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Article Open Access

MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer

  • Authors:
    • Yujing Sun
    • Xiaoyu Weng
    • Wei Chen
    • Jiangzhen Ge
    • Bo Ding
    • Junnan Ru
    • Yunguo Lei
    • Xin Hu
    • Da Man
    • Shaobing Cheng
    • Ruoshu Duan
    • Jingjing Ren
    • Beng Yang
  • View Affiliations / Copyright

    Affiliations: Department of General Practice, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China, General Practice Department, The Second Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310005, P.R. China, Zhejiang University School of Medicine, Hangzhou, Zhejiang 310058, P.R. China, Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang 310003, P.R. China
    Copyright: © Sun et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 4
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    Published online on: November 26, 2024
       https://doi.org/10.3892/ijo.2024.5710
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Abstract

Metastatic hepatocellular carcinoma (HCC) seriously threatens patients' prognosis. It was previously suggested that the insulin growth factor binding protein (IGFBP) family could serve as cancer suppressors in the development and metastasis of HCC. However, the role of IGFBP4 and its underlying molecular mechanism in HCC metastasis is elusive. In the present study, it was found that IGFBP4 is significantly downregulated in HCC, whose expression is positively correlated with the prognosis of patients with HCC. Overexpression of IGFBP4 restrained migration abilities and cancer metastasis of HCC cells both in vitro and in vivo. Furthermore, it was found that IGFBP4 represses HCC metastasis by inhibiting epithelial‑mesenchymal transition. Molecular mechanism studies showed that overexpression of IGFBP4 obviously suppresses NOTCH1 signaling in HCC. As for the upstream regulatory mechanism, it was revealed that downregulation of IGFBP4 in HCC was caused by CpG islands' hyper‑methylation‑dependent degradation mediated by MYBBP1A. Inhibition of MYBBP1A limited HCC metastatic ability and silence of IGFBP4 at the same time restored HCC metastatic potentials. Clinical data demonstrated that low expression of IGFBP4 was found in patients with HCC, especially with lymphatic metastasis. High MYBBP1A expression and low IGFBP4 expression in HCC were correlated with poor survival of patients with HCC. Summarily, in the present study, it was revealed that MYBBP1A/IGFBP4/NOTCH1 pathway could play a crucial role in the progression and metastasis of HCC, which stimulates novel therapeutic and diagnostic strategies against metastatic HCC.
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Copy and paste a formatted citation
Spandidos Publications style
Sun Y, Weng X, Chen W, Ge J, Ding B, Ru J, Lei Y, Hu X, Man D, Cheng S, Cheng S, et al: MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer. Int J Oncol 66: 4, 2025.
APA
Sun, Y., Weng, X., Chen, W., Ge, J., Ding, B., Ru, J. ... Yang, B. (2025). MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer. International Journal of Oncology, 66, 4. https://doi.org/10.3892/ijo.2024.5710
MLA
Sun, Y., Weng, X., Chen, W., Ge, J., Ding, B., Ru, J., Lei, Y., Hu, X., Man, D., Cheng, S., Duan, R., Ren, J., Yang, B."MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer". International Journal of Oncology 66.1 (2025): 4.
Chicago
Sun, Y., Weng, X., Chen, W., Ge, J., Ding, B., Ru, J., Lei, Y., Hu, X., Man, D., Cheng, S., Duan, R., Ren, J., Yang, B."MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer". International Journal of Oncology 66, no. 1 (2025): 4. https://doi.org/10.3892/ijo.2024.5710
Copy and paste a formatted citation
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Spandidos Publications style
Sun Y, Weng X, Chen W, Ge J, Ding B, Ru J, Lei Y, Hu X, Man D, Cheng S, Cheng S, et al: MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer. Int J Oncol 66: 4, 2025.
APA
Sun, Y., Weng, X., Chen, W., Ge, J., Ding, B., Ru, J. ... Yang, B. (2025). MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer. International Journal of Oncology, 66, 4. https://doi.org/10.3892/ijo.2024.5710
MLA
Sun, Y., Weng, X., Chen, W., Ge, J., Ding, B., Ru, J., Lei, Y., Hu, X., Man, D., Cheng, S., Duan, R., Ren, J., Yang, B."MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer". International Journal of Oncology 66.1 (2025): 4.
Chicago
Sun, Y., Weng, X., Chen, W., Ge, J., Ding, B., Ru, J., Lei, Y., Hu, X., Man, D., Cheng, S., Duan, R., Ren, J., Yang, B."MYBBP1A‑mediated IGFBP4 promoter methylation promotes epithelial‑mesenchymal transition and metastasis through activation of NOTCH pathway in liver cancer". International Journal of Oncology 66, no. 1 (2025): 4. https://doi.org/10.3892/ijo.2024.5710
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