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MicroRNA-375 represses tumor angiogenesis and reverses resistance to sorafenib in hepatocarcinoma

Cancer Gene Therapy volume 28, pages 126–140 (2021)Cite this article

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Abstract

Sorafenib was originally identified as an inhibitor of multiple oncogenic kinases and remains the first-line systemic therapy for advanced hepatocellular carcinoma (HCC). MicroRNAs (miRNAs) have been reported to play critical roles in the initiation, progression, and drug resistance of HCC. In this study, we aimed to identify sorafenib-induced miRNAs and demonstrate their regulatory roles. First, we identified that the expression of the tumor-suppressive miRNA miR-375 was significantly induced in hepatoma cells treated with sorafenib, and miR-375 could exert its antiangiogenic effect partially via platelet-derived growth factor C (PDGFC) inhibition. Then, we demonstrated that sorafenib inhibited PDGFC expression by inducing the expression of miR-375 and a transcription factor, achaete-scute homolog-1 (ASH1), mediated the induction of miR-375 by sorafeinb administration in hepatoma cells. Finally, we verified that the expression of miR-375 was reduced in sorafenib-resistant cells and that the restoration of miR-375 could resensitize sorafenib-resistant cells to sorafenib partially by the degradation of astrocyte elevated gene-1 (AEG-1). In conclusion, our data demonstrate that miR-375 is a critical determinant of HCC angiogenesis and sorafenib tolerance, revealing a novel miRNA-mediated mechanism underlying sorafenib treatment.

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Fig. 1: Sorafenib induces miR-375 expression in hepatoma cells, and miR-375 is downregulated in HCC tissues and cells.
Fig. 2: MiR-375 suppressed angiogenesis in HCC by targeting PDGFC.
Fig. 3: MiR-375 impaired the growth of hepatoma xenografts and suppressed angiogenesis in HCC in vivo.
Fig. 4: Sorafenib inhibited PDGFC expression via miR-375 induction in hepatoma cells.
Fig. 5: MiR-375 attenuated acquired resistance to sorafenib by suppressing astrocyte elevated gene-1 (AEG-1).
Fig. 6: MiR-375 renders sorafenib-resistant cells sensitive to sorafenib in vivo.
Fig. 7: Molecular mechanisms by which miR-375 represses tumor angiogenesis and reverses resistance to sorafenib in HCC.

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Data availability

Data generated for the current study are available from the corresponding author on reasonable request.

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Acknowledgements

Infrastructure for this research was supported by Institute of Aging and Immunity, Chengdu Medical College, Chengdu 610083, Sichuan Province, China.

Funding information

The research was funded by the Scientific Research Foundation of the Science and Technology Department of Sichuan Province (Grants 2017SZ0066 and 2015FZ0073), the National Natural Science Foundation of China (Grant 81101634), the Scientific Research Project of the Health Department of Sichuan Province (No. 16PJ026) and the Scientific Research Project of the Administration of Traditional Chinese Medicine of Sichuan Province (No. 2014K057).

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Author notes

  1. These authors contributed equally: Dong Li, Tao Wang, Fei-Fan Sun

Authors and Affiliations

  1. Department of Oncology, The General Hospital of Western Theater Command PLA, Chengdu, 610083, Sichuan Province, China

    Dong Li, Tao Wang, Fei-Fan Sun, Jian-Qiong Feng, Jing-Jing Peng, Hua Li, Dan Wang, Yu Liu, Yu-Di Bai, Mao-Lin Shi & Tao Zhang

  2. Department of Pathology, The General Hospital of Western Theater Command PLA, Chengdu, 610083, Sichuan Province, China

    Chao Wang

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Contributions

D.L., T.W., F.-F.S. and T.Z.: conceived the study, conducted experiments, acquired and analysed data, and wrote the manuscript; J.-Q.F., J.-J.P., H.L., C.W., D.W., Y.L., Y.-D.B., M.-L.S.: responsible for conception and supervision of the study, and wrote the manuscript. All authors corrected draft versions and approved the final version of the manuscript.

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Correspondence to Tao Zhang.

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The study was approved by the Ethics Committee of General Hospital of Western Theater Command, and informed consent was obtained from all patients, which is accredited by the National Council on Ethics in Human Research.

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The authors declare that they have no conflict of interest.

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Li, D., Wang, T., Sun, FF. et al. MicroRNA-375 represses tumor angiogenesis and reverses resistance to sorafenib in hepatocarcinoma. Cancer Gene Ther 28, 126–140 (2021). https://doi.org/10.1038/s41417-020-0191-x

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