MDM2-p53 Interactions in Human Hepatocellular Carcinoma: What Is the Role of Nutlins and New Therapeutic Options?
Abstract
:1. Introduction
2. Tumor Suppressor p53
3. Role of p53 in Human Hepatocellular Carcinoma (HCC)
4. Murine Double Minute 2 (MDM2)-p53 Interactions in HCC
4.1. Ribosomal Proteins
4.2. Ribosomal RNA
4.3. MicroRNAs
4.4. LIM Domain Protein Enigma
4.5. Serum Response Factors
4.6. Phosphatase of Regenerating Liver 1
4.7. MDM2 Binding Protein
5. Effects of Nutlin in HCC
6. Future Directions and Therapeutic Applications
7. Conclusions
Acknowledgments
Conflicts of Interest
References
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Author [Reference] | Study Design/Study Purpose | What Was Exained? | Key Findings | Conclusions |
---|---|---|---|---|
Lu et al. [41] | Cancerous and non-cancerous specimens from 12 patients with HCC from western China. | A 372 cancer-associated genes including TP53 were screened using NGS technique. | Results confirmed mutations of previously identified HCC drivers including p53 and Kras. | Additionally, mutations in several cancer genes which had not been previously associated with HCC were identified including RUNX1 and JAK 3. |
Huang et al. [42] | Exome sequencing to identify somatic mutations. | The whole exome (10 samples) and validation set (100 samples), in HBV positive with HCC. | TP53 was the candidate driver in 27% (it was the most frequently mutated tumor suppressor). | The study provided a view of the somatic mutations that may be implicated in advanced HCC. |
Kan et al. [43] | Identify genetically altered genes and pathways implicated in HBV-associated HCC. | A whole-genome sequencing study of 88 matched HCC tumor/normal pairs, 81 of which were Hepatitis B virus (HBV) positive. | TP53 was the most frequently mutated tumour suppressor (35.2%). Beta-catenin is the most frequently mutated oncogene (15.9%). | The study also identified several prevalent and potentially actionable mutations, including activating mutations of Janus kinase 1 (JAK1), in 9.1% of patients. |
Ahn et al. [44] | Exome sequencing to identify somatic mutations. | A whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas. | Recurrent somatic mutations were identified in nine genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. | RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. However, further studies are needed to explore other roles played by mutations. |
Totoki et al. [45] | Use of NGS techniques in understanding the genetic changes in HCC genomes. | A collection of data from 503 liver cancer genomes uncovered 30 candidate driver genes and 11 core pathway modules. | TP53 was the candidate drive in 31% of cases. | De-regulation was detected in p53 signaling (72%), Wnt signaling (66%), Chromatin remodeling (67%), Telomere maintenance (68%). Newly identified alterations in genes encoding metabolic enzymes, chromatin remodelers and a high proportion of mTOR pathway activations offer potential therapeutic and diagnostic opportunities. |
Schulze et al. [46] | Exome sequencing to identify somatic mutations. | Exome sequencing analysis of 243 liver tumors identified mutational signatures associated with specific risk factors; combined alcohol and tobacco consumption and exposure to aflatoxin B1. | The authors identified 161 putative driver genes associated with 11 recurrently altered pathways. Associations of mutations defined 3 groups of genes related to risk factors: CTNNB1 (alcohol), TP53 (hepatitis B virus) and AXIN1. | The study identified risk factor-specific mutational signatures and defined the landscape of altered genes and pathways in HCC. |
Niu et al. [47] | An update on recurrently mutated genes including p53 and deregulated signaling pathways in HCC using NGS techniques. | Current literature | TP53 mutation has been identified as the most frequently molecular alterations in HCC and can be used to predict HCC development and is associated with shorter survival time. | Understanding genetic alterations in HCC could provide new insight into newly targeted therapies. |
Schulze et al. [48] | A review on genetic profiling of hepatocellular carcinoma using NGS | Current literature | Differences in mutation rates of cancer drivers and associated pathway among different studies may be partially due to clinical heterogeneity. In hepatitis B virus –related HCC, inactivating mutations of TP53 and KMT2B are more frequently involved. | NGS data will soon allow to better understanding of tumour heterogeneity and its potential role in treatment decision-making. |
Author, [Reference] | Study Design | What Was Examined? | Key Findings | Conclusions |
---|---|---|---|---|
Higashitsuji et al. [73] | In vivo and in vitro | The effect of Gankyrin on p53 and MDM2 interactions. | Gankyrin, an ankyrin repeat oncoprotein overexpressed in HCC, enhances MDM2 autoubiquitination in the absence of p53. | Gankyrin is a cofactor that increases the activities of MDM2 on p53. |
Jalbkowski et al. [74] | Specimens from patients with HCC, and patients with cirrhosis linked to HBV infection. | The expression of p53 and MDM2. | Mutation of p53 gene and MDM2 immunopositivity were detected more in HCC. MDM2 positivity was not associated with MDM2 amplification . | Besides p53 alteration, MDM2 gene deregulation plays a role in HCC. |
Yoon et al. [75] | Samples from patients with HBV with and without HCC | Evaluation of the association of MDM2 and p53 polymorphisms with the presence and onset of HCC in Korean patients with HBV infection. | Multivariate analysis for the presence of HCC revealed an odd ratio for MDM2 G/G over T/T of 4.89 and for p53 Pro/Pro over Arg/Arg of 3.03. Both were significant. | MDM2 and p53 are associated with early development of HCC in Korean patients with HBV infection. |
Edamoto et al. [76] | Samples from patients with HCV infection, HBV infection, and excessive alcohol intake. | Screening the three groups for alterations in genes involved in RB1 pathway, p53 pathway and Wnt pathway. | Alterations in the p53 pathway consisted mostly of p53 mutations or p14 promoter methylation. Mutations of the p53 gene were found in similar frequency. | RB1, p53, and Wnt pathways were commonly affected in HCC of the three groups. |
Lim et al. [77] | Human hepatoma cells, and human hepatoblastoma cells. | The relationship between p53 and Snail proteins in HCC and whether Snail and p53 contribute to HCC. | Only p53 wild-type induced endogenous Snail protein degradation via MDM2 ubiquitination whereas p53 mutant did not induce Snail degradation. | The results show the role of p53 mutation and Snail overexpression as a late event in HCC development. |
Qiu [78] | Samples from patients with HCC | The relationship between MDM2 gene expression and p53 gene mutation in HCC and their correlation with the invasiveness of the disease. | MDM2 genes overexpression was found in 26% of samples while p53 mutation was found in 47% of samples. | Either MDM2 overexpression or p53 mutation may be related to the invasion of HCC. |
Xian et al. [79] | Human hepatoma cells | Identify the underlying mechanism by which p53 induce hepatitis B virus X protein (HBx) degradation and express its oncogenic functions. | Over expression of p53 protein reduces the level of HBx protein and shortens its half-life. In MDM2 knock out cells, p53 can accelerate turnover of HBx protein. | P53 mediated HBx degradation in MDM2-dependent. MDM2 interacts with HBx but does not promote its ubiquitination. In HCC tissues with wild-type p53, HBx protein is hardly detected. |
Kim et al. [64] | Tissue specimens from HCC patients | Test the role of epithelial-mesenchymal transition (EMT) in tumor progression and metastasis and the role of transcription factor ZEB1 and ZEB2 in regard to HCC. | P53 up-regulates microRNA including miR-200 and miR-192 family members. Inhibition of miRNAs affects p53-regulated EMT by altering ZEB1 and ZEB2 expression. | P53 can regulate EMT in HCC. |
Eferl et al. [80] | Mice carrying a “floxed” c-Jun allele. | Study the effect of liver-specific inactivation of C-Jun at different stages of tumor development and its role in development of HCC in mice. | The number and size of hepatic tumors was dramatically reduced when c-Jun was inactivated after the tumor was initiated. The impaired tumor development was associated with increased levels of p53. | c-Jun prevents apoptosis by antagonizing p53 activity. This may illustrate a possible mechanism in early stages of HCC development. |
Yang et al. [81] | Patients with HCC, non-HCC patients and control | Investigate the influence of combined p53 Arg72 Pro and MDM2 SNP309 on the risk of developing HCC in patients with chronic hepatitis B virus infection. | Patients with combined p53 Pro/Pro and MDM2 G/G genotypes had a poorer prognosis than other genotypes. | There is increased risk for HCC in the presence of p53 Pro/Pro and MDM2 G/G genotype in combination. |
Dongiovanni et al. [82] | Immortalized mouse hepatocytes and rat livers. | Identify iron regulated gene pathways involved in HCC. | Iron down-regulated whereas deferoxamine up-regulated mRNA levels of MDM2, the ubiquitin ligase involved in the degradation of p53. Iron status affected p53 ubiquitination and degradation rate. | Iron status influences p53 activity and antioxidant response by modulating MDM2 expression. |
Umemura et al. [83] | Specimens of HCC. | Assess the clinical significance of gankyrin overexpression in HCC by using monoclonal-anti-gankyrin antibody and immune-histochemical technique. | The cumulative survival rate of patients with gankyrin-positive HCC was significantly higher than that with gankyrin-negative HCC. | Gankyrin plays an important oncogenic role mainly in early stages of HCC. |
Di Vuolo et al. [84] | Patients with viral hepatitis-related HCC and control. | Analyze the role of polymorphisms in the development of HCC. | Frequency of TP53 codon 72 alleles was not significantly different between cases and control. A significant increase of MDM2 SNP309 G/G and T/G genotypes were observed among HCC cases. | There is a significant role for MDM2 SNP309 G allele as a susceptibility gene for the development of viral hepatitis-related HCC. |
Xie et al. [85] | Human hepatoma cells. | Identify the mechanism by which nucleolar protein, CSIG, regulates the MDM2-p53 pathway. | CSIG translocates from nucleolus to nucleoplasm in response to nucleolar stress. Knockdown of CSIG attenuates the induction of p53 and abrogates G1 phase arrest in response to nucleolar stress. CSIG interacts directly with MDM2 and inhibits MDM2 E3 ubiquitin. | CSIG-MDM2-p53 regulatory pathway an important role in cellular response to nucleolar stress. |
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Azer, S.A. MDM2-p53 Interactions in Human Hepatocellular Carcinoma: What Is the Role of Nutlins and New Therapeutic Options? J. Clin. Med. 2018, 7, 64. https://doi.org/10.3390/jcm7040064
Azer SA. MDM2-p53 Interactions in Human Hepatocellular Carcinoma: What Is the Role of Nutlins and New Therapeutic Options? Journal of Clinical Medicine. 2018; 7(4):64. https://doi.org/10.3390/jcm7040064
Chicago/Turabian StyleAzer, Samy A. 2018. "MDM2-p53 Interactions in Human Hepatocellular Carcinoma: What Is the Role of Nutlins and New Therapeutic Options?" Journal of Clinical Medicine 7, no. 4: 64. https://doi.org/10.3390/jcm7040064