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for diagnosis, the sensitivity and specificity may be further improved, which will be helpful for early diagnosis of MM.

      Differential Expression of miRNAs in Pleural Effusion

      Cytological miRNA examination of pleural effusion is a very challenging task: to distinguish MM from reactive mesothelial cells (RMCS), even if combined with in situ hybridization staining or immunofluorescence, is quite difficult. Cappellesso et al. (2016) screened and verified the differential expression of miRNA-19a (miR-19a, miR-19b), miR-21, and miR-126 in MM cell lines and mesothelioma patient tissue samples. The diagnostic sensitivity and specificity are both over 80%. The combined use of miR-21 and miR-126 can make the diagnostic sensitivity and specificity reach 86% and 87% respectively. In pleural effusion cells, combining miR-143, miR-210, and miR-200c could differentiate MPM with an area under the curve (AUC) of 0.92 (Birnie et al. 2019).

MicroRNAs Associated with Malignant Mesothelioma Tissue Subtypes

      Different histopathological subtypes have great influence on the curative effect and prognosis of MM, so correctly distinguishing histopathological subtypes is also an important part of the diagnosis of MM. Researchers have studied the difference of miRNAs expression in different tissue subtypes of MM, hoping to apply it to the tissue classification of MM.

      Busacca et al. (2010) analyzed miRNAs expression in two MM cell lines (MPP-89 and REN) and formalin-immobilized tumor samples using microarray and RT-qPCR methods. They found that there were seven kinds of miRNAs (miR-17-5p, miR-21, miR-29a, miR-30c, miR-30e-5p, miR-106a, and miR-143) with significant differences in expression, and it can distinguish the three tissue subtypes of MM tumors. The specific expression levels are high expression in epithelial MM, biphasic MM, and low expression in sarcomatous MM. Guled et al. (2009) also compare and analyze that expression of miRNAs in different subtypes of MM tissue. Seven miRNAs were specifically expressed in epithelial MM (miR-135b, miR-181a-2*, miR-499-5p, miR-517b, miR-519d, miR-615-5p, and miR-624), five miRNAs were specifically expressed in biphasic MM (miR-218-2*, miR-346, miR-377*, miR-485-5p, and miR-525-3p), and three miRNAs were specifically expressed in sarcomatous MM (miR-301b, miR-433, and miR-543). Tese miRNAs were specifically expressed in tissue subtypes.

      Differential Diagnosis

      The diagnostic performances of miR-130a expression analysis and immunohistochemistry appear to be similar. miR-130a quantification could be used reliably as a second-level diagnostic tool to differentiate MM from lung adenocarcinoma in pleural effusion cytology, mainly in those cases with ambiguous or negative immunohistochemistry (Cappellesso et al. 2017).

      Multiple miRNAs were combined to diagnose a MM and can better distinguish it from other tumors or from pleural metastatic carcinoma.

      Benjamin et al. (2010) were the first to find that eleven miRNAs were differentially expressed by gene chip in MPM patients and in twelve tumor patients—namely patients with bladder cancer, breast cancer, intestinal cancer, endometrial cancer, esophageal cancer, renal cancer, liver cancer, lung cancer, ovarian cancer, pancreatic cancer, prostate cancer, and gastric cancer. Among these miRNAs, four (in the miR-193 family, which includes miR-193a-3p/5p and -193b and miR-152) are highly expressed in MPM tissues, whereas seven (in the miR-200 family, which includes miR-141, miR-200a/b/c and miR-429, miR-192, and miR-194) are highly expressed in other tumor tissues. Further validation results showed that the combination of miR-200c/193a-3p was sufficient to distinguish MPM from most tumors except renal cell carcinoma, while miR-192 could be used to distinguish MPM from renal cell carcinoma, liver cancer, and gastrointestinal cancer. Subsequent double-blind experiments showed that the combination of miR-200c/193a-3p could make the accuracy of distinguishing MPM from breast cancer, intestinal cancer, endometrial cancer, renal cancer, lung cancer, ovarian cancer, and other tumors reach 95%. In pleural effusion cells, combining miR-143, miR-210, and miR-200c could discriminate MPM from a further adenocarcinoma with an AUC of 0.9887 (Birnie et al. 2019).

Gee et al. (2010) also found that miR-141, miR-200a/b/c, and miR-429 were downregulated in MPM samples and that miR-203 and miR-205 were downregulated as well. All seven miRNA markers can effectively distinguish MPM from lung adenocarcinoma, and their sensitivity or specificity exceeds the 80% recommended by the International Mesothelioma Interest Group. All members of the miR-200 family had AUCs above 0.9, while the remaining markers had AUCs between 0.83 and 0.89. In addition, these seven miRNA markers are only suitable for differential diagnosis, but cannot classify histological subtypes.

      MicroRNAs Related to the Occurrence and Development of Mesothelioma

      Because different miRNAs may have either carcinogenic or antitumor effects, researchers tried to clarify their role in the occurrence and development of MM. In vitro experiments and animal experiments have found that some miRNAs can inhibit tumor growth by regulating cell cycle, proliferation, clone formation, migration, invasion, apoptosis, and other biological processes. Some studies have also shown that miRNAs can directly inhibit the growth of tumors implanted in experimental mice.

      MicroRNAs Related to Cell Cycle Regulation

      Uncontrolled cell cycle is one of the key steps in tumorigenesis. Almost all tumor cells have cell cycle regulation defects, and MM is no exception. MicroRNAs can regulate the process of cell cycle by targeting key regulators that promote or inhibit cell cycle, such as cyclin-cyclin-dependent protein kinase (CDK) complex or other cell growth regulatory genes. Kubo et al. (2011) and Maki et al. (2012) found that the expression level of miR-34b/c in MM cell lines (H2052 and H28) decreased. After the level of miR-34 in cells was increased by transfection, the expression of the cell cycle-related proteins CDK4, CDK6, and CCND1 was inhibited and the proportion of G1 phase cells was significantly increased. When normal pleural cells (LP-9) were transfected with miR-34 inhibitor, the number of G1 phase cells decreased significantly and the expression levels of miR-34 target genes c-MET and Bcl-2 were significantly upregulated. This indicates that miR-34b/c plays an important role in regulating G1 cell cycle arrest (Tanaka et al. 2013). Some studies have also found that tumor cells are inhibited and in S phase by transfecting miR-31 into MM cell HP-1 or inhibiting the expression of endogenous miR-31 in MM cell H2461 (Ivanov et al. 2010).

      MicroRNAs Related to Proliferation and Clone Formation

      Abnormal cell proliferation is an important feature of tumors, and miRNA can regulate genes related to cell proliferation. Therefore the targeted regulation of miRNAs involved in cell proliferation may be helpful to the treatment of MM, and related studies have been reported. Some studies have transfected miR-31 analogues into MM cells and induced miR-31 precursor expression, and found that cell proliferation and the clone formation ability were significantly weakened. Similarly, there have been studies on the decrease of intracellular target protein expression after the transfection of miR-16 analogue and miR-145 activator into tumor cell lines, and the decrease of target protein expression is positively correlated with miRNA transfection concentration, while cell proliferation and clone formation are inhibited. However, the proliferation of normal mesothelial cells transfected with related miRNAs was not affected (Cioce et al. 2014; Reid et al. 2013). In addition, it has been reported that butterfly element (EphA2) inhibits the growth of MM cells by promoting the expression of let-7a1 and by inhibiting the proto-oncogene RAS. When MM cells are transfected with the precursor of miRNAlet-7, the expression of proto-oncogene RAS is inhibited, and cell proliferation is also inhibited (Khodayari et al. 2011).

MicroRNAs Associated with Migration and Invasion

      Malignant tumors have the characteristics of metastasis and invasiveness. They can metastasize from the primary site of the tumor to distant ones and invade adjacent tissues or organs. At the cellular level, they show the ability of cell migration and invasion. Identifying metastasis-related factors and understanding their role in the metastasis mechanism are helpful processes for the treatment of MM. Studies have found that the upregulation or deletion of some specific miRNAs makes cancer cells have potential metastasis ability. Fassina et al. (2012) used biphasic

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