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CircHIF1A regulated by FUS accelerates triple-negative breast cancer progression by modulating NFIB expression and translocation

Oncogene volume 40, pages 2756–2771 (2021)Cite this article

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Abstract

Emerging evidence has demonstrated that circular RNAs (circRNAs) play critical roles in the development and progression of human cancer. However, the biological functions and underlying mechanisms of circRNAs in triple-negative breast cancer (TNBC) remain to be investigated. In our present study, we found that the novel circRNA circHIF1A was significantly overexpressed in breast cancer tissues and that it was associated with metastasis, poor prognosis, and the TNBC subtype. Gain- and loss-of-function experiments were conducted to investigate the biological roles of circHIF1A in TNBC. Overexpression of circHIF1A significantly promoted TNBC growth and metastasis in vitro and in vivo, while knockdown of circHIF1A exerted the opposite effects. Mechanistically, circHIF1A modulated the expression and translocation of NFIB through posttranscriptional and posttranslational modifications, resulting in the activation of the AKT/STAT3 signaling pathway and inhibition of P21. The RNA binding protein FUS could regulate the biogenesis of circHIF1A by interacting with the flanking intron, and FUS was transcriptionally regulated by NFIB, thus forming the circHIF1A/NFIB/FUS positive feedback loop. Moreover, circHIF1A could be packaged into exosomes and was upregulated in the plasma of breast cancer patients. Our findings indicated that circHIF1A played a critical role in the growth and metastasis of TNBC via a positive feedback loop and that circHIF1A could be a promising biomarker for breast cancer diagnosis and a potential therapeutic target for TNBC treatment.

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Fig. 1: Identification and characteristics of circHIF1A in breast cancer.
Fig. 2: CircHIF1A promoted TNBC progression both in vitro and in vivo.
Fig. 3: CircHIF1A promoted NFIB expression and nuclear translocation via post-transcriptional and post-translational modulation.
Fig. 4: CircHIF1A promoted TNBC progression through modulation of miR-149-5p and NFIB.
Fig. 5: FUS promoted circHIF1A biogenesis and NFIB enhanced transcription of FUS.
Fig. 6: FUS acted as an oncogene in TNBC cells.
Fig. 7: CircHIF1A could be packaged into exosomes and detected in plasma.

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Acknowledgements

This work was supported by National Key Research and Development Program (No. 2020YFA0712400; No. 2018YFC0114705), Special Foundation for Taishan Scholars (No. ts20190971), National Natural Science Foundation of China (No. 81672613; No. 81874119; No. 82072912; No. 82004122), Shandong Provincial Natural Science Foundation, China (No. ZR2019LZL003, No. ZR201911010260, No. ZR201911050391), Special Support Plan for National High Level Talents (Ten Thousand Talents Program W01020103), Foundation from Clinical Research Center of Shandong University (No.2020SDUCRCA015), Qilu Hospital Clinical New Technology Developing Foundation (No. 2018-7; No. 2019-3).

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  1. These authors contributed equally: Tong Chen, Xiaolong Wang

Authors and Affiliations

  1. Department of Breast Surgery, General Surgery, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Tong Chen, Xiaolong Wang, Chen Li, Hanwen Zhang, Ying Liu, Dianwen Han, Yaming Li, Zheng Li, Dan Luo, Ning Zhang & Qifeng Yang

  2. Department of Breast Surgery, Shandong Cancer Hospital and Institute, Shandong First Medical University, Shandong Academy of Medical Sciences, Jinan, Shandong, China

    Meizhu Zheng

  3. Pathology Tissue Bank, Qilu Hospital of Shandong University, Jinan, Shandong, China

    Bing Chen, Lijuan Wang, Wenjing Zhao & Qifeng Yang

  4. Research Institute of Breast Cancer, Shandong University, Jinan, Shandong, China

    Qifeng Yang

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Chen, T., Wang, X., Li, C. et al. CircHIF1A regulated by FUS accelerates triple-negative breast cancer progression by modulating NFIB expression and translocation. Oncogene 40, 2756–2771 (2021). https://doi.org/10.1038/s41388-021-01739-z

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