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RNF126 contributes to stem cell-like properties and metastasis in hepatocellular carcinoma through ubiquitination and degradation of LKB1

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Abstract

Hepatocellular carcinoma (HCC) is one of the malignant tumors with the worst prognosis, and tumor recurrence and metastasis are the main factors leading to poor prognosis of HCC patients. Accumulating studies show that RNF126, ring finger protein 126, is involved in the pathological process of many tumors. However, the biological function and exact molecular mechanism of RNF126 in HCC remain unclear. In this study, we investigated the role of RNF126 in the pathogenesis of HCC. By analyzing database and verifying with our clinical specimens, it was found that RNF126 was highly expressed in HCC tissues, which is associated with shorter overall survival and higher recurrence rate. Overexpressed RNF126 can significantly promote the proliferation, migration, invasion and angiogenesis of HCC cells, whereas knockdown RNF126 can reverse this effect. Mechanically, RNF126 down-regulates liver kinase B1 (LKB1) expression by ubiquitination of LKB1 to weaken its stability, thereby significantly promoting stem-cell-like activity, migration, and angiogenesis of HCC. Notably, consistent with in vitro results, RNF126 was stably transformed in Hep3B and subcutaneously injected into nude mice. In established mouse xenograft models, tumor growth can be effectively inhibited and the occurrence of lung metastasis is reduced. In HCC, RNF126 may down-regulate LKB1 through ubiquitination, thus becoming a powerful prognostic biomarker and a recognized tumor suppressor. Therefore, our study may provide a promising new therapeutic strategy for targeting RNF126 for HCC patients.

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Acknowledgements

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Funding

This work was supported by the Yunnan Science and Technology Department and Kunming Medical University Special Fund (Grant No. 202001AY070001-229), the Yun nan Fundamental Research Projects (Grant No. 202101AT070239) and the Investigator Initiated Trail Projects of the Second Affiliated Hospital of Kunming Medical University (Grant No. 2020ynlc004).

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Authors and Affiliations

  1. Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Kunming Medical University, No. 374 Dianmian Avenue, Kunming, 650102, Yunnan, China

    Jie Huang, Yan Li, Mengyao Zheng, Haiyu He, Dingwei Xu & Daguang Tian

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  1. Jie Huang
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  2. Yan Li
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  3. Mengyao Zheng
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  4. Haiyu He
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Contributions

All authors contributed to the study conception and design. Material preparation and the experiments were performed by JH. Data collection and analysis were performed by YL, MZ and HH. The first draft of the manuscript was written by DX and DT and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jie Huang.

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All procedures performed in studies involving human participants were in accordance with the standards upheld by the Ethics Committee of the Second Affiliated Hospital of Kunming Medical University and with those of the 1964 Helsinki Declaration and its later amendments for ethical research involving human subjects. All animal experiments were approved by the Ethics Committee of the Second Affiliated Hospital of Kunming Medical University for the use of animals and conducted in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines(Approval No.kmmu20200411).

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Huang, J., Li, Y., Zheng, M. et al. RNF126 contributes to stem cell-like properties and metastasis in hepatocellular carcinoma through ubiquitination and degradation of LKB1. Human Cell 35, 1869–1884 (2022). https://doi.org/10.1007/s13577-022-00782-6

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