BACKGROUND & AIMS: p73 belongs to the p53 family of transcription factors known 
to regulate cell cycle and apoptosis. The Trp73 gene has two promoters that 
drive the expression of two major p73 isoform subfamilies: TA and ΔN. In 
general, TAp73 isoforms show proapoptotic activities, whereas members of the 
N-terminally truncated (ΔN) p73 subfamily that lack the transactivation domain 
show antiapoptotic functions. We found that upregulation of ΔNp73 in 
hepatocellular carcinoma (HCC) correlated with reduced survival. Here, we 
investigated the molecular mechanisms accounting for the oncogenic role of ΔNp73 
in HCC.
RESULTS: ΔNp73β can directly interfere with the transcriptional activation 
function of the TA (containing the transactivation domain) isoforms of the p53 
family and consequently inhibit transactivation of proapoptotic target genes. 
Interference of ΔNp73β with apoptosis-/chemosensitivity takes place at several 
levels of apoptosis signaling. ΔNp73β negatively regulates the genes encoding 
for the death receptors CD95, TNF-R1, TRAIL-R2 and TNFRSF18. Furthermore, ΔNp73β 
represses the genes encoding caspase-2, -3, -6, -8 and -9. Concomitantly, ΔNp73β 
inhibits apoptosis emanating from mitochondria.
CONCLUSIONS: Thus, ΔNp73 expression in HCC selects against both the death 
receptor and the mitochondrial apoptosis activity of the TA isoforms. Our data 
suggest that ΔNp73 isoforms repress apoptosis-related genes of the extrinsic and 
intrinsic apoptosis signaling pathways thereby contributing to chemoresistance. 
The clinical importance of these data is evidenced by our finding that the 
ΔNp73ß target gene signature can predict the prognosis of patients suffering 
from HCC.