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

reported MPM-associated miRNAs), there is no clear consensus of results among heterogeneous studies. A
more recent article demonstrated that low let-7c-5p expression, which shares the same seed sequence as all
[45]
let-7 members and therefore similar targets, in FFPE MPM samples was associated with poor survival .

A later study of a similar design seeking to elucidate underlying mechanism(s) of the EphrinA1 axis in
MPM implicated miR-302b-3p as a mediator of anti-MPM effects via targeting myeloid cell leukemia-1 (
[46]
MCL-1), a member of the anti-apoptotic Bcl-2 family . miR-302b levels in MPM are dependent on ephrin
A1/EphA2 signaling, whereby administration of Ephrin A1 induced miR-302b expression. Overexpression
of miR-302b inhibited cell proliferation, tumorigenicity, and induced apoptotic cell death in MPM cells.
This in vitro study did not describe the basal expression level of miR-302b-3p in MPM tissues nor any
associations with outcomes. A PCR-array miRNA profiling of MPM tumors (n = 5 patients) compared with
[47]
non-MPM tissues identified miR-302b-3p among the top overexpressed miRNAs . However, in The
Cancer Genome Atlas-meso database, miR-302-3p is nearly undetectable in MPM tumors .
[48]
The tissue and cell line expression signature of miR-137-3p was heterogenous in both MPM (n = 115) and
normal pleura (n = 23). The variability of miR-137-3p expression, including over- and under-expression,
was associated with copy number variation and promoter hypermethylation of miR-137-3p. Regardless of
expression levels, miR-137-3p suppressed MPM cell line growth by targeting Y-box binding protein 1
[49]
(YBX1) . Overexpressing miR-137-3p inhibited cell growth and migration/invasion in MPM cells, and
unexpectedly even in cell lines with high endogenous expression of the miRNA. An antisense inhibitor of
miR-137-3p had no effect on proliferation. Higher miR-137-3p expression was associated with poor, not
better, survival among patients who had extra-pleural pneumonectomy or pleurectomy and/or
decortication (P/D). These inconsistencies in expression level, biologic activity, and prognosis are difficult
to reconcile for this miRNA and more experimentation is required.

CONCLUSION
The importance of endogenous miRNAs and noncoding regulatory RNAs arranged into complex miRNAs
include modulating mRNA signaling networks and diverse aspects of cellular homeostasis. For cancer
translational applications, miRNAs with naturally low expression in tumors relative to the normal
counterparts represent a practical and promising strategy to further pursue, especially regarding MPM, a
recalcitrant surface malignancy without a cure nor durable treatment. This review highlights the
surprisingly short list of bona fide tumor suppressor miRNAs in MPM with verified gene targets and
consistent in vivo effects [Table 1]. Thus, there is a continued need to verify the miRNAs already reported
but with incomplete pathologic characterization, especially regarding the multiple targets of each miRNA.
Doing so will fill in knowledge gaps about the physiology of MPM. Additionally, there is the implied
necessity for continued discovery of novel MPM-associated miRNAs, as multiple miRNAs may fulfill an
anti-MPM role in the context of inherent inter-tumor molecular and pathologic heterogeneity.

There should be great optimism for miRNA-based therapies for MPM, as novel approaches have addressed
the barrier of effective in vivo delivery vehicle(s). Notably, the best characterized tumor suppressor miRNAs
in this review have been used to demonstrate anti-MPM efficacy. Systemic delivery of miR-16-5p for MPM
was well tolerated and safe in a phase 1 setting, as well as showing early signs of activity, warranting
additional clinical trials [35,50] . More recently, there was successful locoregional (intrapleural and
intraperitoneal murine xenograft models) delivery of miR-215-5p and miR-206 complexed as nanoparticles
in a composite peptide surface-fill hydrogel (SFH) carrier as a primary and adjuvant MPM therapy . SFH
[51]
is a deformable polymer that can be sprayed onto large anatomically complex surfaces, such as the pleural
space, as an adherent coating, which in turn functions as a therapy eluting depot. The encapsulated miRNA