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MiR-3677-3p promotes development and sorafenib resistance of hepatitis B-related hepatocellular carcinoma by inhibiting FOXM1 ubiquitination

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Abstract

Being encoded by hepatitis B, hepatitis B X (HBx) protein plays crucial roles in hepatitis B-related hepatocellular carcinoma (HCC) occurrence, development, and metastasis. miRNAs also function in the progression of hepatitis B-related HCC. Hence, the objective of this study was to explore the impacts of miR-3677-3p on tumor progression and sorafenib resistance in hepatitis B-related HCC and the related underlying mechanisms. Our research revealed that miR-3677-3p and FOXM1 was up-regulated and FBXO31 was down-regulated in HBV+ HCC cells and tumor tissues from nude mice. After miR-3677-3p overexpression, cell proliferative, invasive, and migrating potentials and stemness-related protein (CD133, EpCAM, and OCT4) levels were enhanced, and cell apoptosis was reduced in Huh7 + HBx/SR cells and HepG2.2.15/SR cells. Besides, miR-3677-3p promoted the drug resistance of Huh7 + HBx/SR cells and HepG2.2.15/SR cells to sorafenib and lifted IC50. In vivo experiments, miR-3677-3p down-regulation suppressed the tumor growth in the hepatitis B HCC nude mouse models. Mechanistically, miR-3677-3p targeted and negatively-regulated FBXO31 and FBXO31 could enrich FOXM1 protein. miR-3677-3p down-regulation or FBXO31 overexpression promoted the ubiquitylation of FOXM1. In a word, miR-3677-3p bound to FBXO31 and inhibited FBXO31 expression, thus curtailing the ubiquitylation degradation of FOXM1, contributing to HCC development and sorafenib resistance.

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Data availability

The datasets used or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We appreciate Hunan Provincial Brain Hospital, Changsha Science and Technology Bureau, Hunan University of Traditional Chinese Medicine for supporting this study.

Funding

This study was funded by the Natural Science Foundation of Changsha (No. kq2014189).

Author information

Authors and Affiliations

  1. Department of Minimally Invasive Surgery, The Brain Hospital of Hunan Province, Changsha, 410007, Hunan, People’s Republic of China

    Hengzheng He & Fahui Cheng

  2. Department of Quality Control, The Brain Hospital of Hunan Province, Changsha, 410007, Hunan, People’s Republic of China

    Jian Zhou

  3. Department of Gastroenterology, The Brain Hospital of Hunan Province, No.427, Sec.3, Furong Mid Road, Changsha, 410007, Hunan, People’s Republic of China

    Huijuan Li & Yangya Quan

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  1. Hengzheng He
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  2. Jian Zhou
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Corresponding author

Correspondence to Yangya Quan.

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Ethical approval

All the animal experiments in the current research were conducted in accordance with Guidelines for the care and use of laboratory animals (formulated by the Chinese Commission for Institutional Animal Protection and Use) and approved by the Animal Care Ethics Committee of the Brain Hospital of Hunan Province (approval number: 2019K033).

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He, H., Zhou, J., Cheng, F. et al. MiR-3677-3p promotes development and sorafenib resistance of hepatitis B-related hepatocellular carcinoma by inhibiting FOXM1 ubiquitination. Human Cell 36, 1773–1789 (2023). https://doi.org/10.1007/s13577-023-00945-z

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  • DOI: https://doi.org/10.1007/s13577-023-00945-z

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