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CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis

Oncogene volume 41, pages 1895–1906 (2022)Cite this article

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Abstract

Increasing studies have indicated that circular RNAs (circRNAs) play pivotal roles in various cancers. Here, we aimed to explore the roles of circRNAs in breast cancer. We identified a novel circRNA circKDM4B (hsa_circ_0002926) by whole-transcriptome sequencing and validated this by Real-time quantitative polymerase chain reaction (RT-qPCR) and Sanger sequencing. It was significantly decreased in breast cancer tissues compared with adjacent non-tumor tissues. Furthermore, circKDM4B, which is mainly localized in the cytoplasm, was more resistant to actinomycin D or ribonuclease R than its linear transcript KDM4B. In addition, the overexpression of circKDM4B inhibited cell migration and invasion in vitro, while knockdown of circKDM4B induced the opposite effects. In vivo, circKDM4B suppressed tumor growth and metastasis. Additionally, circKDM4B inhibited migration and tube formation of human umbilical vein endothelial cells (HUVECs) in vitro and angiogenesis in vivo. Mechanically, circKDM4B sponged miR-675 to upregulate the expression of NEDD4-like E3 ubiquitin protein ligase (NEDD4L), which catalyzes ubiquitination of PI3KCA, thereby inhibiting PI3K/AKT and VEGFA secretion. Collectively, these findings uncovered the tumor-suppressor role of circKDM4B in breast cancer, especially in angiogenesis and tumor metastasis, indicating that circKDM4B could be a potential therapeutic target for breast cancer progression.

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Fig. 1: Characterization of circKDM4B, which is significantly decreased in BC tissues.
Fig. 2: CircKDM4B inhibits cell migration and invasion in BC cells.
Fig. 3: CircKDM4B serves as a molecular sponge for miR-675 in BC cells.
Fig. 4: NEDD4L is a direct target of miR-675 and can be upregulated by circKDM4B.
Fig. 5: CircKDM4B negatively regulates PI3KCA by ubiquitination and inhibits PI3K/AKT signaling and VEGFA expression via miR-675/NEDD4L axis.
Fig. 6: CircKDM4B could be a promising target for BC treatment.

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Acknowledgements

We thank LetPub (www.letpub.com) for its linguistic assistance during the preparation of this manuscript.

Funding

This study was supported by the National Natural Science Foundation of China (Grant nos. 81872362 and 82072665), the Taishan Scholars Program of Shandong Province (Grant no. ts201511096).

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Authors and Affiliations

  1. Key Laboratory for Experimental Teratology of the Ministry of Education and Department of Pathology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, Jinan, China

    Xiang-Yu Guo, Tian-Tian Liu, Wen-Jie Zhu, Hai-Ting Liu, Guo-Hao Zhang, Rui-Nan Zhao & Peng Gao

  2. Department of Pathology, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, China

    Xiang-Yu Guo, Tian-Tian Liu, Wen-Jie Zhu, Hai-Ting Liu, Guo-Hao Zhang, Lin Song, Rui-Nan Zhao, Xu Chen & Peng Gao

  3. Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China

    Lin Song

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Contributions

X-YG and PG conceived the experiment and wrote the manuscript. X-YG performed the experiments and analysed the data. T-TL, W-J, H-TL, G-HZ, L-S, R-NZ, and XC helped with the experiments and analysis.

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Correspondence to Peng Gao.

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This study was approved by the Ethics Committee of Shandong University and conformed to the ethical standards of Helsinki Declaration. Informed consent was obtained from all patients included in this study.

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Guo, XY., Liu, TT., Zhu, WJ. et al. CircKDM4B suppresses breast cancer progression via the miR-675/NEDD4L axis. Oncogene 41, 1895–1906 (2022). https://doi.org/10.1038/s41388-022-02232-x

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