We developed liver cancer cell lines that endogenously expressed a mutant form of TP53 (R249S) or overexpressed mutant forms of STAT3 (D170Y, K348E, and Y640F) or JAK1 (S703I and L910P) and tested the abilities of pharmacologic agents to reduce activity.
Our results suggested that ALX4 was inactivated by DNA methylation and played a tumor suppressor function through the P53 pathway in MC-LR induced liver cancer.
A mouse model of liver cancer reveals that downregulation of mevalonate pathway gene expression by p53 occurs in premalignant hepatocytes, when p53 is needed to actively suppress tumorigenesis.
In a second approach, functional wild type p53 is delivered into p53-null liver cancer (Hep3B) cells, sensitizing the cells toward the p53 pathway drug, Nutlin.
We observed RBM38 protein expression was commonly silenced coupled with increased mdm2 and decreased wild type (wt) p53 in liver cancer cells and HCC tissues compared to the corresponding normal liver cells and adjacent liver tissues.
For the first time, it was shown the possibility to induce the exogenous expression of the pro-apoptotic gene TRAIL and p53 in a liver cancer HepG2 cells via a sonoporation procedure.
The hepatocellular abundance of phosphorylated PKR is elevated in HCV-infected chimpanzees, suggesting that PKR activation and consequent p53 inhibition accompany HCV infection <i>in vivo</i> These findings reveal a feature of the host response to HCV infection that may contribute to hepatocellular carcinogenesis.<b>IMPORTANCE</b> Chronic infection with hepatitis C virus (HCV) is the leading cause of liver cancer in most developed nations.
We conclude that repression of GMPS by p53 through p21 is a functionally relevant part of the p53-mediated senescence program limiting tumor cell growth in liver cancer.
Since hepatitis B and C viral proteins lead to inactivation of the tumor suppressors p53 and Retinoblastoma (Rb), we hypothesize that surgery in the context of p53/Rb inactivation initiate de novo tumorigenesis.We, therefore, generated transgenic mice with hepatocyte and cholangiocyte/liver progenitor cell (LPC)-specific deletion of p53 and Rb, by interbreeding conditional p53/Rb knockout mice with either Albumin-cre or Cytokeratin-19-cre transgenic mice.We show that liver cancer develops at the necrotic injury site after surgical resection or radiofrequency ablation in p53/Rb deficient livers.
Ultimately, P53 (N340Q/L344R) accerlerates the growth of liver cancer cells Hep3B by activating telomerase and prolonging telomere through the cascade of P53 (N340Q/L344R)-CUDR-PKM2-pH3T11- (H3K9me1-HP1α)-Pim1- (TERT-HOTAIR-TERRA).
One such example is hepatitis virus-induced liver cancer whereby p53 is inactivated upon the binding of a specific viral protein, leading to the loss of its tumor suppressive activity.
A joint effect between the MDM2 and TP53 polymorphisms and an increased risk of liver cancer was detected, with the odds ratio for the presence of both MDM2 309GG and TP53 72Pro/Pro genotypes being 10 (95% confidence interval 0.39-255.55).