The E3 ubiquitin ligase TRIM7 suppressed hepatocellular carcinoma progression by directly targeting Src protein
Lihui Zhu1,2,3, Chengyong Qin2,3, Tao Li4
1Department of Immunology, Shandong Provincial Key Laboratory of Infection & Immunology, Shandong University School of Basic Medical Sciences, Jinan, 250012, China.
Abstract:
Aberrant Src kinase activity is known to be involved in a variety of human malignancies, whereas the regulatory mechanism of Src has not been completely clarified. Here, we demonstrated that tripartite motif containing 7 (TRIM7) directly interacted with Src, induced Lys48-linked polyubiquitination of Src and reduced the abundance of Src protein in hepatocellular carcinoma (HCC) cells. We further identified TRIM7 as a tumor suppressor in HCC cells through its negative modulation of the Src-mTORC1-S6K1 axis in vivo and in vitro in several HCC models. Moreover, we verified the dysregulated expression of TRIM7 in clinical liver cancer tissues and its negative correlation with Src protein in clinical HCC specimens. Overall, we demonstrated that TRIM7 suppressed HCC progression through its direct negative regulation of Src and modulation of the Src-mTORC1-S6K1 axis; thus, we provided a novel insight into the development of HCC and defined a promising therapeutic strategy for cancers with overactive Src by modulating TRIM7.
Insights
Tripartite motif containing 7 (TRIM7) acts as a tumor suppressor in liver cancer by reducing Src protein levels. This finding offers a new therapeutic strategy for cancers driven by overactive Src kinase.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Aberrant Src kinase activity contributes to human malignancies.
- The regulatory mechanisms governing Src kinase activity remain incompletely understood.
- Understanding Src regulation is crucial for developing targeted cancer therapies.
Purpose of the Study:
- To investigate the role of tripartite motif containing 7 (TRIM7) in hepatocellular carcinoma (HCC).
- To elucidate the molecular mechanism by which TRIM7 regulates Src kinase in HCC.
- To evaluate TRIM7 as a potential tumor suppressor and therapeutic target in HCC.
Main Methods:
- Co-immunoprecipitation assays to confirm TRIM7-Src interaction.
- Western blotting to assess protein levels and ubiquitination.
- In vivo and in vitro HCC models to study TRIM7 function.
- Analysis of clinical HCC specimens for TRIM7 and Src expression.
Main Results:
- TRIM7 directly interacts with Src and promotes its Lys48-linked polyubiquitination.
- TRIM7 overexpression reduces Src protein abundance in HCC cells.
- TRIM7 functions as a tumor suppressor by inhibiting the Src-mTORC1-S6K1 signaling pathway.
- Downregulation of TRIM7 and upregulation of Src are observed in clinical HCC tissues.
Conclusions:
- TRIM7 suppresses HCC progression via direct negative regulation of Src kinase.
- TRIM7 modulates the Src-mTORC1-S6K1 axis, impacting tumor development.
- TRIM7 represents a novel therapeutic target for HCC and other Src-driven cancers.
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