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MiRNA-3662 reverses the gemcitabine resistance in pancreatic cancer through regulating the tumor metabolism

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Cancer Chemotherapy and Pharmacology Aims and scope Submit manuscript

Abstract

Objectives

Gemcitabine (Gem) is one of the most commonly used chemotherapeutic drugs in treating patients with pancreatic ductal adenocarcinoma (PDAC). Acquired drug resistance against Gem presents a major clinical challenge in the chemotherapy of PDAC. It has been shown that miRNA-3662 is lowly expressed and implicated with quantities of biological processes in cancer. However, whether miRNA-3662 regulates chemoresistance in PDAC remains largely unknown.

Materials and methods

The level of miRNA-3662 in PDAC tissues was determined by real-time qPCR (RT-qPCR). Functional experiments were used to investigate the biological role of miRNA-3662 on Gem resistance of PDAC in vitro and in vivo. Fluorescence in situ hybridization (FISH), RT-qPCR, western blotting, bioinformatics analysis and luciferase reporter assay were employed to determine the precise regulation mechanisms.

Results

In this study, it was investigated that miRNA-3662 was down-regulated in PDAC clinical samples as well as cell lines. Functional assays revealed that miRNA-3662 was sufficient to inhibit Gem resistance in PDAC cells both in vitro and in vivo. Mechanistically, hypoxia-inducible factor 1ɑ (HIF-1ɑ) was one of the transcriptional target of miRNA-3662 and was up-regulated in PDAC samples. Importantly, genetic promoting of HIF-1ɑ largely compromised miR-3662-mediated chemosensitive effects. In addition, miR-3662 could impair the aerobic glycolysis in PDAC cells.

Conclusions

This study sheds light on miRNA-3662 inhibits PDAC cell chemoresistance and aerobic glycolysis through a negative feedback loop with HIF-1ɑ. Therefore, the co-delivery of miR-3662 and Gem could be served as a promising therapeutic regimen for PDAC patients.

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Abbreviations

Gem:

Gemcitabine

PDAC:

Pancreatic cancer

FISH:

Fluorescence in situ hybridization

RT-qPCR:

Real-time qPCR

HIF-1ɑ:

Hypoxia-inducible factor 1ɑ

miRNAs:

MicroRNAs

dCK:

Deoxycytidine kinase

IHC:

Immunohistochemical

Tunel:

Terminal deoxyribonucleotidyl transferase-mediated dUTP nick end labeling

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Acknowledgements

We thank the Scientific Research Fund of Hunan Provincial Education Department (No. 20A213 and No. 19B236) and Natural Science Foundation of Hunan Province (No. 2020JJ5221) for financial support.

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Authors and Affiliations

  1. Department of Chemistry and Chemical Engineering, Hunan Institute of Science and Technology, Yueyang, 414006, People’s Republic of China

    An Liu, Tian Zhao & Binbin Zhou

  2. Department of Gastrointestinal Surgery, The First People’s Hospital of Yueyang, Yueyang, 414000, People’s Republic of China

    Yonggui Zhou & Jia Xu

  3. Department of Intensive Care, The Second People’s Hospital of Yueyang, Yueyang, 414006, People’s Republic of China

    Xu Tang

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  1. An Liu
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  2. Yonggui Zhou
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  3. Tian Zhao
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  4. Xu Tang
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Contributions

(I) Conception and design: all the authors; (II) administrative support: An Liu and Yonggui Zhou; (III) provision of study materials or patients: Jia Xu; (IV) collection and assembly of data: Tian Zhao and Xu Tang; (V) data analysis and interpretation: Binbin Zhou; (VI) manuscript writing: all the authors; (VII) final approval of manuscript: all the authors.

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Correspondence to Xu Tang, Binbin Zhou or Jia Xu.

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Liu, A., Zhou, Y., Zhao, T. et al. MiRNA-3662 reverses the gemcitabine resistance in pancreatic cancer through regulating the tumor metabolism. Cancer Chemother Pharmacol 88, 343–357 (2021). https://doi.org/10.1007/s00280-021-04289-z

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  • DOI: https://doi.org/10.1007/s00280-021-04289-z

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