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Page 6 of 11 Dixit et al. J Cancer Metastasis Treat 2022;8:47 https://dx.doi.org/10.20517/2394-4722.2022.70

[28]
miR-34b/c targeting BCL-2 . The underlying targets that mediate the phenotypic effects of miR-34b/c
overexpression include c-MET, c-MYC, CDK4/6, CCND1, and CCNE2. In vivo, an adenovirus vector
expressing miR-34b/c intratumorally injected into subcutaneous MPM murine xenografts (average 5 mm
[29]
diameter) inhibited tumor growth and reduced tumor volumes compared with vehicle .

MIRNAS THAT INHIBIT IMMUNE CHECKPOINTS
Among their multiple molecular targets, some miRNAs affect immune checkpoint regulation, an area of
intense basic and clinical research. Interestingly, examples of miRNAs suppressing the immune checkpoint
pathway in MPM are contrary to prevailing immuno-oncologic notions. For MPM and other solid tumors,
the goal of epigenetic priming for enhanced tumor response to immune checkpoint inhibitors is dependent
[30]
on the upregulation (not down) of PD-L1 on tumor cells . Furthermore, the hypothetical benefits of
downregulating PD-L1 in MPM (by miRNA regulators as reviewed here) remain unclear, given current
clinical trial results. Positive expression of PD-L1 in MPM is associated with a better objective response rate,
and overall survival trended worse with no or loss of PD-L1 expression [31,32] .

The miR-15/16 family of miRNAs (miR-15a-5p, miR-15b-5p, and miR-16-5p) have identical seed
sequences, consequently with much overlap in their predicted mRNA targets. All three miRNAs are under-
expressed in MPM tumors compared with normal pleura, with miR-16-5p exhibiting the most profound
loss and the most significant cell growth inhibition when transfected into MPM cells . Re-expression of the
[33]
miR-16-5p mimic stunted colony formation, induced G0/G1 cell cycle arrest, and increased apoptosis. In
the presence of miR-16-5p mimic, there was increased sensitivity to gemcitabine and pemetrexed but not to
cisplatin in a panel of MPM cells. These in vitro effects correlated with the downregulation of BCL-2 and
CCND1. Subcutaneous mouse xenografts were inhibited in a dose-dependent manner with multiple
systemic administrations of miR-16-5p mimic loaded into EGFR-targeted bacterially-derived minicells.
Another target of miR-16-5p is programmed death-ligand 1 (PD-L1), which is downregulated, and is an
[34]
important factor for immune escape of cancer cells . A phase 1, first-in-man trial assessed systemic
administration of miR-16-5p mimic to treat MPM and demonstrated a 5% objective response rate (partial
response by CT image, n = 22) and 68% disease control rate (stable tumor volume by CT image after
treatment) .
[35]
Compared with normal pleura, miR-193a-3p expression is lower in MPM tumors and cell lines as well as
being associated with poor overall survival in MPM patients . Re-expression of miR-193a-3p mimic in
[36]
MPM cells inhibited their growth while inducing late apoptosis and necrosis. Some of the underlying
affected gene targets associated with the killing of MPM cells included MCL-1, which encodes an anti-
apoptotic protein of the BCL-2 family. In vivo, miR-193a-3p suppressed tumor growth and induced
apoptosis in mouse subcutaneous xenografts. Multiple systemic doses of miR-193a-3p mimic loaded in
EGFR-targeted bacterially-derived minicells were required. In a follow-up study, miR-193a-3p modulated
PD-L1 mRNA and protein levels, although in an inconsistent pattern among the panel of tested MPM cell
lines . Unlike other miRNAs that directly regulate PD-L1, miR-193a-3p binds to PD-L1 transcripts at a
[34]
noncanonical 8-mer site in the 3′-UTR.

MIRNAS THAT MODULATE CELL METABOLISM
While the diagnostic utility of miR-126-3p remains to be validated, it was underexpressed in MPM tumors
compared with adjacent non-cancerous tissues . The in vitro effects of miR-126-3p re-expression were
[37]
assessed in MPM cells under conditions of oxidative stress, mitochondrial dysfunction, mitochondrial DNA
depletion, and hypoxia . Cell models with ectopic miR-126-3p and stable cell lines expressing miR-126-3p
[38]
were evaluated. Compared with controls, miR-126-3p reduced glucose uptake, facilitated metabolic