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RNF125 attenuates hepatocellular carcinoma progression by downregulating SRSF1-ERK pathway

Oncogene volume 42, pages 2017–2030 (2023)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) is one of the most deadly malignant cancers worldwide. Research into the crucial genes responsible for maintaining the aggressive behaviour of cancer cells is important for the clinical treatment of HCC. The purpose of this study was to determine whether the E3 ubiquitin ligase Ring Finger Protein 125 (RNF125) plays a role in the proliferation and metastasis of HCC. RNF125 expression in human HCC samples and cell lines was investigated using TCGA dataset mining, qRT‒PCR, western blot, and immunohistochemistry assays. In addition, 80 patients with HCC were studied for the clinical value of RNF125. Furthermore, the molecular mechanism by which RNF125 contributes to hepatocellular carcinoma progression was determined with mass spectrometry (MS), coimmunoprecipitation (Co-IP), dual-luciferase reporter assays, and ubiquitin ladder assays. We found that RNF125 was markedly downregulated in HCC tumour tissues, which was associated with a poor prognosis for patients with HCC. Moreover, the overexpression of RNF125 inhibited HCC proliferation and metastasis both in vitro and in vivo, whereas the knockdown of RNF125 exerted antithetical effects. Mechanistically, mass spectrometry analysis revealed a protein interaction between RNF125 and SRSF1, and RNF125 accelerated the proteasome-mediated degradation of SRSF1, which impeded HCC progression by inhibiting the ERK signalling pathway. Furthermore, RNF125 was detected to be the downstream target of miR-103a-3p. In this study, we identified that RNF125 is a tumour suppressor in HCC and inhibits HCC progression by inhibiting the SRSF1/ERK pathway. These findings provide a promising treatment target for HCC.

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Fig. 1: RNF125 is downregulated in HCC tissues and associated with a poor prognosis for patients with HCC.
Fig. 2: RNF125 overexpression suppressed HCC cell proliferation and metastasis.
Fig. 3: RNF125 knockdown promoted HCC cell proliferation and metastasis.
Fig. 4: HCC proliferation and metastasis were affected by knockdown and overexpression of RNF125 in vivo.
Fig. 5: SRSF1 is inhibited in HCC progression by RNF125.
Fig. 6: RNF125 accelerated the proteasome-mediated degradation of SRSF1, which impeded HCC progression by inhibiting the ERK signalling pathway.
Fig. 7: RNF125 is a direct downstream target of miR-103a-3p.
Fig. 8: The working model showing the role and mechanism of RNF125 in HCC cells.

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Data availability

Datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank all the study investigators and staff who participated in this study.

Funding

This work was jointly supported by grants from the Natural Science Foundation of Heilongjiang Province of China (LC2018037), Outstanding Youth Training Fund from Academician Yu Weihan of Harbin Medical University (2014), Scientific Foundation of the First Affiliated Hospital of Harbin Medical University (HYD2020JQ0007, HYD2020JQ0012 and 2019L01), The National Natural Scientific Foundation of China (81100305, 81470876, and 81502605), Heilongjiang Postdoctoral Foundation (LBH-Q17097 and LBH-Z11066), and China Postdoctoral Science Foundation (2012M510990, 2012M520769, and 2013T60387).

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Author notes

  1. These authors contributed equally: Zhigang Feng, Shanjia Ke, Chaoqun Wang, Shounan Lu.

Authors and Affiliations

  1. Department of Minimal Invasive Hepatic Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Zhigang Feng, Shanjia Ke, Shounan Lu, Hongjun Yu, Zihao Li, Bing Yin, Xinglong Li, Baolin Qian, Miaoyu Bai & Yong Ma

  2. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Zhigang Feng, Shanjia Ke, Shounan Lu, Hongjun Yu, Zihao Li, Bing Yin, Xinglong Li, Yongliang Hua, Baolin Qian, Miaoyu Bai, Yingmei Zhang, Yaohua Wu & Yong Ma

  3. The First Department of General Surgery, Affiliated Hospital of Inner Mongolia Minzu University, Tongliao, China

    Zhigang Feng

  4. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Army Medical University, Chongqing, China

    Chaoqun Wang

  5. Department of Hepatopancreatobiliary Surgery, Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China

    Yanan Xu

  6. Department of Pediatric Surgery, The Six Affiliated Hospital of Harbin Medical University, Harbin, China

    Yongliang Hua

  7. Department of Ultrasound, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Yao Fu

  8. Department of Thyroid Surgery, The First Affiliated Hospital of Harbin Medical University, Harbin, China

    Yaohua Wu

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  1. Zhigang Feng
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Contributions

ZF, SK, CW and SL designed and performed experiments, analyzed data and wrote the paper; YX and HY performed experiments and analyzed the data; ZL and BY performed some of the experiments; XL and YH analyzed the data; BQ and MB provided the patient samples for clinical data analysis; YF and YZ provide assistance in the study; YW and YM initiated the study, organized, designed and wrote the paper. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yaohua Wu or Yong Ma.

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The authors declare no competing interests.

Ethics Approval

The study protocol was approved by the Ethics Committee of The First Affiliated Hospital of Harbin Medical University (2021041; 201823). All animal use and experiments were performed in strict accordance with the procedures approved by the National Cancer Institute Animal Care and Use Committee (ACUC).

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Feng, Z., Ke, S., Wang, C. et al. RNF125 attenuates hepatocellular carcinoma progression by downregulating SRSF1-ERK pathway. Oncogene 42, 2017–2030 (2023). https://doi.org/10.1038/s41388-023-02710-w

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