circ_C20orf11 enhances DDP resistance by inhibiting miR-527/YWHAZ through the promotion of extracellular vesicle-mediated macrophage M2 polarization in ovarian cancer

ABSTRACT

Ovarian cancer is a fatal gynecologic tumor, and conventional treatment is mainly limited by chemoresistance. The mechanism contributing to chemoresistance in ovarian cancer has yet to be established. This study aimed to investigate the specific role of circ_C20orf11 in regulating chemoresistance to cisplatin (DDP)in ovarian cancer. We first established two DDP-resistant ovarian cancer cell lines. Then, we identified the effect of circ_C20orf11 on specific cellular characteristics (proliferation, apoptosis, DDP resistance) via a series of experiments. The binding sites between circ_C20orf11 and miR-527 and between miR-527 and YWHAZ were predicted using a bioinformatics tool and confirmed with a dual-luciferase reporter assay. Furthermore, extracellular vesicles (EVs) derived from DDP-resistant cell lines were identified, and the effect of EVs on macrophage polarization was examined. circ_C20orf11 was upregulated in ovarian cancer. Increased circ_C20orf11 expression enhanced DDP resistance and cell proliferation and reduced cell apoptosis in DDP-resistant cell lines after DDP treatment by sponging miR-527 and promoting YWHAZ expression. In addition, we found that DDP-resistant cell-derived EVs can induce macrophage M2 polarization, whereas silencing of circ_C20orf11 inhibited EV-induced macrophage M2 polarization. Consistent with these results, silencing of circ_C20orf11 enhanced sensitivity to DDP in vivo. Importantly, we proved that circ_C20orf11 expression was upregulated in EVs extracted from the serum of DDP-resistant patients. Our study demonstrated that silencing circ_C20orf11 sensitizes ovarian cancer to DDP by promoting miR-527/YWHAZ signaling and EV-mediated macrophage M2 polarization.

KEYWORDS:

• circ_C20orf11
• miR-527
• YWHAZ
• EVs
• ovarian cancer cells
• cisplatin
• M2 macrophage polarization

Funding

This work was supported by Natural Science Foundation of Xinjiang Autonomous Region (No.2021D01C403)

Disclosure statement

No potential conflict of interest was reported by the author(s).

Availability of data and material

All data generated or analyzed during this study are included in this article. The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Ethical approval

This study was approved by the Animal Care and Utilization Committee of Affiliated Tumor Hospital of Xinjiang Medical University and carried out according to the Guidelines for the Care and Use of Laboratory Animals. The study was approved by the Medical Ethics Committee of The Affiliated Tumor Hospital of Xinjiang Medical University.

Consent for publication

The informed consent was obtained from study participants.

Authors’ contribution

Conception and study design: Jun Yin, Hai-Yan Huang;

Data acquisition: Ying Long;

Data analysis: Yan Ma;

Manuscript drafting: Maerkeya Kamalibaike;

Manuscript revising: Reyanguli Dawuti, Li Li.

Abbreviations

circRNAs: circulating RNAs; DDP: cisplatin; EVs: extracellular vesicles; FBS: foetal bovine serum; HOSEpiCs: human ovarian surface epithelial cells; IC50: half maximal inhibitory concentration; iNOS: inducible nitric oxide synthase; IL-10: interleukin-10; mRNAs: messenger RNAs; miRNAs: microRNAs; ncRNA: non-coding RNA; PD-L1: programmed death-ligand 1; siRNA: small interfering RNA; TNF-α: tumour necrosis factor-alpha; YWHAZ: tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein zeta.