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Page 2 of 11 Dixit et al. J Cancer Metastasis Treat 2022;8:47 https://dx.doi.org/10.20517/2394-4722.2022.70

[2]
phenotypic changes upon expression or suppression in cell-specific contexts . These properties may be
highly relevant to malignant pleural mesothelioma (MPM), a recalcitrant surface cancer that continues to
[3]
defy therapeutic attempts and is associated with poor survival .

According to the World Health Organization classification, MPM is divided into three main histological
subtypes: epithelioid (60%-80%), biphasic (10%-15%) and sarcomatoid (10%) . Patients with epithelioid
[4]
[5]
histological subtype MPM have a better overall survival (OS) than their sarcomatoid counterparts . The OS
rates among patients harboring the biphasic subtype depend on the amount of sarcomatoid tumor
component. MPM cisplatin-based therapy has not dramatically improved the median survival time of 12 to
18 months .
[6]

Recently, the USA Food and Drug Administration approved a new therapeutic regimen for MPM patients
(primarily for non-epithelioid histology) of combined nivolumab and ipilimumab . These drugs target the
[7]
immune checkpoint inhibitors programmed cell death 1 (PD-1) and cytotoxic T-lymphocyte associated
protein 4 (CTLA-4), respectively, and resulted in improved OS compared with standard-of-care
chemotherapy (18.1 months vs. 14.1 months). Despite these advances, substantial improvements in OS are
still elusive, demonstrating the critical need for more effective therapies against MPM.

A PubMed search starting from 2008 and using the terms “microRNA” and “mesothelioma” yielded 204
articles (searched in June 2022). This rough estimate provides context for the selected articles and the total
[8]
numbers of associated miRNAs. Multiple miRNAs are underexpressed in MPM , but only a few have been
functionally well characterized, among which several have exhibited potent anticancer activity in vitro and
in vivo. In this review, we highlight MPM-specific tumor suppressor miRNAs in the context of translational
potential for clinical use [Table 1]. We apply several criteria to focus on such miRNAs: (1) miRNAs
expressed at a low level in human MPM specimens (preferably vs. non-cancerous mesothelium); (2) low
tumor miRNA expression associated with poor outcomes; and (3) high tumor miRNA expression associated
with good outcomes.

MIRNAS THAT INHIBIT CELL PROLIFERATION AND MIGRATION/INVASION
miR-205 expression is lower in biphasic and sarcomatoid MPM than in the epithelioid type. Ectopic
expression of miR-205 in biphasic MPM cells (MSTO-211H) inhibited invasion and cell motility. This was
accompanied by downregulation of ZEB1 and ZEB2 and upregulation of CDH1 (E-cadherin), all of which
functionally contribute to epithelial-to-mesothelial transition (EMT) .
[9]

High miR-29c-5p expression in MPM is associated with improved survival irrespective of asbestos
[10]
exposure . miR-29c-5p targets DNMT1, DNMT3A, and DNMT3B, all of which are epigenetic regulators of
DNA methylation. Furthermore, overexpression of miR-29c-5p upregulated DNA demethylation genes
such as CTRP1, CTRP8, and Adiponectin. These molecular changes downstream of miR-29c-5p contributed
to inhibiting cell proliferation, invasion/migration, and colony formation.

MPM tumor tissues as well as MPM cell lines express low levels of miR-223-3p, which behaves as a tumor
suppressor by inhibiting Stathmin (STMN1) . STMN1 plays an important role in intracellular transport,
[11]
mitosis, cell motility, and maintenance of the cytoskeleton. miR-223-3p overexpression in MPM cells
reduced STMN1 levels, which ultimately led to the inhibition of MPM cell proliferation and migration.