miR-133a targets YES1 to reduce cisplatin resistance in ovarian cancer by regulating cell autophagy

Abstract

Background Accumulating evidence has revealed that aberrant microRNA (miRNA) expression can affect the development of chemotherapy drug resistance by modulating the expression of relevant target proteins. Emerging evidence has demonstrated that miR-133a participates in the tumorigenesis of various cancers. However, whether miR-133a is associated with cisplatin resistance in ovarian cancer remains unclear. Objective To investigate the role of miR-133a in the development of cisplatin resistance in ovarian cancer. Methods MiR-133a expression in cisplatin-resistant ovarian cancer cell lines was assessed by reverse-transcription quantitative PCR (RT–qPCR). A cell counting kit-8 (CCK-8) assay was used to evaluate the viability of tumour cells treated with cisplatin in the presence or absence of miR-133a. A luciferase reporter assay was used to analyse the binding of miR-133a with the 3′ untranslated region (3′UTR) of YES proto-oncogene 1 (YES1). The YES1 expression level was analysed using a dataset from the International Cancer Genome Consortium (ICGC) and assessed by RT–qPCR and western blotting in vitro. The roles and mechanisms of YES1 in cell functions were further probed via gain- and loss-of-function analysis. Results The expression of miR-133a was significantly decreased in cisplatin-resistant ovarian cancer cell lines (A2780-DDP and SKOV3-DDP), and the overexpression of the miR-133a mimic reduced cisplatin resistance in A2780-DDP and SKOV3-DDP cells. Treatment with the miR-133a inhibitor increased cisplatin sensitivity in normal A2780 and SKOV3 cells. MiR-133a binds the 3’UTR of YES1 and downregulates its expression. Bioinformatics analysis revealed that YES1 expression was upregulated in recurrent cisplatin-resistant ovarian cancer tissue, and in vitro experiments also verified its upregulation in cisplatin-resistant cell lines. Furthermore, we discovered that miR-133a downregulated the expression of YES1 and thus inhibited cell autophagy to reduce cisplatin resistance. Yes1 knockdown significantly suppressed the cisplatin resistance of ovarian cancer cells by inhibiting autophagy in vitro. Xenograft tumour implantation further demonstrated that Yes1 overexpression promoted ovarian tumour development and cisplatin resistance. Conclusions Our results suggest that the miR-133a/YES1 axis plays a critical role in cisplatin resistance in human ovarian cancer by regulating cell autophagy, which might serve as a promising therapeutic target for ovarian cancer chemotherapy treatment in the future.

FOXD3 confers chemo-sensitivity in ovarian cancer through a miR-335/DAAM1/myosin II axis-dependent mechanism

“…The corresponding CP-resistant OC cell lines A2780CP and SKOV3/CDDP were constructed by our laboratory. Sensitive parental A2780S cells and SKOV3 cells were co-cultured with 10–80 μM CP (Sigma-Aldrich, St. Louis, MO) for 48 h, during which the concentration of CP was gradually increased [ 23 , 24 ]. After resuscitation, these cells were cultured in DMEM (Gibco, Carlsbad, CA) containing 10% FBS (Gibco), 100 U/mL penicillin and 100 μg/mL streptomycin in a 5% CO 2 incubator (BB15, Thermo Fisher Scientific Inc., Waltham, MA) at 37℃.…”

Non-coding RNAs: The recently accentuated molecules in the regulation of cell autophagy for ovarian cancer pathogenesis and therapeutic response

“…NF-κB signaling pathway could be inhibited by miR-1301 to attenuate cisplatin resistance and delay the development of EMT in OC, ultimately refraining the progression of OC (Yu and Gao, 2020). Additionally, autophagy could be suppressed by miR-133a and miR-1301, thereby suppressing cisplatin resistance (Yu and Gao, 2020;Zhou et al, 2022). More importantly, the imbalance of ncRNA homeostasis was also closely related to the clinical characteristics of OC patients.…”

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

“…found that miR-133a was significantly downregulated in CDDP-resistant OC cell lines A2780 and SKOV3. The overexpression of miR-133a significantly enhanced the CDDP sensitivity in CDDP-resistant A2780 and SKOV3 cells by inhibiting autophagy via directly targeting YES1 ( 45 ). Li et al.…”