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Circ-GSK3B up-regulates GSK3B to suppress the progression of lung adenocarcinoma

Cancer Gene Therapy volume 29, pages 1761–1772 (2022)Cite this article

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Abstract

GSK3B is the mRNA form of glycogen synthase kinase 3 beta (GSK-3β), which is a critical repressor of Wnt/β-catenin signaling pathway and generally inhibited in cancer cells. Plenty of researches have disclosed that circular RNAs, namely circRNAs exert important functions in the progression of various human malignancies including lung adenocarcinoma (LUAD). Therefore, we attempted to explore whether there existed certain circRNAs that could mediate LUAD development by regulating GSK3B expression and Wnt/β-catenin pathway. In the present research, circ-GSK3B (hsa_circ_0066903) was found to be significantly down-regulated in LUAD tissues and cells and it suppressed the proliferation, migration and stemness of LUAD cells. Furthermore, it was discovered that circ-GSK3B competitively sponged miR-3681-3p and miR-3909 to elevate GSK3B expression. Circ-GSK3B could impair the binding ability of FKBP51 to GSK-3β to inhibit the phosphorylation of GSK-3βS9, resulting in the inactivation of Wnt/β-catenin signaling. In addition, the regulatory effect of circ-GSK3B on LUAD tumorigenesis and cell progression was testified through in vitro and in vivo rescue experiments. In conclusion, circ-GSK3B suppressed LUAD development through up-regulating and activating GSK3B.

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Fig. 1: Circ-GSK3B is with low expression in LUAD cells.
Fig. 2: Circ-GSK3B represses LUAD cell proliferation, migration and stemness.
Fig. 3: Circ-GSK3B regulates GSK3B mRNA level by serving as a ceRNA in LUAD.
Fig. 4: Circ-GSK3B hinders the binding of FKBP51 to GSK-3β in LUAD.
Fig. 5: Circ-GSK3B regulates LUAD progression via up-regulating and activating GSK3B.
Fig. 6: Circ-GSK3B inhibits the tumorigenesis of LUAD via elevating GSK3B expression.

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Data availability

All data available on reasonable request from the corresponding author, MZ.

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Acknowledgements

The authors would like to thank Mrs. Hui-Fen Liu for her assistance.

Funding

This study was supported by fundings from Health Committee of Hubei Province of China (WJ2019M146 to MZ); Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province (CXPJJH11900018-06 to MZ) and Tongji Hospital Project (2016HGRY to MZ).

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  1. These authors contributed equally: Mingchuang Zhu, Yanhong Zhang.

Authors and Affiliations

  1. Department of Thoracic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Ming-Chuang Zhu, Peng Xiong, Xiao-Wu Fan, Guo-Liang Li & Min Zhu

  2. Department of Human Anatomy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, Hubei, China

    Yan-Hong Zhang

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MCZ and YHZ revised this study and wrote the draft. PX, XWF, and GLL performed experiment and interpreted data. MZ funded this study. All authors have read and approved the paper.

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Zhu, MC., Zhang, YH., Xiong, P. et al. Circ-GSK3B up-regulates GSK3B to suppress the progression of lung adenocarcinoma. Cancer Gene Ther 29, 1761–1772 (2022). https://doi.org/10.1038/s41417-022-00489-8

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