inhibit the effect of carcinogenic miRNA, block endogenous miRNA from being processed by RISC, or lead to the degradation of endogenous miRNA. The second idea is to enhance the expression level of the endogenous tumor suppressor miRNA and inhibit the expression of its target proto-oncogene (Benjamin et al. 2010). The third idea is to use the artificial miRNA (amiRNA) expression vector that targets genes related to the malignant tumor phenotype. These methods could become a new way of treating MM, namely by interfering with the changes in miRNA expression level related to the occurrence and development of the tumor.
Exosomal miRNA as a Target for Malignant Mesothelioma
Exosomes provide the opportunity to deliver therapeutic cargo to cancer stroma. The cells were treated with exosome-enriched miR-126. The reduced miR-126 content in fibroblasts in favor of endothelial cells reduced angiogenesis and suppressed cell growth in an miR-126-sensitive environment. Conversely, the accumulation of miR-126 in fibroblasts and the reduced level of miR-126 in endothelial cells induced tube formation in a miR-126-resistant environment via VEGF/EGFL7 upregulation and IRS1-mediated cell proliferation. These findings suggest that the transfer of miR-126 via exosomes represents a novel strategy to inhibit angiogenesis and cell growth in MM (Monaco et al. 2019).
Munson et al. (2019) employed small molecule inhibitors to block exosome secretion, thereby reducing miR-16-5p exosome loss and replenishing cellular miR-16-5p. These processes led to reduced tumorigenic capacity and miR-16-5p target oncoproteins CCND1 and BCL2. Additionally, the researchers force-fed MM tumor exosomes back to MM tumor cells, which caused cell death and a reduction in the same oncoproteins.
MicroRNAs Related to Prognosis of Malignant Mesothelioma
Patients with MM have poor prognosis, and their average survival time is generally seven to twenty-four months. There are many factors affecting the survival time or prognosis of patients. . For example, Fassina et al. (2012) analyzed the average survival time of an epithelial MM: the survival curve is thirteen months, the average survival time of a biphasic MM is fourteen months, and the survival time of a sarcomatous MM is only six months. The COX model also shows that a sarcomatous MM has the worst prognosis. It is not only tissue subtypes are related to prognosis; studies have shown that the expression level of some specific miRNAs is related to prognosis too. Pass et al. (2010) found that miR-29c* in tissue samples of MM patients with good prognosis was significantly downregulated. After comparing it with tissue subtypes, they found that miR-29c* expression in epithelial MM tissues was significantly upregulated and that the prognosis of patients was better (Jean et al. 2012). Some studies have also found that, when the expression of miR-17 and miR-30c in sarcomatous MM is down-regulated (Cappellesso et al. 2016; Jean et al. 2012; Pass et al. 2010), the prognosis of patients is also better. Another study found, through Kaplan-Meier analysis, that the low expression of miR-126 in the serum of patients with MM has a strong correlation with poor prognosis (Tomasetti et al. 2012). Kaplan-Meier analysis showed that hsa-miR-2053 is an independent prognostic factor in MPM (Matboli et al. 2019). Also, a 2-miRNA prognostic signature (Let-7c-5p and miR-151a-5p) related to hypoxia and energy metabolism was identified (De Santi et al. 2017). The expression of miRNA-16 in plasma and tissue was positively related with cumulative survival in MPM patients (Fennell 2017; Mozzoni et al. 2017). miR-215-5p is a poor prognosis miRNA, downregulated in MPM tissues (Singh et al. 2019). Another study found that miR-299-3p, -301,-379 and-455-3p were differentially expressed in smokers and non-smokers, but related miRNAs not significantly different were found in asbestos-exposed and -non-exposed patients (Price 2011). It can be seen that specific miRNA can be used not only to distinguish tumor types but also to predict prognosis for patients (Jean et al. 2012). These results can help clinicians to use tissue or serum samples better, so as to predict the progression and outcome of MMs.
To sum up, although some progress has been made in the research on miRNA in branches of oncology such as the study of MM, there are still many problems. The sensitivity and specificity of miRNA as a biomarker in the diagnosis and prognosis of MM need to be further improved. At present, no miRNA marker has been found that can be used to distinguish between the various pathological tissue subtypes and clinical stages of MMs. Research on miRNA in the treatment of MM is limited to the observation of short-term curative effects displayed by the cell model and the rat tumor model, while research on long-term treatments and their side effects is relatively scarce. However, with