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Curcumin attenuates Adriamycin-resistance of acute myeloid leukemia by inhibiting the lncRNA HOTAIR/miR-20a-5p/WT1 axis

Abstract

Acute myeloid leukemia (AML) is a common subtype of leukemia, and a large proportion of patients with AML eventually develop drug resistance. Curcumin exerts cancer suppressive effects and increases sensitivity to chemotherapy in several diseases. This study aimed to investigate the mechanism by which curcumin affects the resistance of AML to Adriamycin by regulating HOX transcript antisense RNA (HOTAIR) expression. Cell viability, colony-formation, flow cytometry, and Transwell assays were used to assess cell proliferation, apoptosis, and migration. A dual-luciferase reporter assay was used to verify the interaction between microRNA (miR)-20a-5p and HOTAIR or Wilms’ tumor 1 (WT1). RT-qPCR and Western blotting assays were performed to detect gene and protein expression. The results showed that curcumin suppressed the resistance to Adriamycin, inhibited the expression of HOTAIR and WT1, and promoted the expression of miR-20a-5p in human acute leukemia cells (HL-60) or Adriamycin-resistant HL-60 cells (HL-60/ADR). Furthermore, curcumin suppressed proliferation and promoted apoptosis of HL-60/ADR cells. Overexpression of HOTAIR reversed the regulatory effect of curcumin on apoptosis and migration and restored the effect of curcumin on inducing the expression of cleaved caspase3, Bax, and P27. In addition, HOTAIR upregulated WT1 expression by targeting miR-20a-5p, and inhibition of miR-20a-5p reversed the regulation of Adriamycin resistance by curcumin in AML cells. Finally, curcumin inhibited Adriamycin resistance by suppressing the HOTAIR/miR-20a-5p/WT1 pathway in vivo. In short, curcumin suppressed the proliferation and migration, blocked the cell cycle progression of AML cells, and sensitized AML cells to Adriamycin by regulating the HOTAIR/miR-20a-5p/WT1 axis. These findings suggest a potential role of curcumin and HOTAIR in AML treatment.

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Fig. 1: Curcumin suppresses the resistance of HL-60 cells to Adriamycin.
Fig. 2: Curcumin suppresses the expression of HOTAIR and WT1 and promotes the expression of miR-20a-5p.
Fig. 3: Overexpression of HOTAIR reverses the suppression of Adriamycin resistance by curcumin by targeting miR-20a-5p.
Fig. 4: HOTAIR positively regulates the expression of WT1 by targeting miR-20a-5p.
Fig. 5: Curcumin inhibits the resistance of leukemia cells to Adriamycin by regulating the miR-20a-5p/WT1 axis.
Fig. 6: Curcumin suppresses the resistance of leukemia cells to Adriamycin by inhibiting the HOTAIR/miR-20a-5p/WT1 axis in vivo.
Fig. 7: The schematic diagram of this study.

Data availability

All data generated or analyzed during this study are included in this article.

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Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

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Guarantor of integrity of the entire study: J-ML, study concepts: J-ML, study design: J-ML, definition of intellectual content: J-ML, literature research: WL, experimental studies: ML, data acquisition: ML, data analysis: J-ML, ML, statistical analysis: J-ML, paper preparation: J-ML, paper editing: J-ML, paper review: H-BS.

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Correspondence to Jun-Min Liu.

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This study was supported by Shenzhen science and technology R&D Funds (No. JCY2018022864237514).

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The study was approved by the Animal Ethics Committee of the People’s Hospital of Longhua District.

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Liu, JM., Li, M., Luo, W. et al. Curcumin attenuates Adriamycin-resistance of acute myeloid leukemia by inhibiting the lncRNA HOTAIR/miR-20a-5p/WT1 axis. Lab Invest (2021). https://doi.org/10.1038/s41374-021-00640-3

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