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Page 4 of 11 Dixit et al. J Cancer Metastasis Treat 2022;8:47 https://dx.doi.org/10.20517/2394-4722.2022.70

• Drug resistance
Induces Apoptosis
miR-16- Low No Inhibits Tumor • BCL-2, CCND1, PD-L1 - Subcutaneous
5p [33-35,50,55] • Proliferation suppression xenograft** Phase
• Clonogenicity II clinical trial -
• Drug resistance planned †
Induces
• G0/G1 cell cycle
arrest
• Apoptosis
miR- Low High Inhibits proliferation Tumor • MCL-1, PD-L1 - Subcutaneous
193a- expression = Induces suppression xenograft**
3p [34,36] better survival • Apoptosis
• Necrosis
Modulate cell metabolism
miR-126- Low - Inhibits Tumor • IRS1, VEGF-A, PDK, - Subcutaneous
[38,39,56]
3p • Mitochondrial suppression ACL xenograft*
function
• Angiogenesis
Induces autophagy
Inhibit oncogenes
miR- Low - Inhibits Tumor • KRAS, EGFR, VEGF-A, - Subcutaneous and
206 [40,51] • Proliferation suppression IGF1R, CDK4, CDK6, intrapleural
•Migration/invasion CCND1, c-MET xenograft
Induces
• G1/S cell cycle
arrest
• Senescence

All miRNAs are named according to their sequence identity in miRBase (release 22.1; Available from: www.mirbase.org), which may defer from
#
their nomenclature in the original articles. Low in biphasic and sarcomatoid histological subtypes; *although mouse flank xenografts were
reported, the MPM cell line had been transfected beforehand with miR-145-5p and then grafted into the mouse; **systemic delivery of miRNA;
† [50]
as indicated by the reference .

Re-expression of miR-1294 suppressed MPM cell proliferation, migration/invasion, and clonogenicity by
downregulating HMGA1. Interestingly, miR-1294 expression is influenced by the circular RNA (circRNA)
polo-like kinase 1 (circPLK1) in MPM progression . circRNAs are closed noncoding RNAs generated by
[12]
back-splicing of exons from precursor pre-mRNAs. circRNAs are widely expressed in mammalian cells in
tissue-specific patterns and regulate various biological processes. circPLK1 directly binds miR-1294 by
complementary base pairing to sequester its expression in MPM. This reciprocal relationship has been
observed in gene profiling studies where circPLK1 was overexpressed with concomitant miR-1294
downregulation.

MIRNAS THAT INDUCE CELL CYCLE ARREST AND APOPTOSIS
A microarray analysis of 31 human samples (25 MPM tumors and 6 normal pleura) was performed to
identify global miRNA signatures. miR-1-3p was among the top downregulated miRNAs in human MPM
tumors compared with normal pleura (6.6-fold) . miR-1-3p inhibited MPM cell proliferation and induced
[13]
G1/S cell cycle arrest and apoptosis. Re-expression of miR-1-3p modulated the expression of signaling
molecules that impact cell cycle progression and apoptosis such as p16, p21, p53, BAX, BCL-2, and Survivin.
Another physiologic effect of miR-1-3p was inhibition of cell migration and invasion by downregulating the
proto-oncogene PIM-1, a serine/threonine-protein kinase .
[14]

MIRNAS ASSOCIATED WITH P53
Unlike other solid epithelial tumors, there is a low frequency (approximately 9%) of p53 mutations in MPM
irrespective of histotype . However, p53 functionality is bypassed, wherein 50% to 75% of MPM tumors
[15]