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reprogramming, and stimulated hypoxia-inducible factor-1α (HIF-1α). Primarily, the target that mediated
these cellular disturbances downstream of miR-126-3p was insulin receptor substrate-1 (IRS1) and its
complex signaling network that involves the Akt/FoxO1/ACL pathways, converging on HIF-1α lowering
VEGF-A activity (also a direct target of miR-126-3p). These perturbances inhibited MPM cell growth
in vitro. With similar caveats to the animal model used to test miR-145-5p, MPM cells as subcutaneous
xenografts in mice were transfected with miR-126-3p before implantation, but not treated in true in vivo
fashion upon tumor growth. This study also identified other targets of miR-126-3p, including pyruvate
dehydrogenase kinase (PDK) and acetyl-CoA-citrate lyase (ACL), which induce autophagy when
inhibited .
[39]

MIRNAS THAT INHIBIT ONCOGENES
Hyperactivated (but non-mutated) tyrosine-kinase-RAS signaling is a peculiar pathologic feature of MPM
that has been an elusive pathway to target by conventional drugs. miR-206 is a member of the miR-1 family
that is downregulated in MPM tissues and cell lines . Re-expression of miR-206 inhibited cell growth,
[40]
clonogenicity, and invasiveness in MPM cell lines. miR-206 caused a G1/S cell cycle arrest and cell death by
inducing senescence. miR-206 regulates multiple members of the receptor tyrosine kinase/Ras/cell cycle
network (VEGF-A, EGFR, c-MET, and CDK6), some of which were also prognostic genes in MPM (IGF1R,
KRAS, CCND1, and CDK4). Along with in vitro anticancer effects, when miR-206 was delivered locally in an
anatomic compartment, it suppressed the growth of subcutaneous and orthotopic xenografts, increasing
survival in mice. A novel therapeutic strategy consisting of systemic-route abemaciclib (CDK 4/6 inhibitor)
and local-route miR-206 was demonstrated to have additive antitumor efficacy, validating the notion that
simultaneous knockdown of an oncogenic transcript and inhibition of its protein activity is synergistic.

AMBIGUOUS TUMOR SUPPRESSOR MIRNAS
Several miRNAs have been purported to be tumor suppressors in MPM largely on the basis of in vitro
results, but their bona fide status in this category remains unclear because of a lack of in-depth studies and
characterizations. Using our more stringent criteria for tumor suppressor function, miRNAs whose high
expression in MPM tissue was associated with worse prognosis or alternatively whose low expression was
associated with better prognosis were excluded from further review except where noted. Furthermore,
inconsistency between miRNA expression level and biological activity in MPM cell line experiments
suggests that such miRNAs may not be robust candidates for ongoing anti-MPM therapeutic development.

Initially, loss of miR-31-5p was described in MPM cell lines derived from patients with more aggressive
disease . When re-expressed, miR-31-5p inhibited proliferation, invasion/migration, and clonogenicity of
[41]
MPM cells. These effects were accompanied by G1/S phase cell cycle arrest, which was attributed to reduced
expression of the direct target pro-survival protein phosphatase PPP6C. Contrary to these effects, when
[42]
miR-31-5p was re-expressed in other MPM cells, there was increased chemoresistance, not sensitivity .
Another discrepancy of miR-31-5p in MPM is that in biphasic and sarcomatoid subtypes (albeit a small
sample size from a larger pathologic cohort analysis), its expression was elevated and associated with worse
prognosis . Therefore, the role of miR-31-5p in MPM remains convoluted.
[43]
EphrinA1 binding induced let-7a miRNA, which subsequently repressed the RAS proto-oncogene in MPM
cells, attenuating proliferation as part of the ephrinA1/EphA2 signaling axis . The baseline expression of
[44]
let-7a in MPM cells was not reported. Furthermore, the relative expression of let-7a in MPM tumors
compared with normal tissues remains obscure, with mentions of several different let-7 isoforms varying in
[8]
their relative expression level in tumors and their importance for either diagnosis or prognosis . The
primary message in this comprehensive miRNA review was that for let-7 (among several other heavily