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miR-219-5p attenuates cisplatin resistance of ovarian cancer by inactivating Wnt/β-catenin signaling and autophagy via targeting HMGA2

Cancer Gene Therapy volume 30, pages 596–607 (2023)Cite this article

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Abstract

Our previous study confirmed that miR-219-5p inhibits the progression of ovarian cancer (OC) by targeting high mobility group AT-hook 2 (HMGA2), while the role of miR-219-5p on the chemoresistance of OC is unclear. HMGA2 and miR-219-5p expression in OC tumors and various types of OC cells were determined by reverse transcription-quantitative PCR (RT-qPCR) and western blotting. The miRNA profiles in A2780 and cisplatin-resistant A2780 cells were investigated via bulk miRNA sequencing, and the interactions of miR-219-5p and HMGA2 were determined by luciferase reporter activity assay. Cell function was verified through Cell Counting Kit-8, invasion assay, wound-healing, and TUNEL assays. HMGA2 level is highly expressed in cisplatin-resistant OC cell lines compared to normal OC cells, while the expression trend of miR-219-5p is the opposite. In addition, we found that miR-219-5p is one of the miRNAs that have the most significant reduction in levels in the cisplatin-resistant A2780/DDP cell line compared to A2780 cells. Then, we reveal that miR-219-5p directly targets HMGA2 in cisplatin-resistant OC cells, and upregulation of miR-219-5p significantly reduces the resistance of OC cells to cisplatin both in vitro and in vivo. Finally, our results suggest that Wnt/β-catenin signaling and autophagy pathway is involved in the role of miR-219-5p/HMGA2 on resistance of OC cells to cisplatin via gain-of-function experiments. Collectively, the present study shows that miR-219-5p decreases the resistance of OC cells to cisplatin via Wnt/β-catenin signaling and autophagy by regulating HMGA2, which provides a feasible solution for the resistance of OC to chemotherapy.

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Fig. 1: Upregulated expression of high mobility group AT-hook 2 (HMGA2) in ovarian cancer (OC) is associated with the poor prognosis of patients.
Fig. 2: Decreased miR-219-5p level in OC is also related to the poor patient prognosis.
Fig. 3: miR-219-5p targets and downregulates HMGA2 in OC cells.
Fig. 4: miR-219-5p reduces the OC cell resistance to cisplatin.
Fig. 5: miR-219-5p limits the growth of OC tumors in a xenograft model.
Fig. 6: The increased cisplatin sensitivity of OC cells induced by miR-219-5p is related with Wnt/β-catenin signaling and autophagy.
Fig. 7: miR-219-5p-mediated increase in cisplatin sensitivity in SKOV3 OC cells is also associated with Wnt/β-catenin and autophagy.

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The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding authors.

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Funding

This study was supported by grants from the project of Shanghai Zhabei Central Hospital construction of important and weak medical disciplines (2021BR03).

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Author notes

  1. These authors contributed equally: Zhijiao Song, Caihe Liao.

Authors and Affiliations

  1. Department of Gynecology and Obstetrics, Zhabei Central Hospital, Jingan District, Shanghai, 200070, China

    Zhijiao Song, Liqun Yao, Xuexiang Xu, Xuezhen Shen, Siqi Tian & Feng Xing

  2. Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China

    Caihe Liao

  3. Department of Ultrasonography, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200092, China

    Shuo Wang

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Contributions

Concepts: F.X., Z.S., and S.W.; resources: F.X. and S.W.; experiments and data analysis: Z.S., L.Y., X.X., X.S., and S.T.; bioinformatics and manuscript preparation: C.L. and F.X.; revision and editing: Z.S., F.X., and S.W. All authors read and approved the final manuscript.

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Correspondence to Shuo Wang or Feng Xing.

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This study received approval from the Ethics Committee of Shanghai Zhabei Central Hospital, and all patients and participants signed informed consent. The procedures involving animals were approved by the Institutional Animal Care and Use Committee (IACUC) of Tongji University.

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Song, Z., Liao, C., Yao, L. et al. miR-219-5p attenuates cisplatin resistance of ovarian cancer by inactivating Wnt/β-catenin signaling and autophagy via targeting HMGA2. Cancer Gene Ther 30, 596–607 (2023). https://doi.org/10.1038/s41417-022-00574-y

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