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Ring finger protein 152-dependent degradation of TSPAN12 suppresses hepatocellular carcinoma progression
Jian Wan1,2, Shunfang Liu3, Wanju Sun1
1Department of Emergency and Critical Care Medicine, Shanghai Pudong New Area People's Hospital, Shanghai University of Medicine and Health Sciences, Shanghai, 201299, China.
Background:
Hepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it. The E3 ubiquitin ligase RNF152 has been reported to regulate the activity of the mechanistic target of rapamycin complex 1 (mTORC1), induce autophagy and apoptosis. However, the relationship between RNF152 and HCC is unclear.
Methods:
Transcriptome RNA-sequencing data of HCC samples and normal tissues were used to detect the mRNA expression of RNF152. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of RNF152 in HCC by FoxO1. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of RNF152. Mouse xenograft models were used to study the in vivo effects of RNF152. The immunoprecipitation assay was used to determine the interaction between RNF152 and TSPAN12. The in vivo ubiquitination assay was performed to determine the regulation of TSPAN12 by RNF152.
Results:
We found that RNF152 is significantly down-regulated in clinic HCC samples, and its down-regulation is associated with pool overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) in HCC patients. The transcription factor FoxO1 was significantly positively correlated RNF152 expression in HCC tissues. FoxO1 recognizes a classic insulin response element (IRE) on the RNF152 promoter to regulate its expression in HCC. RNF152 suppressed HCC cell proliferation, clonogenic survival, invasion in vitro, and tumorigenesis in vivo. Mechanistically, RNF152 interacted with TSPAN12 and targeted it for ubiquitination and proteasomal degradation, thereby inhibiting TSPAN12-dependent CXCL6 expression and HCC progression.
Conclusion:
Collectively, our data revealed a tumor suppressor role of RNF152 and a connection between RNF152 and FoxO1 in HCC. Our results support an important role of the FoxO1-RNF152-TSPAN12 axis in the development of HCC. Therapeutic targeting this axis may be an effective means of treating HCC.
Insights
RNF152 acts as a tumor suppressor in hepatocellular carcinoma (HCC) by inhibiting proliferation and invasion. Targeting the FoxO1-RNF152-TSPAN12 pathway offers a potential therapeutic strategy for HCC treatment.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Hepatocellular carcinoma (HCC) is a leading cause of cancer mortality with limited targeted therapies.
- The E3 ubiquitin ligase RNF152's role in HCC remains largely unexplored.
- RNF152 is known to influence mTORC1 signaling, autophagy, and apoptosis.
Purpose of the Study:
- To investigate the role of RNF152 in hepatocellular carcinoma (HCC).
- To elucidate the regulatory mechanisms and functional impact of RNF152 in HCC.
- To explore the potential of targeting the RNF152 pathway for HCC therapy.
Main Methods:
- RNA-sequencing of HCC and normal tissues to assess RNF152 mRNA levels.
- Luciferase reporter and ChIP assays to determine FoxO1-mediated transcriptional regulation of RNF152.
- In vitro (RNAi, proliferation, colony formation, Transwell) and in vivo (mouse xenograft) assays to evaluate RNF152 function.
- Immunoprecipitation and ubiquitination assays to identify RNF152's interaction with and regulation of TSPAN12.
Main Results:
- RNF152 is significantly downregulated in HCC tissues, correlating with poorer patient survival.
- The transcription factor FoxO1 directly regulates RNF152 expression in HCC.
- RNF152 suppresses HCC cell proliferation, invasion, and tumor growth.
- RNF152 interacts with TSPAN12, promoting its ubiquitination and degradation, thus inhibiting TSPAN12-dependent CXCL6 expression and HCC progression.
Conclusions:
- RNF152 functions as a tumor suppressor in HCC.
- A novel regulatory axis involving FoxO1, RNF152, and TSPAN12 is identified in HCC development.
- Targeting the FoxO1-RNF152-TSPAN12 axis presents a promising therapeutic strategy for HCC.
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