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Page 288 Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010

with cisplatin-resistant ovarian cancer cells transfected with miR-449a, they exhibited enhanced cisplatin
sensitivity in vivo.

Based on the interplay between miR-483-3p and protein kinase Cd, Arrighetti et al. explained the
[128]
mechanism of resistance to cisplatin. They observed that miR-483-3p usually involved in apoptosis and cell
proliferation was up-regulated in cisplatin resistant ovarian cancer cells. This up-regulation of miR-483-3p
and possibly its binding to protein kinase Cd mRNA interfered with the proliferation of resistant ovarian
cancer cells, thus, protecting them from DNA damage induced by platinum compounds.

MiR-509-3p has been reported to sensitize ovarian cancer cells to cisplatin treatment by targeting multiple
anti-apoptosis genes including BCL2 [129,130] . Niu et al. compared the expression profiles of miRNAs between
[131]
three pairs of platinum-resistant and platinum-sensitive ovarian tissues and found that miR-509-3p was
significantly down-regulated in cisplatin-resistant ovarian cancer tissues. Functional studies demonstrated
that miR-509-3p inhibitor decreased cell response to cisplatin and promoted cell survival in ovarian cancer
cells. In this process, miR-509-3p regulated the expression of Golgi phosphoprotein-3 (GOLPH3) and wntless
Wnt ligand secretion mediator (WLS).

Previously, Zhang et al. detected that miR-520g contributes to tumor progression and cisplatin resistance
[132]
by post-transcriptionally downregulating its target mRNA of death-associated protein kinase 2 (DAPK2).
MiR-520g expression gradually increased across normal, benign, borderline and ovarian cancer tissues.
High miR-520g levels promoted tumor progression and chemo-resistance to cisplatin, and reduced survival
in ovarian cancer patients. DAPK2 overexpression or miR-520g knockdown reduced ovarian cancer cell
proliferation, invasion, wound healing and chemo-resistance.

Ovarian cancer stem cells are involved in tumor growth, metastasis and recurrence. The main characteristics
of this subpopulation of cancer cells are their uncontrolled proliferation, high invasiveness and resistance
to the current platinum-based therapies . Using a quantitative PCR array, Wei et al. demonstrated that
[133]
[134]
miR-551b was upregulated in ovarian cancer stem cells and that its levels correlated with the pathological
grades. In vitro experiments indicated that miR-551b inhibited the transcription factor forkhead box O3
and RING finger, B-box and coiled-coil domain protein TRIM31 (tripartite motif), promoted proliferation,
invasion and chemo-resistance of ovarian cancer cells and cancer stem cells. Accordingly, in mouse
xenograft models, the inhibition of miR-551b significantly increased the susceptibility of ovarian cancer
cells to cisplatin and prolonged the survival of the host mice.

Excision repair crossing-complementing group 2 (ERCC2), also called xeroderma pigmentosum complementary
group D (XPD), plays a crucial role in the nucleotide excision repair pathway. In concert with XPA, ERCCR2
verifies the presence of a relevant base lesion by scanning a DNA strand in the 5'-3' direction, so ensuring the
accurate removal of the lesion from the genome . In this regard, Zhao et al. examined the function of
[135]
[136]
miR-770-5p which targets ERCCR2 in cisplatin chemotherapy resistance in ovarian cancer patients. MiR-770-5p
expression was reduced in these patients. Overexpression of miR-770-5p reduced survival in chemo-resistant
cell lines after cisplatin treatment by downregulating ERCC2. A comet assay confirmed that the restoration of
cisplatin chemo-sensitivity was due to the inhibition of DNA repair.

The insulin-like growth factor-1 receptor (IGF-1R) is expressed on most transformed cells, where it has
anti-apoptotic, cell-survival and transforming activities. Its activation is a hallmark for tumor initiation
and progression . Zhang et al. investigated the effect of miR-1294 on platinum-resistant ovarian cancer
[137]
[138]
and documented that miR-1294 dysregulation manipulated ovarian cancer cisplatin resistance through
regulating IGF1R. Knockdown of IGF1R decreased cell proliferation, migration, invasion and EMT of
cisplatin-resistant cells. Overexpression of miR-1294 inhibited cisplatin resistance, suggesting that epigenetic
regulation of IGF1R by miR-1294 was essential for cisplatin resistance.