MDM2-p53 pathway in hepatocellular carcinoma

Abstract

Abnormalities in the TP53 gene and overexpression of MDM2, a transcriptional target and negative regulator of p53, are commonly observed in cancers. The MDM2-p53 feedback loop plays an important role in tumor progression and thus, increased understanding of the pathway has the potential to improve clinical outcomes for cancer patients. Hepatocellular carcinoma (HCC) has emerged as one of the most commonly diagnosed forms of human cancer; yet, the current treatment for HCC is less effective than those used against other cancers. We review the current studies of the MDM2-p53 pathway in cancer with a focus on HCC and specifically discuss the impact of p53 mutations along with other alterations of the MDM2-p53 feedback loop in HCC. We also discuss the potential diagnostic and prognostic applications of p53 and MDM2 in malignant tumors as well as therapeutic avenues that are being developed to target the MDM2-p53 pathway.

Figure 1. The MDM2-p53 auto-regulatory feedback loop

MDM2 inhibits p53 by stimulating its degradation, blocking its transcriptional activity and promoting its nuclear export. In turn, p53 activates the expression of MDM2. DNA-damage induces p53 phosphorylation, which prevent the MDM2-p53 binding and leads to p53 stabilization. Oncogenes such as c-Myc can activate p53 through p14ARF-MDM2-p53 pathway.

Figure 2. MDM2-p53 Pathway alterations in HCC with WT p53

In normal tissues the expression of MDM2 and p53 are balanced; whereas in HCC cells the balance is disrupted, where the expression of MDM2 can be high and p53 can be low. This imbalance can be attained through the higher expression of SRF, Enigma Lim, HBx and PRL-1 in combination with lower expression of KLF6, Sirt3, and ING1. Furthermore, up-regulation of rRNA synthesis can inhibit p53 due to reduced ribosomal protein availability for MDM2 binding. (Larger shapes depict higher expression of the indicated proteins and thicker lines depict up-regulation of indicated pathways.)