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Hypoxic exosomal HIF-1α-stabilizing circZNF91 promotes chemoresistance of normoxic pancreatic cancer cells via enhancing glycolysis

Oncogene volume 40, pages 5505–5517 (2021)Cite this article

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Abstract

Research has indicated that hypoxia profoundly contributes to chemoresistance of pancreatic cancer (PC), while the precise mechanism has not been fully elucidated. In this study, we report a hypoxic exosomal circular RNA (circRNA)-mediated mechanism of conferred chemoresistance in PC cells. Gemcitabine (GEM) resistance was enhanced in normoxic PC cells incubated with exosomes derived from hypoxic PC cells. CircRNA microarray displayed that circZNF91 was remarkably increased in hypoxic exosomes of PC cells compared with normoxic exosomes. Overexpression of circZNF91 obviously stimulated chemoresistance in PC cells, while knockdown of circZNF91 retarded the hypoxic exosome-transmitted chemoresistance. Mechanistically, the hypoxic-induced exosomal circZNF91 transmitted into normoxic PC cells could competitively bind to miR-23b-3p, which deprives the inhibition of miR-23b-3p on expression of deacetylase Sirtuin1 (SIRT1). Consequently, the upregulated SIRT1 enhanced deacetylation-dependent stability of HIF-1α protein, leading to glycolysis and GEM chemoresistance of recipient PC cells. In addition, we revealed that the increased circZNF91 in hypoxic exosome was attributed to the transcriptional regulation by HIF-1α. Coincidently, transmission of hypoxic exosomes into subcutaneous xenografts in nude mice obviously facilitated the chemoresistance of transplanted PC tumor, which could be reversed by depletion of circZNF91 or upregulation of miR-23b-3p. Furthermore, clinical data showed that circZNF91 was significantly upregulated in PC tissues and correlated with overexpression of glycolytic enzymes and short overall survival time. Collectively, exosomal circZNF91 can function as a cargo mediating the signal transmission between hypoxic and normoxic tumor cells to promote GEM chemoresistance of PC and may potentially serve as a therapeutic target.

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Fig. 1: CircZNF91 is critical for the hypoxic exosome-promoted GEM resistance in normoxic cancer cells.
Fig. 2: Exosomal circZNF91 functions as a sponge of miR-23b-3p.
Fig. 3: CircZNF91 upregulates SIRT1 expression via competitively binding to miR-23b-3p.
Fig. 4: Exosomal circZNF91 stabilizes HIF-1α protein by SIRT1-dependent deacetylation.
Fig. 5: Hypoxic exosomal circZNF91 promotes GEM resistance of normoxic PC cells by enhancing HIF-1α-regulated glycolysis.
Fig. 6: Exosomal circZNF91 is transcriptionally upregulated by HIF-1α during hypoxic condition.
Fig. 7: Targeting circZNF91/miR-23b-3p impedes the hypoxic exosome-promoted chemoresistance of PC in vivo.
Fig. 8: CircZNF91 is overexpressed in PC tissues and associated with poor prognosis.

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Acknowledgements

The National Science Foundation Committee of China (Grant Number: 81372666, 81672406 to GZ; 81802450 to SZ; 81802377 to YN); and Clinical Research Physician Program of Tongji Medical College, Huazhong University of Science and Technology to GZ supported this study.

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  1. These authors contributed equally: Zhu Zeng, Yong Zhao, QingYong Chen, Shuai Zhu

Authors and Affiliations

  1. Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Zhu Zeng, Yong Zhao, QingYong Chen, Shuai Zhu, Zeng Ye, Ping Hu, Ding Chen, Peng Xu, Jinghuang Chen, Chaojie Hu, Yuhang Hu, Fengyu Xu, Jiang Tang, Fan Wang, Shengbo Han, Mengqi Huang & Gang Zhao

  2. Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Yi Niu

  3. Department of Pancreatic Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Chunyou Wang

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Contributions

Designed and supervised the research: GZ. Performed cellular experiments: ZZ, YZ, SZ, ZY, YH, FX, JT, FW,SH and MH. Conducted animal experiments: ZZ, YZ, SZ. Provided the clinical data: QYC, YN, PH, DC, PX, JC, CH and CYW. Analyzed the data: GZ and ZZ.Wrote the manuscript: GZ and ZZ.

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Correspondence to Gang Zhao.

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Zeng, Z., Zhao, Y., Chen, Q. et al. Hypoxic exosomal HIF-1α-stabilizing circZNF91 promotes chemoresistance of normoxic pancreatic cancer cells via enhancing glycolysis. Oncogene 40, 5505–5517 (2021). https://doi.org/10.1038/s41388-021-01960-w

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