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Page 284 Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010

been identified and related to cancer . MiRNAs are small ncRNAs that bind to 3’-untranslated regions
[99]
of target mRNA in a sequence-specific fashion and either inhibit the translation of their target mRNA or
degrade it. MiRNAs are involved in both normal and cancer cellular processes linked to cell division, growth,
differentiation and ageing . Their behavior is complex in that they are present in both, the nucleus and
[100]
cytoplasm, and their nuclear presence permits them to control gene expression [101,102] . However, subgroups of
miRNAs, e.g., deregulated epi-miRNAs present in different cancer types target specific epigenetic regulators,
such as DNMT and histone deacetylase [103,104] .

A number of clinically regulated miRNAs have been identified in ovarian cancer. These include upregulated
miRNAs, miR-15a/16 miR-20a, miR-23a/b, miR-30a/b/c, miR-92, miR-93, miR-106a, miR-146b, miR-182, miR-200,
miR-203, miR-205, miR-223 and downregulated Let-7a/b/d/f, miR-22, miR-31, miR-34a/b/c, miR-125b, miR-127-3p,
miR-152, miR-155, miR-181a-3p, miR-382 .
[105]

Cisplatin resistance
A wealth of publications deals with the role of miRNAs in platinum resistance [Table 3]. For example,
Vera et al. identified four miRNAs (miR-7, miR-132, miR-335 and miR-148a) the deregulation of which
[106]
appears to be a common event in the development of resistance to cisplatin in ovarian cancer. In particular,
the specific DNA methylation of miR-7 in cisplatin-resistant cell lines was associated with a poor prognosis
in ovarian cancer patients. The direct regulation of MAFG by miR-7 seems to cause this resistance.

The human let-7 family comprises 13 members located on nine different chromosomes. The majority of the
members is involved in the modulation of drug sensitivity in different cancer types . In epithelial ovarian
[107]
cancer, the laboratory of Wang demonstrated that deregulation of let-7e promoted the development of resistance
to cisplatin . In situ hybridization revealed significantly lower expression levels of let-7e in chemo-resistant
[108]
than chemo-sensitive ovarian cancer tissues. Transfection with let-7e sensitized ovarian cancer cells to cisplatin,
down-regulated BRCA1 and Rad51 expression and repressed the repair of cisplatin-induced DNA double strand
break. Low let-7e and high Rad51 levels were significantly associated with poor overall and progression-free
survival. Multivariate regression and receiver operating characteristic analyses showed that let-7e was an
independent predictor for chemotherapy response and highly predictive of resistance to cisplatin, suggesting
that re-expression of let-7e may be an effective strategy for overcoming chemo-resistance . Zhao et al.
[110]
[109]
revealed that primary cancer cells from drug sensitive patients are more tumorigenic than those from drug
resistant women. In 26 drug-sensitive patients, the expression levels of miR-9, miR-145 and miR-429 were
higher than in 20 drug-resistant cases. Conversely, higher miR-26a expression was observed in resistant
patients. Inhibition of miR-9 resulted in decreased clonal cell formation and sensitivity to cisplatin, while
knockdown of the other three miRNAs did not influence drug sensitivity. Sun et al. analyzed the effects of
[111]
miR-9 on cisplatin and PARP [Poly(ADP ribose) polymerase] inhibitor sensitivity in ovarian cancer cells and
xenograft mice. The impact of miR-9 on prognosis was assessed in a cohort of 113 ovarian cancer patients.
In ovarian cancer cells, miR-9 bound directly to the 3’-UTR of BRCA1, downregulated BRCA1 expression
and impeded DNA damage repair. Treatment with miR-9 sensitized BRCA1-proficient xenograft tumors to
cisplatin. Patients with higher levels of miR-9 had better chemotherapy responses, platinum sensitivity and
longer progression-free survival.

Using microarrays, Pink et al. identified miR-21-3p, the passenger strand of the known oncogenic miR-21,
[112]
to direct increased resistance to cisplatin in a range of ovarian cell lines, whereas miR-21-5p had an opposite
effect and increased cisplatin sensitivity. The induction of resistance to cisplatin by miR-21-3p may be caused
by the binding to its mRNA target of the neuron navigator NAV3. NAV3 is involved in axon guidance during
development and its knockdown increased resistance to cisplatin.

Jin et al. showed that inhibition of miR-23a expression could significantly increase the sensitivity to
[113]
cisplatin in ovarian cancer cells. The cells were arrested in G0/G1 phase along with an increased apoptosis