The role of MDM2–p53 axis dysfunction in the hepatocellular carcinoma transformation

Abstract

Liver cancer is the second most frequent cause of cancer-related death globally. The main histological subtype is hepatocellular carcinoma (HCC), which is derived from hepatocytes. According to the epidemiologic studies, the most important risk factors of HCC are chronic viral infections (HBV, HCV, and HIV) and metabolic disease (metabolic syndrome). Interestingly, these carcinogenic factors that contributed to HCC are associated with MDM2-p53 axis dysfunction, which presented with inactivation of p53 and overactivation of MDM2 (a transcriptional target and negative regulator of p53). Mechanically, the homeostasis of MDM2-p53 feedback loop plays an important role in controlling the initiation and progression of HCC, which has been found to be dysregulated in HCC tissues. To maintain long-term survival in hepatocytes, hepatitis viruses have lots of ways to destroy the defense strategies of hepatocytes by inducing TP53 mutation and silencing, promoting MDM2 overexpression, accelerating p53 degradation, and stabilizing MDM2. As a result, genetic instability, chronic ER stress, oxidative stress, energy metabolism switch, and abnormalities in antitumor genes can be induced, all of which might promote hepatocytes' transformation into hepatoma cells. In addition, abnormal proliferative hepatocytes and precancerous cells cannot be killed, because of hepatitis viruses-mediated exhaustion of Kupffer cells and hepatic stellate cells (HSCs) and CD4 + T cells by disrupting their MDM2-p53 axis. Moreover, inefficiency of hepatic immune response can be further aggravated when hepatitis viruses co-infected with HIV. Unlike with chronic viral infections, MDM2-p53 axis might play a dual role in glucolipid metabolism of hepatocytes, which presented with enhancing glucolipid catabolism, but promoting hepatocyte injury at the early and late stages of glucolipid metabolism disorder. Oxidative stress, fatty degeneration, and abnormal cell growth can be detected in hepatocytes that were suffering from glucolipid metabolism disorder, and all of which could contribute to HCC initiation. In this review, we focus on the current studies of the MDM2-p53 axis in HCC, and specifically discuss the impact of MDM2-p53 axis dysfunction by viral infection and metabolic disease in the transformation of normal hepatocytes into hepatoma cells. We also discuss the therapeutic avenues and potential targets that are being developed to normalize the MDM2-p53 axis in HCC.

Roles of CCR2 and CCR5 for Hepatic Macrophage Polarization in Mice With Liver Parenchymal Cell-Specific NEMO Deletion

“…In the NEMO LPC-KO and the NEMO LPC-KO Ccr5 -/mice, Mdm2 is upregulated and thus, it is very likely that it thereby inhibits p53 expression, an important tumor suppressor, and consequently accelerates tumor growth in WT mice. 30 However, the significantly increased liver injury observed in the NEMO LPC-KO Ccr2 -/mice apparently cannot be led back to the effects on cell death. Importantly, CCR2 and CCL2 have been shown to not only promote inflammation and putative organ damage, but they have also support healing and regeneration.…”

Identification of NAA40 as a Potential Prognostic Marker for Aggressive Liver Cancer Subtypes

“…It is important to note that in LIHC, as well as other cancers, P53-mediated processes can also be functionally inactivated even when the P53 gene itself is not mutated through alternative mechanisms including mutation of MDM proteins, dysregulation of microRNAs, as well as action of the hepatitis viruses ( 41 , 42 ). To investigate NAA40 expression in LIHC samples with alternative P53 inactivation, we utilised a previously defined 10-gene signature of P53 repressed genes whose expression is indicative of P53 activity ( 30 ).…”

BRD7 inhibits tumor progression by positively regulating the p53 pathway in hepatocellular carcinoma

“…On the other hand, p53 seems to exerts a negative feedback regulation on BRD7 expression in this study (Figure 3 A,down). Indeed, as a transcription factor,p53 can form an auto-regulatory feedback loop with its regulator such as MDM2 41 . Nevertheless, how p53 in turn regulate BRD7 expression in HCC remains unclear,which should be further investigated.…”