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Published on: May 24, 2024
TAp73/Delta Np73 influences apoptotic response, chemosensitivity and prognosis in hepatocellular carcinoma
M Müller1, T Schilling, A E Sayan
1Department of Internal Medicine IV, Hepatology and Gastroenterology, University of Heidelberg, Im Neuenheimer Feld 410, 69120 Heidelberg, Germany. Martina_Mueller-Schilling@med.uni-heidelberg.de
Abstract:
We investigated the mechanisms by which TAp73 beta and dominant-negative p73 (Delta Np73) regulate apoptosis. TAp73 beta transactivated the CD95 gene via the p53-binding site in the first intron. In addition, TAp73 beta induced expression of proapoptotic Bcl-2 family members and led to apoptosis via the mitochondrial pathway. Endogenous TAp73 was upregulated in response to DNA damage by chemotherapeutic drugs. On the contrary, DeltaNp73 conferred resistance to chemotherapy. Inhibition of CD95 gene transactivation was one mechanism by which DeltaNp73 functionally inactivated the tumor suppressor action of p53 and TAp73 beta. Concomitantly, DeltaNp73 inhibited apoptosis emanating from mitochondria. Thus, DeltaNp73 expression in tumors selects against both the death receptor and the mitochondrial apoptosis activity of TAp73 beta. The importance of these data is evidenced by our finding that upregulation of DeltaNp73 in hepatocellular carcinoma patients correlates with reduced survival. Our data indicate that Delta Np73 is an important gene in hepatocarcinogenesis and a relevant prognostic factor.
Insights
The study reveals how TAp73 beta promotes apoptosis, while Delta Np73 confers chemoresistance by inhibiting apoptosis. Delta Np73 upregulation in liver cancer patients correlates with poorer survival, highlighting its role in hepatocarcinogenesis.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The p73 protein family, including TAp73 beta and Delta Np73, plays a crucial role in regulating apoptosis and tumor suppression.
- Understanding the distinct functions of TAp73 beta and Delta Np73 is vital for cancer therapy development.
Purpose of the Study:
- To elucidate the mechanisms by which TAp73 beta and Delta Np73 regulate apoptosis.
- To investigate the role of Delta Np73 in conferring chemoresistance and its prognostic significance in hepatocellular carcinoma.
Main Methods:
- Investigated TAp73 beta and Delta Np73's regulation of apoptosis.
- Analyzed CD95 gene transactivation and mitochondrial apoptosis pathways.
- Assessed endogenous TAp73 upregulation in response to DNA damage.
- Correlated Delta Np73 expression with patient survival in hepatocellular carcinoma.
Main Results:
- TAp73 beta transactivates the CD95 gene and induces apoptosis via the mitochondrial pathway.
- Endogenous TAp73 is upregulated by DNA-damaging chemotherapeutic drugs.
- Delta Np73 confers resistance to chemotherapy by inhibiting CD95 transactivation and mitochondrial apoptosis.
- Delta Np73 expression in hepatocellular carcinoma correlates with reduced patient survival.
Conclusions:
- Delta Np73 acts as a tumor suppressor antagonist by inhibiting both death receptor and mitochondrial apoptosis pathways.
- Delta Np73 is a significant gene in hepatocarcinogenesis and a relevant prognostic factor.
- Targeting Delta Np73 may offer therapeutic strategies for hepatocellular carcinoma.
