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KBTBD8/RRP15 as a potential novel therapeutic target associates with lenvatinib-inhibited progression in hepatocellular carcinoma both in vitro and in vivo

  • 0Department of Gastroenterology, Nanjing Drum Tower Hospital Clinical College of Xuzhou Medical University, Nanjing China.
Journal of Advanced Research +

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December 13, 2024

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December 13, 2024

View abstract on PubMed

Summary

This summary is machine-generated.

Lenvatinib enhances hepatocellular carcinoma (HCC) treatment by degrading RRP15 protein via KBTBD8. Targeting the RRP15-KBTBD8 axis offers a new therapeutic strategy for HCC patients.

Area Of Science

  • Oncology
  • Molecular Biology
  • Biochemistry

Background

  • Ribosomal RNA Processing 15 Homolog (RRP15) is elevated in hepatocellular carcinoma (HCC) and linked to poor prognosis.
  • RRP15 suppression inhibits HCC progression by inducing senescence and apoptosis.
  • The effect of RRP15 on lenvatinib's therapeutic potential in HCC remains unclear.

Purpose Of The Study

  • To determine the relationship between RRP15 expression and lenvatinib sensitivity in HCC.
  • To explore targeting RRP15 with lenvatinib to inhibit HCC progression.

Main Methods

  • Western blot and immunohistochemistry to assess RRP15 and KBTBD8 expression.
  • Cell viability, proliferation, migration, invasion, and apoptosis assays (CCK-8, clonogenic, Transwell, TUNEL, Annexin V).
  • Mass spectrometry, co-immunoprecipitation, and immunofluorescence to study RRP15-KBTBD8 interaction and degradation pathways in vitro and in vivo.

Main Results

  • RRP15 downregulation correlates with enhanced lenvatinib sensitivity, reducing metastasis and invasiveness.
  • KBTBD8, an E3 ubiquitin ligase, mediates RRP15 ubiquitination and degradation after lenvatinib treatment.
  • KBTBD8 overexpression accelerates RRP15 degradation, while its inhibition blocks this process; RRP15 overexpression-induced proliferation and metastasis are mitigated by KBTBD8.
  • In vivo models confirm lenvatinib promotes RRP15 degradation through KBTBD8 upregulation.

Conclusions

  • A novel mechanism of lenvatinib action in HCC involves KBTBD8-mediated RRP15 degradation.
  • The RRP15-KBTBD8 axis represents a new therapeutic target for HCC treatment.

Keywords:

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