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Circ_0098823 binding with IGF2BP3 regulates DNM1L stability to promote metastasis of hepatocellular carcinoma via mitochondrial fission

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Abstract

Hepatocellular carcinoma (HCC) is highly metastatic and invasive. CircRNA participates in gene regulation of multiple tumor metastases, but little is known whether it is a bystander or an actual player in HCC metastasis. We aim to explore the molecular mechanisms of novel circRNAs in HCC metastasis. RT-qPCR was used to detect the expression of 13 circRNAs derived by the ERBB3 gene. The function of circ_0098823 and DNM1L in HCC cells were estimated by CCK-8, transwell assays, flow cytometry, electron microscope, and in vivo experiments. RNA binding protein of circ_0098823 was confirmed by RNA pull-down, mass spectrometry, and RNA immunoprecipitation. The expression of DNM1L after IGF2BP3 knockdown was detected by RT-qPCR and western blot. Circ_0098823 was significantly up-regulated both in HCC tissues and HGF induced cell lines. Circ_0098823 overexpression significantly enhanced proliferation, migration, and invasion but decreased apoptosis of HCC cells, particularly promoted mitochondrial fission. Compared with the control group, the tumors in the circ_0098823 knockdown mice were significantly smaller and lighter. Circ_0098823 silencing suppressed DNM1L expression, a key molecule for fission, which enhanced proliferation, migration and invasion, and inhibited apoptosis of HCC cell. IGF2BP3 was a binding protein of circ_0098823. The expression and mRNA stability of DNM1L were down-regulated by IGF2BP3 knockdown. IGF2BP3 knockdown significantly alleviated the excessive migration, invasion and apoptosis of HCC cells caused by circ_0098823 overexpression. This study uncovered a novel circ_0098823 with tumor-promoting effect, and the mechanism by which circ_0098823 participates in HCC progression through IGF2BP3-guided DNM1L. Our study broadens molecular understanding of HCC progression.

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Acknowledgements

Not applicable.

Funding

This study was supported by the National Natural Science Foundation of China [82003117].

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Author notes

  1. Jiuliang Yan, Xiaofeng Wang, Zongyu Fan contributed equally in this study.

Authors and Affiliations

  1. Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, China

    Jiuliang Yan

  2. Department of Medical Oncology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China

    Xiaofeng Wang

  3. Department of Oral and Maxillofacial-Head and Neck Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China

    Zongyu Fan

  4. Department of Radiation Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, No.85, Wujin Road, Hongkou District, Shanghai, 200080, China

    Yiqing Xu, Yingzi Zhang, Yi Liu & Dongli Liu

  5. Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Fudan University, Shanghai, 200032, China

    Lei Guo

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  1. Jiuliang Yan
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Contributions

Conceptualization: JY, XW, ZF, LG, and DL; Methodology: JY, XW, ZF, and YX; Formal analysis and investigation: JY, XW, ZF, YX, YZ, and YL; Writing—original draft preparation: JY, XW, ZF, and YX; Writing—review and editing: YZ, YL, LG, and DL; Funding acquisition: DL; Resources: YX; Supervision: YZ.

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Correspondence to Lei Guo or Dongli Liu.

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10495_2023_1903_MOESM1_ESM.tif

Fig. S1. Overexpression of circ_0098823 significantly promoted HCC cells migration, invasion, and mitochondrial fission(A) Overexpressing efficacy of circ_0098823 in HCCLM3 cells was confirmed by RT-qPCR (n=3).(B) The viability of HCCLM3 cells after overexpression of circ_0098823 was measured by CCK-8 assays (n=6). (C) The migration and invasion of HCCLM3 cells after overexpressing of circ_0098823 was measured by transwell assays. Scale bars, 50 μm.(D) The migration statistics of HCCLM3 cells after circ_0098823 overexpressing (n=3).(E) The invasion statistics of HCCLM3 cells after circ_0098823 overexpressing (n=3).(F) The apoptosis of HCCLM3 cells after overexpressing of circ_0098823 was measured by flow cytometry assays.(G) The apoptosis statistics of HCCLM3 cells after circ_0098823 overexpressing (n=3).(H) Electron microscopy observed the number of mitochondria in HCCLM3 cells after overexpressing of circ_0098823 (n=3). Scale bars, 2 μm and 50 μm.ns means P > 0.05, * means P < 0.05, ** means P < 0.01, *** means P < 0.001. (TIF 9030 kb)

10495_2023_1903_MOESM2_ESM.tif

Fig. S2. Overexpression of DNM1L significantly promotes the migration and invasion of HCC cells and inhibited apoptosis.(A) Overexpressing efficacy of DNM1L in HCCLM3 and HepG2 cells were confirmed by RT-qPCR.(B) The viability of HCCLM3 cells after overexpressing of DNM1L was measured by CCK-8 assays (n=6).(C) The migration and invasion of HCCLM3 and HepG2 cells after overexpressing of DNM1L was measured by transwell assays. Scale bars, 50 μm.(D) The migration statistics of HCCLM3 and HepG2 cells after DNM1L overexpressing.(E) The invasion statistics of HCCLM3 and HepG2 cells after DNM1L overexpressing.(F) The apoptosis statistics of HCCLM3 and HepG2 cells after DNM1L overexpressing.(G) The apoptosis of HCCLM3 and HepG2 cells after overexpressing of DNM1L were measured by flow cytometry assays.** means P < 0.01, *** means P < 0.001, n=3. (TIF 6464 kb)

Fig. S3 Positive correlation between IGF2BP3 and DNM1L. (TIF 82 kb)

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Yan, J., Wang, X., Fan, Z. et al. Circ_0098823 binding with IGF2BP3 regulates DNM1L stability to promote metastasis of hepatocellular carcinoma via mitochondrial fission. Apoptosis 29, 709–725 (2024). https://doi.org/10.1007/s10495-023-01903-8

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