Notch1 differentially regulates oncogenesis by wildtype p53 overexpression and p53 mutation in grade III hepatocellular carcinoma

Abstract

The tumor suppressor p53 is a key prognostic factor in hepatocellular carcinoma (HCC), yet only 35% of grade III tumors exhibit mutation of p53. Several other pathways have been implicated in HCC and, among these, the role of the Notch1/Snail pathway remains unclear. Therefore, we investigated the expression of p53, Notch1, and Snail proteins in HCC with regard to both clinical grade and p53 mutational status. Immunoblotting for p53 revealed that, whereas in many tumors increased p53 was a result of p53 mutation, wildtype p53 (p53WT) expression was also frequently elevated in HCCs. Coordinated evaluation of p53, Notch1, and Snail expression suggests that grade III HCC can be subdivided based on the expression of these three proteins. We found that Notch1 expression in HCC tissues and cell lines is differentially affected by p53WT and mutant p53 (p53Mut). Notch1 expression was correlated with p53 expression in cells expressing p53WT, but was not elevated in p53Mut‐expressing cells. Virally mediated expression or silencing of p53WT or p53Mut confirmed that p53WT overexpression causes Notch1 up‐regulation in HCC. Surprisingly, the consequence of Notch1 overexpression for the proliferative and invasive capacity of HCC cells depends on both the p53 mutational status and activation of the Snail pathway. Conclusion: In the presence of p53WT, Snail/Notch1 activation increased the invasiveness of HCC cells. In contrast, in the absence of p53WT, Notch1 decreased the invasiveness of HCC. Taken together, these findings shed new light on the complex role of the Notch1/Snail axis in HCC and provide a framework for further classifying HCC based on the expression and mutational status of p53 and the expression of Notch1 and Snail. (HEPATOLOGY 2011;53:1352‐1362)

Notch1 binds and induces degradation of Snail in hepatocellular carcinoma

“…The inhibition of invasion by NICD and Snail coexpression was observed in both Hep3B cells (p53-null) and Huh7 cells (p53-mutant). On the other hand, in p53 WT cells such as HepG2, NICD and Snail coexpression promotes invasiveness [25]. In the present study, we showed NICD regulated invasion via Snail degradation in p53-null or p53-mutant status.…”

Hypo- and hyperactivated Notch signaling induce a glycolytic switch through distinct mechanisms

“…Activated Notch1 has been reported to directly bind p53 and inhibit its phosphorylation and transactivation (45), and a direct interaction between NICD4, p53, and murine double minute 2 (Mdm2) was recently shown to be important for Mdm2-mediated degradation of Notch (46). Conversely, modulation of p53 levels directly altered Notch levels in hepatocellular carcinoma, and p53 was required for Notch-induced growth and invasiveness (47). Notch may also be part of p53's antiapoptotic activity (48).…”

RBP-J-interacting and tubulin-associated protein induces apoptosis and cell cycle arrest in human hepatocellular carcinoma by activating the p53–Fbxw7 pathway

“…The protein of p53 and Fbxw7 were significantly decreased, Hes-1and NF-jB p65 were significantly increased in RITA siRNA cells compared to control siRNA cells (P < 0.05). and despite strong data indicating that Notch activation facilitates tumor progression in the liver [14][15][16][17], some reports have suggested otherwise [12,18,19]. Aberrant Notch1 and Notch3 gene expression has been observed in HCC and has been associated with modulation of cell growth and response to chemotherapy.…”