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

  • Cancer Gene Ther. 2022 Dec 9. doi: 10.1038/s41417-022-00574-y.
Zhijiao Song  #  1 ,  Caihe Liao  #  2 ,  Liqun Yao  1 ,  Xuexiang Xu  1 ,  Xuezhen Shen  1 ,  Siqi Tian  1 ,  Shuo Wang  3 ,  Feng Xing  4
Affiliations
  • 1. Department of Gynecology and Obstetrics, Zhabei Central Hospital, Jingan District, Shanghai, 200070, China.
  • 2. Department of Phototherapy, Shanghai Skin Disease Hospital, School of Medicine, Tongji University, Shanghai, 200443, China.
  • 3. Department of Ultrasonography, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200092, China. [email protected].
  • 4. Department of Gynecology and Obstetrics, Zhabei Central Hospital, Jingan District, Shanghai, 200070, China. [email protected].
  • # Contributed equally.
PMID: 36494581 DOI: 10.1038/s41417-022-00574-y
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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