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Schwarzenbach et al. Cancer Drug Resist 2019;2:271-96 I http://dx.doi.org/10.20517/cdr.2019.010 Page 287

differentiation and its hypermethylation. Demethylation by the treatment with 5-aza-CdR re-activated miR-130b
expression in drug resistant ovarian cancer cell lines along with an increase in sensitivity to cisplatin and taxol.
Thus, downregulation of miR-130b promotes the development of multidrug resistant ovarian cancer partially by
binding of miR-130b to its target mRNA of the colony-stimulating factor 1 (CSF-1).

As reported by Zhao et al. , miR-136 expression was significantly reduced in 34 primary platinum-resistant
[118]
patients and an ovarian cancer cell line. Overexpression of miR-136 decreased the chemo-resistance to
cisplatin in ovarian cancer cells through inhibition of cell survival and promoting an apoptotic response to
cisplatin. The percentage of DNA in comet tails, tail length, tail moment and olive tail moment exposed the
relevance of miR-136 in the repair of cisplatin-induced DNA damage.

MiRNA-139 has been characterized as a tumor suppressor with anti-oncogenic and anti-metastatic activity
and consequently, is downregulated in different cancer types [119-121] . Jiang et al. revealed that the expression
[122]
of miR-139-5p was decreased in cisplatin-resistant ovarian cancer cell lines. Re-expression of miR-139-5p
increased the sensitivity of these cells to cisplatin treatment, inhibited the expression of the activator protein-1
transcription factor component c-Jun through binding to the 3´UTR of c-Jun mRNA, and decreased the
expression of the BCL family member BCL-xL, promoting cisplatin-induced mitochondrial apoptosis.

Oxidative and electrophilic changes in cells are mainly coordinated by the KEAP1/NRF2 [Kelch-like
erythroid-derived cap-n-collar homology- (ECH-) associated protein-1/nuclear factor (erythroid-derived 2)-
like 2] axis. Electrophiles react with critical thiol groups of KEAP1 causing the loss of its ability to inhibit
NRF2. The KEAP1/NRF2 signaling pathway also down-regulates NF-κB transcriptional activity and
attenuates cytokine-mediated induction of pro-inflammatory genes . van Jaarsveld et al. [124] demonstrated
[123]
that miR-141 directly targets KEAP1, and that downregulation of KEAP1 induced cisplatin resistance.
Conversely, overexpression of KEAP1 significantly enhanced cisplatin sensitivity. The NF-κB pathway,
which is regulated by KEAP1, was activated upon miR-141 overexpression, while inhibition of this pathway
partially reversed miR-141-mediated cisplatin resistance. Furthermore, van Jaarsveld et al. quantified the
[124]
expression levels of miR-141 in 108 serous and 24 non-serous primary ovarian tumors. They found that its
levels were elevated in non-serous ovarian tumors that did not respond well to therapy.

A negative correlation between the collagen receptor tyrosine kinase Discoidin Domain Receptor 1 (DDR1)
and miR-199a-3p was detected by Deng et al. in ovarian cancer tissues. Cell culture experiments confirmed
[125]
that miR-199a-3p decreased the expression of DDR1 via binding to DDR1 mRNA. In ovarian cancer cells,
the miR-199a promoter was hypermethylated, but not in normal cells. Knockdown of DNMT3A increased
miR-199a-3p expression and attenuated the expression of DDR1 in ovarian cancer cells, while overexpression
of miR-199a-3p impaired the migratory, invasive and tumorigenic capabilities of ovarian cancer cells as well
as enhanced cisplatin resistance through inhibiting DDR1 expression.

Using miRNA microarray analyses, Zhao et al. demonstrated that upregulation of miR-224-5p was
[126]
associated with platinum-based chemo-resistance in ovarian cancer patients. They identified the protein
kinase Cd gene as one of the targets of miR-224-5p in mediating resistance to cisplatin in ovarian cancer
patients. These findings indicate that miR-224-5p and protein kinase Cd can serve as predictors and prognostic
biomarkers for ovarian papillary serous cancer patient response to overall disease-specific survival.

The Notch receptor family plays an important role in cell differentiation, organ development and
tumorigenesis, tumor progression, invasion and metastasis. The activation of the Notch signaling pathway
can both accelerate and restrain tumorigenesis, depending on the cell environment . Zhou et al. [127]
[50]
demonstrated that ectopically expressed miR-449a increased cisplatin sensitivity in cisplatin-resistant ovarian
cell lines through targeting Notch1 transcripts, inhibited cell proliferation and promoted apoptosis. These
findings were confirmed with in vitro experiments. When BALB/c nude mice were injected intraperitoneally