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Liver-specific BAG3 knockout delays chemically induced hepatocellular carcinoma development
Verena Damiani1,2,3, Erika Pizzinato1,2,4, Federica Di Marco1,2
1Center for Advanced Studies and Technology (CAST), 'G. D'Annunzio' University of Chieti-Pescara, Italy.
The FEBS Journal
|January 8, 2026
Summary
Bcl-2-associated athanogene 3 (BAG3) protein impacts hepatocellular carcinoma (HCC) development. BAG3 deficiency delayed liver cancer onset and reduced tumor aggressiveness in mice, highlighting its complex role in HCC pathogenesis.
Area of Science:
- Oncology
- Molecular Biology
- Hepatology
Background:
- Bcl-2-associated athanogene 3 (BAG3) is a multifunctional protein implicated in cellular processes like protein folding, degradation, apoptosis, and cytoskeleton dynamics.
- Dysregulation of BAG3 is linked to various pathologies, including cancer, with proposed pro- and antitumorigenic roles in Hepatocellular Carcinoma (HCC).
- HCC is a major global cause of cancer mortality, characterized by a complex molecular landscape.
Purpose of the Study:
- To investigate the specific function of BAG3 in the pathogenesis of Hepatocellular Carcinoma (HCC).
- To establish and utilize a hepatocyte-specific BAG3 knockout mouse model (BAG3albKO) to study its role in liver cancer development and progression.
Main Methods:
- Generation of a hepatocyte-specific BAG3 knockout mouse model (BAG3albKO).
- Induction of hepatocarcinogenesis using diethylnitrosamine (DEN) treatment in wild-type and BAG3albKO mice.
- Histological analysis of liver tissues to assess tumor development.
- Assessment of cell migration and epithelial-to-mesenchymal transition (EMT) in HCC-derived murine cell lines with BAG3 deletion.
- Proteomic analysis of livers from DEN-induced acute liver injury models to identify pathway alterations.
Main Results:
- BAG3 deficiency in hepatocytes (BAG3albKO mice) led to delayed hepatocarcinogenesis following DEN treatment.
- Deletion of BAG3 attenuated cell migration and epithelial-to-mesenchymal transition (EMT) in HCC cell lines, suggesting reduced tumor aggressiveness.
- Proteomic analysis revealed that BAG3 deletion inhibited autophagy and increased liver necrosis in response to DEN-induced acute liver injury.
- BAG3 plays a complex role in HCC, influencing tumor onset and progression.
Conclusions:
- BAG3 deficiency confers resistance to hepatocarcinogenesis and reduces tumor aggressiveness in a mouse model.
- BAG3 influences key cellular pathways, including autophagy and necrosis, during liver injury and cancer development.
- These findings underscore the intricate role of BAG3 in Hepatocellular Carcinoma pathogenesis, impacting both tumor initiation and progression.
