Δ40p53α suppresses tumor cell proliferation and induces cellular senescence in hepatocellular carcinoma cells

Splice variants of certain genes impact on genetic biodiversity in mammals. The tumor suppressor TP53 gene (encoding p53) plays an important role in the regulation of tumorigenesis in hepatocellular carcinoma (HCC). Delta 40p53 alpha is a naturally occurring p53 isoform that lacks the N-terminal transactivation domain, yet little is known about the role of Delta 40p53 alpha in the development of HCC. Here, we first report on the role of Delta 40p53 alpha in HCC cell lines. In the TP53(+/Delta 40) cell clones, clonogenic activity and cell survival dramatically decreased, whereas the percentage of senescence-associated beta-galactosidase (SA-beta-gal)-positive cells and p21 (also known as WAF1, CIP1 and CDKN1A) expression significantly increased. These observations were clearly attenuated in the TP53(+/Delta 40) cell clones after Delta 40p53 alpha knockdown. In addition, exogenous Delta 40p53 expression significantly suppressed cell growth in HCC cells with wild-type TP53, and in those that were mutant or null for TP53. Notably, Delta 40p53 alpha-induced tumor suppressor activity was markedly attenuated in cells expressing the hot-spot mutant Delta 40p53 alpha-R175H, which lacks the transcription factor activity of p53. Moreover, Delta 40p53 alpha expression was associated with increased full-length p53 protein expression. These findings enhance the understanding of the molecular pathogenesis of HCC and show that Delta 40p53 alpha acts as an important tumor suppressor in HCC cells.