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1
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Model-based translation of DNA damage signaling dynamics across cell types. PLoS Comput Biol 2022; 18:e1010264. [PMID: 35802572 PMCID: PMC9269748 DOI: 10.1371/journal.pcbi.1010264] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 05/30/2022] [Indexed: 12/14/2022] Open
Abstract
Interindividual variability in DNA damage response (DDR) dynamics may evoke differences in susceptibility to cancer. However, pathway dynamics are often studied in cell lines as alternative to primary cells, disregarding variability. To compare DDR dynamics in the cell line HepG2 with primary human hepatocytes (PHHs), we developed a HepG2-based computational model that describes the dynamics of DDR regulator p53 and targets MDM2, p21 and BTG2. We used this model to generate simulations of virtual PHHs and compared the results to those for PHH donor samples. Correlations between baseline p53 and p21 or BTG2 mRNA expression in the absence and presence of DNA damage for HepG2-derived virtual samples matched the moderately positive correlations observed for 50 PHH donor samples, but not the negative correlations between p53 and its inhibitor MDM2. Model parameter manipulation that affected p53 or MDM2 dynamics was not sufficient to accurately explain the negative correlation between these genes. Thus, extrapolation from HepG2 to PHH can be done for some DDR elements, yet our analysis also reveals a knowledge gap within p53 pathway regulation, which makes such extrapolation inaccurate for the regulator MDM2. This illustrates the relevance of studying pathway dynamics in addition to gene expression comparisons to allow reliable translation of cellular responses from cell lines to primary cells. Overall, with our approach we show that dynamical modeling can be used to improve our understanding of the sources of interindividual variability of pathway dynamics. Susceptibility to develop cancer varies among people, partially due to differences in genetic background. Ideally, healthy human-derived cells are used to investigate intracellular signaling pathways and their interindividual variability contributing to cancer susceptibility. Because cells from healthy human tissue are difficult to obtain and culture for periods longer than a few days, cell lines are often used as substitute. However, it is unclear to what extent signaling dynamics in cell lines represent dynamics in healthy human tissue. We asked whether we could reproduce interindividual variability in DNA damage response gene expression in a set of 50 human liver cell donors. Therefore, we built a mathematical model that simulates temporal expression dynamics of the DNA damage response in the HepG2 liver cell line upon chemical activation and used the simulations to create virtual donors. Our virtual donors displayed similar relations between genes as the samples from human donors, provided that we adjusted the strength of specific molecular interactions. Thus, our approach can be used to examine the applicability of widely used cell systems to healthy human tissue in terms of their dynamic responses.
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2
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Azer SA. MDM2-p53 Interactions in Human Hepatocellular Carcinoma: What Is the Role of Nutlins and New Therapeutic Options? J Clin Med 2018; 7:64. [PMID: 29584707 PMCID: PMC5920438 DOI: 10.3390/jcm7040064] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/22/2018] [Accepted: 03/23/2018] [Indexed: 12/18/2022] Open
Abstract
Human hepatocellular carcinoma (HCC) is the fifth most common cancer and is associated with poor prognosis worldwide. The molecular mechanisms underlying the pathogenesis of HCC have been an area of continuing interest, and recent studies using next generation sequencing (NGS) have revealed much regarding previously unsettled issues. Molecular studies using HCC samples have been mainly targeted with the aim to identify the fundamental mechanisms contributing to HCC and identify more effective treatments. In response to cellular stresses (e.g., DNA damage or oncogenes), activated p53 elicits appropriate responses that aim at DNA repair, genetic stability, cell cycle arrest, and the deletion of DNA-damaged cells. On the other hand, the murine double minute 2 (MDM2) oncogene protein is an important cellular antagonist of p53. MDM2 negatively regulates p53 activity through the induction of p53 protein degradation. However, current research has shown that the mechanisms underlying MDM2-p53 interactions are more complex than previously thought. Microarray data have added new insight into the transcription changes in HCC. Recently, Nutlin-3 has shown potency against p53-MDM2 binding and the enhancement of p53 stabilization as well as an increment of p53 cellular accumulation with potential therapeutic effects. This review outlines the molecular mechanisms involved in the p53-MDM2 pathways, the biological factors influencing these pathways, and their roles in the pathogenesis of HCC. It also discusses the action of Nutlin-3 treatment in inducing growth arrest in HCC and elaborates on future directions in research in this area. More research on the biology of p53-MDM2 interactions may offer a better understanding of these mechanisms and discover new biomarkers, sensitive prognostic indicators as well as new therapeutic interventions in HCC.
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Affiliation(s)
- Samy A Azer
- Professor of Medical Education and Gastroenterologist, The Chair of Curriculum Development and Research Unit, College of Medicine, King Saud University, Riyadh 11461, Saudi Arabia.
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3
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Jiang D, Cho WC, Li Z, Xu X, Qu Y, Jiang Z, Guo L, Xu G. MiR-758-3p suppresses proliferation, migration and invasion of hepatocellular carcinoma cells via targeting MDM2 and mTOR. Biomed Pharmacother 2017; 96:535-544. [PMID: 29032337 DOI: 10.1016/j.biopha.2017.10.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2017] [Revised: 09/12/2017] [Accepted: 10/02/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocelluar carcinoma (HCC) is one of the most frequently diagnosed cancers worldwide and among the leading causes of cancer-related death. Although deregulation of microRNAs has been frequently described in HCC, imperfection is known about the precise molecular mechanisms by which microRNAs modulate the process of tumorogenesis and behavior of cancer cells. In this study, we demonstrated that miR-758-3p could suppress cell proliferation, migration and invasion in hepatocellular carcinoma cells. We screened and identified two novel miR-758-3p targets, MDM2 and mTOR. Up-regulation of miR-758-3p could specifically and markedly down-regulate the expression of MDM2 and mTOR. Additionally, miR-758-3p over-expression displayed significant suppression in HCC development. To identify the mechanisms, we further investigated the P53 and mTOR pathway and found that p-p70S6 kinase(Ser371), p-p70 S6 kinase(Thr389) and p-4E-BP1were dramatically down-regulated after miR-758-3p transfection, while an enhanced expression of P53, AKT and PRAS40 were visualized, thus suggesting that the role of miR-758-3p in HCC progression may be associated with MDM2-p53 and mTOR signaling pathways. Collectively, our results indicate that miR-758-3pserves as a tumor suppressor and plays a crucial role in inhibiting the proliferation, migration and invasion of HCC via targeting MDM2 and mTOR and implicate its potential application in cancer therapy.
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Affiliation(s)
- Dan Jiang
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China; Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - William C Cho
- Department of Clinical Oncology, Queen Elizabeth Hospital, Kowloon, Hong Kong, China
| | - Zhenhao Li
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China; Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - Xiangrong Xu
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China; Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - Yuliang Qu
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China; Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China
| | - Zhongjia Jiang
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China
| | - Le Guo
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China; Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China; Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Yinchuan, 750004, China
| | - Guangxian Xu
- Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, General Hospital of Ningxia Medical University, Yinchuan, 750004, China; Department of Medical Laboratory, School of Clinical Medicine, Ningxia Medical University, Yinchuan, 750004, China; Ningxia Key Laboratory of Clinical and Pathogenic Microbiology, Yinchuan, 750004, China.
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4
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Yin J, Wang L, Zhu JM, Yu Q, Xue RY, Fang Y, Zhang YA, Chen YJ, Liu TT, Dong L, Shen XZ. Prp19 facilitates invasion of hepatocellular carcinoma via p38 mitogen-activated protein kinase/twist1 pathway. Oncotarget 2016; 7:21939-21951. [PMID: 26959880 PMCID: PMC5008335 DOI: 10.18632/oncotarget.7877] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Accepted: 02/20/2016] [Indexed: 12/18/2022] Open
Abstract
Pre-mRNA processing factor 19 (Prp19) is involved in many cellular events including pre-mRNA processing and DNA damage response. However, the pathological role of Prp19 in hepatocellular carcinoma (HCC) is still elusive. Here, we reported that Prp19 was increased in most HCC tissues and HCC cell lines, and its overexpression in HCC tissues was positively correlated with vascular invasion, tumor capsule breakthrough and poor prognosis. Prp19 potentiated migratory and invasive abilities of HCC cells in vitro and in vivo. Furthermore Prp19 facilitated Twist1-induced epithelial-mesenchymal transition. Mechanistic insights revealed that Prp19 directly binded with TGF-β-activated kinase1 (TAK1) and promoted the activation of p38 mitogen-activated protein kinase (MAPK), preventing Twist1 from degradation. Finally Prp19/p38 MAPK/Twist1 axis was attested in nude mice xenografts and HCC patient specimens. This work implies that the gain of Prp19 is a critical event during the progression of HCC, making it a promising target for malignancies with aberrant Prp19 expression.
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Affiliation(s)
- Jie Yin
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Lan Wang
- Department of Biochemistry and Molecular Biology, Shanghai Medical College of Fudan University, Shanghai, China
| | - Ji-Min Zhu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Qian Yu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ru-Yi Xue
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ying Fang
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yi-An Zhang
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Yan-Jie Chen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Tao-Tao Liu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Ling Dong
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Xi-Zhong Shen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
- Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
- Key Laboratory of Medical Molecular Virology, Shanghai Medical College of Fudan University, Shanghai, China
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5
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Zhang NY, Qi M, Gao X, Zhao L, Liu J, Gu CQ, Song WJ, Krumm CS, Sun LH, Qi DS. Response of the hepatic transcriptome to aflatoxin B1 in ducklings. Toxicon 2016; 111:69-76. [PMID: 26763128 DOI: 10.1016/j.toxicon.2015.12.022] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Accepted: 12/31/2015] [Indexed: 10/22/2022]
Abstract
This study was conducted to determine the effects of aflatoxin B1 (AFB1) on the hepatic transcriptome in ducklings through RNA-sequencing (RNA-Seq). Twenty four, 1-day-old ducklings were divided into 4 treatment groups. Each group received an oral dose of AFB1 at 0, 10, 20, 40 μg/kg BW per day for 2 weeks. Administration of 20 and 40 μg/kg BW of AFB1 significantly decreased body weight, feed intake, serum total protein and albumin, while increasing serum aspartate aminotransferase and alanine aminotransferase activities, and hepatic histopathological lesions. Furthermore, RNA was extracted from the liver of ducklings administrated 0 and 40 μg/kg BW of AFB1. Two RNA-Seq libraries were created from pooled samples and produced over 149 M reads, totaling 14.9 Gb of sequence. Approximately 96,953 predicted transcripts were assembled, 749 of which had significant differential expressions (≥ 2-fold) between the control and AFB1 treatment. GO and KEGG pathway analysis results showed that many genes involved in phase I metabolism, phase II detoxification, oxidation-reduction process, carcinogenesis, apoptosis and cell cycle, and fatty acid metabolism were affected by AFB1 exposure. Conclusion, this study determined the hepatic transcriptome responded to AFB1 exposure, and provide candidate genes can be targeted to prevent and/or reduce aflatoxicosis in ducklings.
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Affiliation(s)
- Ni-Ya Zhang
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Ming Qi
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Xin Gao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Ling Zhao
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Jie Liu
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Chang-Qin Gu
- College of Veterinary Medicine, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | - Wen-Jing Song
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China
| | | | - Lv-Hui Sun
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
| | - De-Sheng Qi
- Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, Huazhong Agricultural University, Wuhan, Hubei 430070, China.
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6
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Chen YJ, Wu H, Shen XZ. The ubiquitin-proteasome system and its potential application in hepatocellular carcinoma therapy. Cancer Lett 2015; 379:245-52. [PMID: 26193663 DOI: 10.1016/j.canlet.2015.06.023] [Citation(s) in RCA: 63] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2015] [Revised: 06/23/2015] [Accepted: 06/25/2015] [Indexed: 02/07/2023]
Abstract
The ubiquitin-proteasome system (UPS) is a complicated tightly controlled system in charge of degrading 80-90% of proteins, and is central to regulating cellular function and keeping protein homeostasis. Therefore, the components of UPS attract considerable attention as potential targets for hepatocellular carcinoma (HCC) therapy. The clinical success of bortezomib in multiple myeloma and mantle cell lymphoma patients has set the precedent for therapeutically targeting this pathway. This review will provide an overview of the UPS in HCC and the current status of therapeutic strategies.
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Affiliation(s)
- Yan-Jie Chen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Hao Wu
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China
| | - Xi-Zhong Shen
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai 200032, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai 200032, China.
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7
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Monson MS, Settlage RE, McMahon KW, Mendoza KM, Rawal S, El-Nezami HS, Coulombe RA, Reed KM. Response of the hepatic transcriptome to aflatoxin B1 in domestic turkey (Meleagris gallopavo). PLoS One 2014; 9:e100930. [PMID: 24979717 PMCID: PMC4076218 DOI: 10.1371/journal.pone.0100930] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2014] [Accepted: 06/02/2014] [Indexed: 12/21/2022] Open
Abstract
Dietary exposure to aflatoxin B1 (AFB1) is detrimental to avian health and leads to major economic losses for the poultry industry. AFB1 is especially hepatotoxic in domestic turkeys (Meleagris gallopavo), since these birds are unable to detoxify AFB1 by glutathione-conjugation. The impacts of AFB1 on the turkey hepatic transcriptome and the potential protection from pretreatment with a Lactobacillus-based probiotic mixture were investigated through RNA-sequencing. Animals were divided into four treatment groups and RNA was subsequently recovered from liver samples. Four pooled RNA-seq libraries were sequenced to produce over 322 M reads totaling 13.8 Gb of sequence. Approximately 170,000 predicted transcripts were de novo assembled, of which 803 had significant differential expression in at least one pair-wise comparison between treatment groups. Functional analysis linked many of the transcripts significantly affected by AFB1 exposure to cancer, apoptosis, the cell cycle or lipid regulation. Most notable were transcripts from the genes encoding E3 ubiquitin-protein ligase Mdm2, osteopontin, S-adenosylmethionine synthase isoform type-2, and lipoprotein lipase. Expression was modulated by the probiotics, but treatment did not completely mitigate the effects of AFB1. Genes identified through transcriptome analysis provide candidates for further study of AFB1 toxicity and targets for efforts to improve the health of domestic turkeys exposed to AFB1.
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Affiliation(s)
- Melissa S. Monson
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America
| | - Robert E. Settlage
- Data Analysis Core, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
| | - Kevin W. McMahon
- Data Analysis Core, Virginia Bioinformatics Institute, Virginia Polytechnic Institute and State University, Blacksburg, Virginia, United States of America
| | - Kristelle M. Mendoza
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America
| | - Sumit Rawal
- Department of Animal, Dairy and Veterinary Sciences, College of Agriculture, Utah State University, Logan, Utah, United States of America
| | - Hani S. El-Nezami
- School of Biological Sciences, University of Hong Kong, Hong Kong, China
| | - Roger A. Coulombe
- Department of Animal, Dairy and Veterinary Sciences, College of Agriculture, Utah State University, Logan, Utah, United States of America
| | - Kent M. Reed
- Department of Veterinary and Biomedical Sciences, College of Veterinary Medicine, University of Minnesota, Saint Paul, Minnesota, United States of America
- * E-mail:
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8
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Liu M, Zheng SJ, Chen Y, Li N, Ren PF, Dai LP, Duan ZP, Zhang JY. Autoantibody response to murine double minute 2 protein in immunodiagnosis of hepatocellular carcinoma. J Immunol Res 2014; 2014:906532. [PMID: 24955377 PMCID: PMC4053260 DOI: 10.1155/2014/906532] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2014] [Accepted: 04/17/2014] [Indexed: 12/31/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide. Although new therapeutic strategies have been continuously developed and applied to clinical treatment for HCC, the prognosis is still very poor. Thus, early detection of HCC may enhance effective and curative management. In this study, autoantibody responses to MDM2 protein in HCC patient's serum were evaluated by enzyme-linked immunosorbent assay (ELISA) and part sera were evaluated by Western blotting and indirect immunofluorescence assay. Immunohistochemistry (IHC) over tissue array slides was also performed to analyze protein expression of MDM2 in HCC and control tissues. The prevalence of autoantibodies against MDM2 was significantly higher than that in liver cirrhosis (LC), chronic hepatitis (CH), and normal human sera (NHS). The average titer of autoantibodies against MDM2 in HCC serum was higher compared to that in LC, CH, and NHS. A high titer of autoantibodies against MDM2 in ELISA could be observed in the serum in 6 to 9 months before the clinical diagnosis of HCC in the serum of several HCC patients with serial bleeding samples. Our preliminary data indicate that MDM2 and anti-MDM2 system may be a potential biomarker for early stage HCC screening and immunodiagnosis.
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Affiliation(s)
- Mei Liu
- Beijing You'an Hospital, Capital Medical University, Beijing 10069, China
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA
| | - Su-jun Zheng
- Beijing You'an Hospital, Capital Medical University, Beijing 10069, China
| | - Yu Chen
- Beijing You'an Hospital, Capital Medical University, Beijing 10069, China
| | - Ning Li
- Beijing You'an Hospital, Capital Medical University, Beijing 10069, China
| | - Peng-fei Ren
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA
| | - Li-ping Dai
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA
| | - Zhong-ping Duan
- Beijing You'an Hospital, Capital Medical University, Beijing 10069, China
| | - Jian-Ying Zhang
- Department of Biological Sciences, The University of Texas at El Paso, El Paso, TX 79968, USA
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9
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Ji YN, Wang Q, Xue J. TP53 immunohistochemical expression is associated with the poor outcome for hepatocellular carcinoma: evidence from a meta-analysis. Tumour Biol 2014; 35:1653-9. [PMID: 24078450 DOI: 10.1007/s13277-013-1228-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2013] [Accepted: 09/17/2013] [Indexed: 12/12/2022] Open
Abstract
Various studies examined the relationship between p53 expression with the clinical outcome in patients with hepatocellular carcinoma (HCC), but yielded conflicting results. Electronic databases updated to July 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between p53 expression and survival of patients with HCC. Survival data were aggregated and quantitatively analyzed. We performed a meta-analysis of 24 studies that evaluated the correlation between p53 expression and survival in patients with HCC. Combined hazard ratios suggested that p53 expression had an unfavorable impact on overall survival (OS) (HR (hazard ratio) = 1.55, 95 % CI (confidence interval) 1.36-1.74) and disease-free survival (DFS) (HR = 1.54, 95 % CI 1.21-1.88) in patients with HCC. No significant heterogeneity was observed among 20 studies for OS (P = 0.786) and among 11 studies for DFS (P = 0.698). P53 expression indicates a poor prognosis for patients with hepatocellular carcinoma.
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Zhan P, Ji YN. Prognostic significance of TP53 expression for patients with hepatocellular carcinoma: a meta-analysis. Hepatobiliary Surg Nutr 2014; 3:11-7. [PMID: 24696834 DOI: 10.3978/j.issn.2304-3881.2014.01.03] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 01/24/2014] [Indexed: 01/01/2023]
Abstract
BACKGROUND Various studies evaluated the relationship between p53 expression and the clinical outcome in patients with hepatocellular carcinoma (HCC), but yielded conflicting results. METHODS Electronic databases updated to Dec 2013 were searched to find relevant studies. A meta-analysis was conducted with eligible studies which quantitatively evaluated the relationship between p53 expression and survival of patients with HCC. Survival data were aggregated and quantitatively analyzed. RESULTS We performed a meta-analysis of 24 studies that evaluated the correlation between p53 expression and survival in patients with HCC. Combined hazard ratios (HRs) suggested that p53 expression had an unfavorable impact on overall survival (OS) [HR =1.64, 95% confidence interval (CI): 1.40-1.85], and disease free survival (DFS) (HR =1.57, 95% CI: 1.26-1.87) in patients with HCC. CONCLUSIONS p53 expression indicates a poor prognosis for patients with HCC.
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Affiliation(s)
- Ping Zhan
- 1 First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, China ; 2 Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing 210029, China
| | - Ya-Nan Ji
- 1 First Department of Respiratory Medicine, Nanjing Chest Hospital, Nanjing 210029, China ; 2 Jiangsu Province Hospital of Traditional Chinese Medicine, Nanjing 210029, China
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11
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Yin J, Zhu JM, Shen XZ. The role and therapeutic implications of RING-finger E3 ubiquitin ligases in hepatocellular carcinoma. Int J Cancer 2014; 136:249-57. [PMID: 24420637 DOI: 10.1002/ijc.28717] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2013] [Accepted: 01/02/2014] [Indexed: 12/30/2022]
Abstract
Increasing evidence indicates that deregulation of RING-finger ubiquitin-protein ligases (E3s) involves in the development of hepatocellular carcinoma (HCC). These RING-finger E3s serve as oncoproteins or tumor suppressors in HCC under specific conditions. In this review, we summarize current knowledge about abnormal RING-finger E3s and their clinical significance in the development of HCC, and discuss parts of critical substrates for these RING-finger E3s in detail. Furthermore, in light of success of Bortezomib in treating hematological malignancies, we describe the preclinical and clinical studies of therapeutic approaches targeting aberrant RING-finger E3s in HCC.
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Affiliation(s)
- Jie Yin
- Department of Gastroenterology, Zhongshan Hospital of Fudan University, Shanghai, China
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12
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Chen QW, Chen H, Cheng JS, Meng ZQ. MDM2 SNP309T>G polymorphism and hepatocellular carcinoma risk: a meta-analysis. Tumour Biol 2013; 35:4147-51. [PMID: 24379140 DOI: 10.1007/s13277-013-1543-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Accepted: 12/11/2013] [Indexed: 02/06/2023] Open
Abstract
Case-control studies on the association between mouse double-minute 2 homolog (MDM2) SNP309T>G polymorphism and hepatocellular carcinoma have provided either controversial or inconclusive results. To clarify the effect of MDM2 SNP309T>G polymorphism on the risk of hepatocellular carcinoma, a meta-analysis of all case-control observational studies was performed. Pooled odds ratios (ORs) for various polymorphisms were estimated using random and fixed effects models. The Q-statistic was used to evaluate the homogeneity, and Egger and Begg tests were used to assess publication bias. Overall, the MDM2 SNP309T>G polymorphism was associated with a risk of hepatocellular carcinoma (OR = 0.68; 95% CI = 0.54-0.85 for allele contrast, p = 0.0005, phet = 0.004). The contrast of homozygotes and the recessive and dominant models produced the same pattern of results as the allele contrast. In the analysis stratified by ethnicity, significant associations were found in the Caucasian population in all of the genetic models. In addition, heterogeneity disappeared in subgroups of Caucasian subjects. Our pooled data suggest evidence for a major role of MDM2 SNP309T>G polymorphism in the carcinogenesis of hepatocellular carcinoma, especially among Caucasian populations.
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Affiliation(s)
- Qi-Wen Chen
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, China
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13
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Ye Y, Li X, Yang J, Miao S, Wang S, Chen Y, Xia X, Wu X, Zhang J, Zhou Y, He S, Tan Y, Qiang F, Li G, Røe OD, Zhou J. MDM2 is a useful prognostic biomarker for resectable gastric cancer. Cancer Sci 2013; 104:590-8. [PMID: 23347235 DOI: 10.1111/cas.12111] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2012] [Revised: 01/12/2013] [Accepted: 01/20/2013] [Indexed: 12/18/2022] Open
Abstract
Expression of MDM2 protein appears to be increased in malignancy and correlated to prognosis of tumors, but its role in gastric cancer remains controversial. Our recent investigations indicated that JWA was a novel candidate biomarker for gastric cancer. To evaluate the impact of MDM2 protein expression alone, and in combination with JWA, on the prognostic and predictive of patients with resectable gastric cancer, expression of MDM2 and JWA were examined by immunohistochemistry in three large cohorts (total n = 1131) of patient with gastric cancer. We found that MDM2 protein levels were significantly upregulated in gastric cancer (70.4%, 57 of 81) compared with adjacent non-cancerous tissues. High tumoral MDM2 expression significantly correlated with clinicopathologic characteristics, as well as with shorter overall survival (OS; P < 0.001 for all cohorts) in patients without adjuvant treatment. The effect of adjuvant fluorouracil-leucovorin-oxaliplatin (FLO) in improving OS compared with surgery alone was evident only in the high MDM2 group (hazard ratio = 0.57; 95% confidence interval, 0.37-0.89; P = 0.013). Furthermore, knockdown of MDM2 and overexpression of JWA had a synergistic effect on suppression of gastric cancer cell proliferation and migration. Patients with low MDM2 and high JWA expression had a better outcome of survival compared with the other groups (P < 0.001 for all cohorts). For the first time, our data suggest that MDM2 is a potent prognostic and predictive factor for benefit from adjuvant fluorouracil-leucovorin-oxaliplatin chemotherapy in resectable gastric cancer. The combination of MDM2 expression and JWA could serve as a more effective candidate prognostic biomarker for gastric cancer.
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Affiliation(s)
- Yang Ye
- Department of Molecular Cell Biology and Toxicology, Cancer Center, School of Public Health, Nanjing Medical University, Nanjing, China
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14
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Wang X, Zhang X, Qiu B, Tang Y, Sun H, Ji H, Liu Y, Shi L, Song G, Yang Y. MDM2 SNP309T>G polymorphism increases susceptibility to hepatitis B virus-related hepatocellular carcinoma in a northeast Han Chinese population. Liver Int 2012; 32:1172-8. [PMID: 22413855 DOI: 10.1111/j.1478-3231.2012.02787.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2011] [Accepted: 02/15/2012] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIMS The murine double minute 2 (MDM2) gene encodes a negative regulator of the tumour protein p53. A single nucleotide polymorphism (SNP) in MDM2 promoter, SNP309 T > G, has been showed to influence MDM2 protein expression and accelerate tumour formation. To investigate further the role of this locus, we examined the association of the SNP with hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) in a northeast Han Chinese population. METHODS MDM2 SNP309 was genotyped in 310 HBV-related HCC patients, 314 non-HCC subjects with HBV infection and 480 healthy controls by using a PCR-RFLP method. RESULTS Significant differences of MDM2 SNP309 were detected between HBV-related HCC patients and healthy controls (OR 1.729, 95%CI 1.369-2.183, P < 0.0001) or non-HCC subjects with HBV infection (OR 1.351, 95% CI 1.060-1.722, P = 0.015) by a logistic regression analysis. Our data also revealed that subjects with the G allele had higher HBV-related HCC susceptibility than those with the T allele in various genetic models. In a meta-analysis, where we pooled our data with other published studies, the association between this loci and the disease was further confirmed (pooled OR 1.54, 95% CI 1.37-1.72, P < 0.0001). CONCLUSIONS These results suggested that the MDM2 SNP309 might influence the risk of developing HBV-related HCC in a northeast Han Chinese population.
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Affiliation(s)
- Xi Wang
- Department of Gastroenterology, First Affiliated Hospital of Harbin Medical University, Harbin, China.
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15
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Molecular and serum markers in hepatocellular carcinoma: Predictive tools for prognosis and recurrence. Crit Rev Oncol Hematol 2012; 82:116-40. [DOI: 10.1016/j.critrevonc.2011.05.005] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2010] [Revised: 04/08/2011] [Accepted: 05/18/2011] [Indexed: 12/12/2022] Open
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Liu J, Ma Q, Zhang M, Wang X, Zhang D, Li W, Wang F, Wu E. Alterations of TP53 are associated with a poor outcome for patients with hepatocellular carcinoma: evidence from a systematic review and meta-analysis. Eur J Cancer 2012; 48:2328-38. [PMID: 22459764 DOI: 10.1016/j.ejca.2012.03.001] [Citation(s) in RCA: 101] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2011] [Revised: 02/29/2012] [Accepted: 03/02/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND The prognostic significance of p53 aberration in hepatocellular carcinoma (HCC) remains inconclusive. This systematic review and meta-analysis aimed to provide comprehensive evidence on the association of p53 alterations with recurrence-free survival (RFS) and overall survival (OS) in HCC patients. METHODS Systematic literature searches were conducted until July 2010. Meta-analysis was performed to estimate prognostic effects of p53 alterations on patient outcomes in HCC. Sensitivity and subgroup analyses were also conducted in the meta-analysis. RESULTS Thirty-seven studies (7 tumour p53 mutation, 23 tumour p53 expression and 7 serum anti-p53 antibodies) were included in the systematic review and meta-analysis. The average percentages of p53 mutation, p53 expression upregulation and anti-p53 antibody level elevation in HCC patients were 31.5%, 35.0% and 23.8%, respectively. Tumour p53 alterations were associated significantly with poor patient outcomes in HCC: the summary hazard ratio (HR) of mutant p53 versus wild type p53 phenotype was 2.58 [95% confidence interval (CI): 1.96-3.41] for OS and 3.19 [95% CI: 2.21-4.60] for RFS, respectively; and the summary HR of upregulated p53 expression versus low/undetectable p53 expression was 1.68 [95% CI: 1.49-1.90] for OS and 1.89 [95% CI: 1.34-2.66] for RFS, respectively. However, elevated serum anti-p53 antibody was only associated with poor OS in HCC group with a high proportion of (≥ 50%) of hepatitis C virus (HCV) infection [HR: 1.92; 95% CI: 1.30-2.85]. Moreover, sensitivity analyses showed that the results of meta-analyses were not altered. CONCLUSION HCC patients with p53 mutation and upregulated expression in tumour tissue have a shorter OS and RFS than patients with wild type p53 and low/undetectable p53 expression. However, the prognostic value of serum anti-p53 antibody is required to be further examined.
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Affiliation(s)
- Jiangbo Liu
- Department of Hepatobiliary Surgery, First Affiliated Hospital, Medical College of Xi'an Jiaotong University, Xi'an, China
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Song TJ, Fong Y, Cho SJ, Gönen M, Hezel M, Tuorto S, Choi SY, Kim YC, Suh SO, Koo BH, Chae YS, Jarnagin WR, Klimstra DS. Comparison of hepatocellular carcinoma in American and Asian patients by tissue array analysis. J Surg Oncol 2012; 106:84-8. [PMID: 22234941 DOI: 10.1002/jso.23036] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2011] [Accepted: 12/19/2011] [Indexed: 12/13/2022]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide. Although some epidemiologic and etiologic differences between Asian and Western HCC are known, detailed comparative studies with pathologic correlations have not been performed. METHODS Paraffin sections of resected HCC specimens from Memorial Sloan-Kettering Cancer Center and Korea University Medical Center were used to construct tissue microarrays. Immunohistochemical staining of microarray sections was performed using antibodies against markers of proliferation and regulators of cell cycle. Patient data were correlated with staining results. RESULTS When comparing both cohorts, significant differences were found in expression of p53 and MDM2. In the Asian group, more frequent positive staining for p53 (24%) was observed compared with the American group (9%; P = 0.037). For MDM2, 26% of American cases stained positive compared with 2% of Asian cases (P = 0.0003). No significant differences were found in expression of Ki67, p21, p27, cyclin D1, or bcl2. Female gender, vascular invasion, and lack of viral hepatitis infection correlated with positive MDM2 staining. CONCLUSION These data likely correlate with differences in molecular pathogenesis of HCC based on racial and regional differences. These findings may have implications in choice of molecular targeted therapies based on patient ethnicity.
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Affiliation(s)
- Tae-Jin Song
- Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
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McClendon AK, Dean JL, Ertel A, Fu Z, Rivadeneira DB, Reed CA, Bourgo RJ, Witkiewicz A, Addya S, Mayhew CN, Grimes HL, Fortina P, Knudsen ES. RB and p53 cooperate to prevent liver tumorigenesis in response to tissue damage. Gastroenterology 2011; 141:1439-50. [PMID: 21704587 PMCID: PMC4562673 DOI: 10.1053/j.gastro.2011.06.046] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/04/2010] [Revised: 06/01/2011] [Accepted: 06/13/2011] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS The tumor suppressors retinoblastoma (RB) and p53 are important regulators of the cell cycle. Although human cancer cells inactivate RB and p53 by many mechanisms, the cooperative roles of these proteins in tumorigenesis are complex and tissue specific. We analyzed the cooperation of RB and p53 in liver development and pathogenesis of hepatocellular carcinoma. METHODS Spontaneous and carcinogen-induced (diethylnitrosamine) tumorigenesis were studied in mice with liver-specific deletions of Rb and/or p53 (Rbf/f;albcre+, p53f/f;albcre+ and Rbf/f; p53f/f;albcre+ mice). Genotype, histologic, immunohistochemical, microarray, quantitative polymerase chain reaction, immunoblot, and comparative genomic hybridization analyses were performed using normal and tumor samples. Comparative microarray analyses were performed against publicly available human microarray data sets. RESULTS Deletion of RB and p53 from livers of mice deregulated the transcriptional programs associated with human disease. These changes were not sufficient for spontaneous tumorigenesis; potent quiescence mechanisms compensated for loss of these tumor suppressors. In response to hepatocarcinogen-induced damage, distinct and cooperative roles of RB and p53 were revealed; their loss affected cell cycle control, checkpoint response, and genome stability. In damaged tissue, combined loss of RB and p53 resulted in early lesion formation, aggressive tumor progression, and gene expression signatures and histologic characteristics of advanced human hepatocellular carcinoma. CONCLUSIONS The effects RB and p53 loss are determined by the tissue environment; cell stresses that promote aggressive disease reveal the functions of these tumor suppressors.
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Affiliation(s)
- A. Kathleen McClendon
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Jeffry L. Dean
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Adam Ertel
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107,Laboratory for Cancer Genomics, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Zhiyan Fu
- The Wistar Institute, Philadelphia, PA 19104
| | - Dayana B. Rivadeneira
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Christopher A. Reed
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Ryan J. Bourgo
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Agnieszka Witkiewicz
- Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, 19107
| | - Sankar Addya
- Laboratory for Cancer Genomics, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Christopher N. Mayhew
- Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229
| | - H. Leighton Grimes
- Divisions of Experimental Hematology and Pathology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229,Division of Immunology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229
| | - Paolo Fortina
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107,Laboratory for Cancer Genomics, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107
| | - Erik S. Knudsen
- Department of Cancer Biology, Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107,Correspondence: Erik S. Knudsen, Kimmel Cancer Center, Thomas Jefferson University, 233 South 10th St. BLSB 1002, Philadelphia, PA 19107, USA, Tel: 215.503.8576, Fax: 215.923.4498,
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Zhao J, Wang C, Wang J, Yang X, Diao N, Li Q, Wang W, Xian L, Fang Z, Yu L. E3 ubiquitin ligase Siah-1 facilitates poly-ubiquitylation and proteasomal degradation of the hepatitis B viral X protein. FEBS Lett 2011; 585:2943-50. [PMID: 21878328 DOI: 10.1016/j.febslet.2011.08.015] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2011] [Revised: 07/23/2011] [Accepted: 08/09/2011] [Indexed: 11/15/2022]
Abstract
Hepatitis B viral X protein (HBx) is a multifunctional transactivator and implicated in hepatitis B virus (HBV) replication and hepatocarcinogenesis. HBx can be ubiquitinated and degraded through ubiquitin-proteasome pathway. However, the E3 ubiquitin ligase regulating HBx ubiquitin-dependent degradation is still unknown. In this study, we identified Siah-1 as a novel E3 ubiquitin ligase for HBx, which interacted with HBx and facilitated HBx poly-ubiquitylation and proteasomal degradation. Co-expression of Siah-1 attenuated the transcriptional transactivation of HBx on glucocorticoid response element (GRE), heat shock response element (HSE) and cAMP response element (CRE) signal pathways. Moreover, Siah-1 participated in p53-mediated HBx degradation. Therefore, Siah-1 may play important roles in ubiquitin-dependent degradation of HBx and may be involved in suppressing the progression of hepatocellular carcinoma (HCC).
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Affiliation(s)
- Jing Zhao
- State Key Laboratory of Genetic Engineering, Institute of Genetics, Shanghai, PR China
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20
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Breuhahn K, Schirmacher P. Signaling networks in human hepatocarcinogenesis--novel aspects and therapeutic options. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2011; 97:251-77. [PMID: 21074736 DOI: 10.1016/b978-0-12-385233-5.00009-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) represents one of the most common human malignancies with poor prognosis. Because therapeutic strategies are insufficient for most HCC patients, there is a great need to determine the central molecular mechanisms and pathways in order to derive novel targets for systemic therapy. There is vast evidence that not only the dysregulation of distinct signaling cascades, but also their interactions at different levels, affect tumor cell function. Through these interactions, the effects of pathways can be increased, and even new tumor-supporting qualities acquired that further facilitate HCC progression. Although several approaches for the modulation of these relevant pathways are under development, future therapeutic strategies should take into account that oncogenic stimuli cannot be understood in a monodimensional manner. In order to avoid escape mechanisms during therapy, strategies based on comprehensive knowledge of the interactive regulatory network in hepatocarcinogenesis are necessary.
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Affiliation(s)
- K Breuhahn
- Institute of Pathology, University Hospital, Heidelberg, Germany
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21
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Liu GY, Jiang DK, Shen SQ, Yu L. MDM2 SNP309T>G polymorphism with hepatocellular carcinoma risk: a meta-analysis. Arch Med Res 2011; 42:149-155. [PMID: 21565629 DOI: 10.1016/j.arcmed.2011.02.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2010] [Accepted: 01/31/2011] [Indexed: 12/20/2022]
Abstract
BACKGROUND AND AIMS The murine double minute 2 (MDM2) gene encodes a negative regulator of the tumor protein p53. A single nucleotide polymorphism (SNP) in MDM2 promoter, SNP309 T>G, has been reported to alter MDM2 protein expression and accelerate tumor formation in humans. Studies investigating the association between the polymorphism and human hepatocellular carcinoma (HCC) risk reported conflicting results. We performed a meta-analysis to explore the association of this polymorphism and HCC risk. METHODS All eligible studies published were searched for in PubMed. Crude odds ratios (ORs) with 95% confidence intervals (CIs) were assessed for the association using fixed- and random-effects models. RESULTS We identified five case-control studies including 738 cases and 1014 controls for the present meta-analysis. In studies with limited data, we detected significant associations for all genetic models in the overall analysis (OR = 2.51, 95% CI = 1.88-3.36 for GG vs. TT, p <0.001, P(het) = 0.666; OR = 1.71, 95% CI = 1.35-2.18 for TG vs. TT, p <0.001, P(het) = 0.925; OR = 1.94, 95% CI = 1.54-2.43 for dominant model TG + GG vs. TT, p <0.001, P(het) = 0.772; OR = 1.74, 95% CI = 1.39-2.20 for recessive model GG vs. TT + TG, p <0.001, P(het) = 0.656). Moreover, in the subgroup analysis based on Hardy-Weinberg equilibrium (HWE) in controls, sample size, and ethnicity, significant associations were observed in most genetic models. CONCLUSIONS This meta-analysis suggests that the MDM2 309 G allele probably acts as an important HCC risk factor. To further confirm our findings, well-designed studies with large sample sizes and representing different ethnicities are required.
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Affiliation(s)
- Guo-Yuan Liu
- The State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
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22
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Jung CR, Lim JH, Choi Y, Kim DG, Kang KJ, Noh SM, Im DS. Enigma negatively regulates p53 through MDM2 and promotes tumor cell survival in mice. J Clin Invest 2010; 120:4493-506. [PMID: 21060154 DOI: 10.1172/jci42674] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2010] [Accepted: 09/22/2010] [Indexed: 12/29/2022] Open
Abstract
The human E3 ubiquitin ligase murine double minute 2 (MDM2) targets the tumor suppressor p53 for ubiquitination and degradation but also promotes its own ubiquitination and subsequent degradation. As the balance between MDM2 and p53 levels plays a crucial role in regulating cell proliferation and apoptosis, we sought to identify factors selectively inhibiting MDM2 self-ubiquitination. Here we have shown that the LIM domain protein Enigma directly interacts with MDM2 to form a ternary complex with p53 in vitro and in human hepatoma and colon carcinoma cell lines and mouse embryonic fibroblasts. We found that Enigma elicited p53 degradation by inhibiting MDM2 self-ubiquitination and increasing its ubiquitin ligase activity toward p53 in cells. Moreover, mitogenic stimuli such as serum, FGF, and HGF increased Enigma transcription via induction of serum response factor (SRF), leading to MDM2 stabilization and subsequent p53 degradation. We observed similar results in the livers of mice treated with HGF. In humans, we found SRF and Enigma coexpressed with MDM2 but not p53 in several liver and stomach tumors. Finally, we showed that Enigma promoted cell survival and chemoresistance by suppressing p53-mediated apoptosis in both cell lines and a mouse xenograft model. Our findings suggest a role for Enigma in tumorigenesis and uncover a mechanism whereby mitogens attenuate p53 antiproliferative activity through an SRF/Enigma/MDM2 pathway.
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Affiliation(s)
- Cho-Rok Jung
- Gene Therapy Research Unit, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon, South Korea
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Leu JD, Lin IF, Sun YF, Chen SM, Liu CC, Lee YJ. Association between MDM2-SNP309 and hepatocellular carcinoma in Taiwanese population. World J Gastroenterol 2009; 15:5592-7. [PMID: 19938200 PMCID: PMC2785064 DOI: 10.3748/wjg.15.5592] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the risk association and compare the onset age of hepatocellular carcinoma (HCC) patients in Taiwan with different genotypes of MDM2-SNP309.
METHODS: We analyzed MDM2-SNP309 genotypes from 58 patients with HCC and 138 cancer-free healthy controls consecutively. Genotyping of MDM2-SNP309 was conducted by restriction fragment length polymorphism assay.
RESULTS: The proportion of homozygous MDM2-SNP309 genotype (G/G) in cases and cancer-free healthy controls was similar (17.2% vs 16.7%). Multivariate analysis showed that the risk of G/G genotype of MDM2-SNP309 vs wild-type T/T genotype in patients with HCC was not significant (OR = 1.265, 95% CI = 0.074-21.77) after adjustment for sex, hepatitis B or C virus infection, age, and cardiovascular disease/diabetes. Nevertheless, there was a trend that GG genotype of MDM2-SNP309 might increase the risk in HCC patients infected with hepatitis virus (OR = 2.568, 95% CI = 0.054-121.69). Besides, the homozygous MDM2-SNP309 genotype did not exhibit a significantly earlier age of onset for HCC.
CONCLUSION: Current data suggest that the association between MDM2-SNP309 GG genotype and HCC is not significant, while the risk may be enhanced in patients infected by hepatitis virus in Taiwan.
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Chen XL, Gao SL, Zhao L. Research progress in roles of murine double minute 2 gene in the gastrointestinal tumor. Shijie Huaren Xiaohua Zazhi 2008; 16:2877-2882. [DOI: 10.11569/wcjd.v16.i25.2877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Murine double minute 2 (MDM2), an oncogene discovered in recent years, can enhance cell survival activity, prolong cell survival duration, promote cell proliferation and stimulate tumor growth. In recent years, it was shown that MDM2 participated in the genesis and development of various tumors. In addition, MDM2 is associated with the invasion, metastasis and poor prognosis of malignant tumors, especially gastrointestinal tumors such as esophageal cancer, gastric cancer, colon cancer, liver cancer, etc. So it is significant to study the relationship between MDM2 and gastrointestinal tumors for tumor prevention and treatment. In combination with domestic and overseas literatures, this article provides a brief review of the research progress in the roles of MDM2 in the genesis, development and metastasis of gastrointestinal tumors.
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Umemura A, Itoh Y, Itoh K, Yamaguchi K, Nakajima T, Higashitsuji H, Onoue H, Fukumoto M, Okanoue T, Fujita J. Association of gankyrin protein expression with early clinical stages and insulin-like growth factor-binding protein 5 expression in human hepatocellular carcinoma. Hepatology 2008; 47:493-502. [PMID: 18161051 DOI: 10.1002/hep.22027] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
UNLABELLED Gankyrin (also known as PSMD10) is a liver oncoprotein that interacts with multiple proteins including MDM2 and accelerates degradation of the tumor suppressors p53 and Rb. We produced a monoclonal anti-gankyrin antibody and immunohistochemically assessed the clinicopathological significance of gankyrin overexpression in 43 specimens of human hepatocellular carcinoma (HCC). Specific cytoplasmic staining for gankyrin was observed in 62.8% (27/43) of HCCs, which was significantly associated with low TNM stage (P = 0.004), no capsular invasion (P = 0.018), no portal venous invasion (P = 0.008), and no intrahepatic metastasis (P = 0.012). The cumulative survival rate of patients with gankyrin-positive HCC was significantly higher than that with gankyrin-negative HCC (P = 0.037). p53 and MDM2 were positively stained by antibodies in 30.2% and 23.3%, respectively, of HCCs, but neither was inversely associated with gankyrin expression. In the Huh-7 human HCC cell line, overexpression of gankyrin up-regulated expression of insulin-like growth factor binding protein 5 (IGFBP-5), whereas suppression of gankyrin expression by siRNA down-regulated it. Supression of IGFBP-5 expression inhibited proliferation of Huh-7 cells as well as U-2 OS osteosarcoma cells. In HCC specimens, positive staining for IGFBP-5 was observed by immunohistochemistry in 41.9% (18/43), and the level of expression was significantly correlated with that of gankyrin (rho = 0.629, P < 0.001). CONCLUSION These results suggest that gankyrin plays an oncogenic role(s) mainly at the early stages of human hepatocarcinogenesis, and that IGFBP-5 inducible by gankyrin overexpression may be involved in it.
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Affiliation(s)
- Atsushi Umemura
- Department of Clinical Molecular Biology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
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He Q, Cheng R, Chen Z, Xiao X, Xiao Z, Li C, Li B, Zhang P, Zheng H, Feng D. Cell transformation and proteome alteration in QSG7701 cells transfected with hepatitis C virus non-structural protein 3. Acta Biochim Biophys Sin (Shanghai) 2007; 39:751-62. [PMID: 17928924 DOI: 10.1111/j.1745-7270.2007.00344.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022] Open
Abstract
Persistent hepatitis C virus (HCV) infection can cause liver cirrhosis and hepatocellular carcinoma. Non-structural protein 3 (NS3), an important part of HCV, has been implicated in the life cycle of the virus and interacts with host cellular proteins. In this study, we investigated the effect of NS3 protein on cell tranformation and related protein alteration in human hepatocyte QSG7701 cells. The results indicated that stable expression of the NS3 protein in QSG7701 cells induced transformed characters with reduced population doubling time, anchorage-independent growth and tumor development. Fifteen differentially-expressed proteins were separated and identified using 2-D electrophoresis and matrix-assisted laser desorption ionization-time of flight mass spectrometry. Western blot analysis confirmed that the increase of phospho-p44/42 and phospho-p38 proteins was associated with transformed cells. These results supported the view that HCV NS3 protein plays a transforming role and provided some clues to elucidate the carcinogenesis mechanism of HCV-related hepatocellular carcinoma.
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Affiliation(s)
- Qiongqiong He
- Department of Pathology, Basic Medical College, Central South University, Changsha 410078, China
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Cho EY, Choi YL, Chae SW, Sohn JH, Ahn GH. Relationship between p53-associated proteins and estrogen receptor status in ovarian serous neoplasms. Int J Gynecol Cancer 2007; 16:1000-6. [PMID: 16803476 DOI: 10.1111/j.1525-1438.2006.00553.x] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023] Open
Abstract
We studied the immunoexpression of p14ARF, MDM2, and p53, in addition to relationships between those protein expressions and estrogen receptor (ER)alpha in ovarian serous tumors including benign (n= 23), borderline (n= 41), and malignant (n= 94). The aberrant expressions of p14ARF, MDM2, and p53 were observed in 19.6% (31/158), 47.5% (75/158), and 39.9% (63/158) of cases, respectively. The expression of MDM2 was significantly higher in borderline tumors compared to benign (P= 0.04) and malignant (P < 0.01) tumors. p53 expression in borderline tumors was uncommon, and p14ARF expression loss was mainly observed in carcinomas. Altered expression of p14ARF, MDM2, and p53 shows significant relationship with stage. Overexpression of MDM2 (P= 0.01) and loss of p14ARF expression (P= 0.04) were significantly associated with ER expression. Our results suggest that alteration of p14ARF-MDM2-p53 pathway proteins may contribute significantly to the tumorigenesis of ovarian serous neoplasms, and ER is involved in cellular regulation of p14ARF-MDM2-p53 pathway in ovarian serous neoplasms.
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Affiliation(s)
- E Y Cho
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50 Ilwon-dong, Kangnam-gu, Seoul 135-710, Korea
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Zhao J, Zhang X, Shi M, Xu H, Jin J, Ni H, Yang S, Dai J, Wu M, Guo Y. TIP30 inhibits growth of HCC cell lines and inhibits HCC xenografts in mice in combination with 5-FU. Hepatology 2006; 44:205-15. [PMID: 16799960 DOI: 10.1002/hep.21213] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive cancer with a poor prognosis. The specific cellular gene alterations responsible for hepatocarcinogenesis are not well known. Previous works showed that loss of TIP30, also called CC3, a putative tumor suppressor, increased the incidence of hepatocellular carcinoma in mice, and some clinical samples of human HCC tissues had aberrant expression of TIP30. Here, we report that the introduction of TIP30 by an adenovirus vector into HCC cell lines that had decreased expressions of TIP30 inhibited cell proliferation, decreased anchorage-dependent growth, suppressed invasion through the extracellular matrix, and inhibited tumorigenesis in nude mice. Moreover, exogenous expression of Tip30 sensitized HCC cells to cytotoxic drugs and to apoptosis induced by tumor necrosis factor-related ligands in vitro. Ectopic expression of TIP30 in HCC cells enhanced p53 expression and decreased Bcl-2/Bcl-xL expression. Treatment of nude mice bearing subcutaneously established HCC tumors with a combination of an adenovirus expressing TIP30 and the cytotoxic drug 5-fluorouracil completely suppressed tumor growth and prolonged survival. In conclusion, TIP30 may play an important role in the suppression of hepatocarcinogenesis by acting as a tumor suppressor. Overexpression of TIP30 might be a promising candidate as a treatment for HCC that would increase sensitivity to chemotherapeutic drugs.
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Affiliation(s)
- Jian Zhao
- International Joint Cancer Institute & Eastern Hospital of Hepatobiliary Surgery, Second Military Medical University, Shanghai, China
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Nakano M, Wu H, Taura Y, Inoue M. Immunohistochemical Detection of Mdm2 and p53 in Feline Mammary Gland Tumors. J Vet Med Sci 2006; 68:421-5. [PMID: 16757883 DOI: 10.1292/jvms.68.421] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The objective of this study was to evaluate nuclear reactivity of Mdm2 and p53 proteins by immunohistochemical means in feline mammary gland tumors; 12 adenomas which included 6 adenomatous lesions obtained from the tissue adjacent to adenocarcinomas, and 22 adenocarcinomas. Seven adenomas and 18 adenocarcinomas showed moderate or marked Mdm2 reactivity. Sixteen adenocarcinomas showed moderate to marked p53 reactivity, but 9 adenomas showed none. Discordant Mdm2 overexpression was found in 5 adenomas and 3 adenocarcinomas, although co-overexpression of Mdm2 and p53 was found in 15 adenocarcinomas. These results suggest that nuclear overexpression of Mdm2 is present in the tumors of early stage without p53 overexpression and related to feline mammary gland tumorigenesis. Nuclear overexpression of p53 is more frequent in adenocarcinomas, but not in adenomas.
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Affiliation(s)
- Masatoshi Nakano
- The United Graduate School of Veterinary Sciences, Yamaguchi University, Japan
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Chang PC, Chi CW, Chau GY, Li FY, Tsai YH, Wu JC, Wu Lee YH. DDX3, a DEAD box RNA helicase, is deregulated in hepatitis virus-associated hepatocellular carcinoma and is involved in cell growth control. Oncogene 2005; 25:1991-2003. [PMID: 16301996 DOI: 10.1038/sj.onc.1209239] [Citation(s) in RCA: 111] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer deaths worldwide and is highly correlated with hepatitis virus infection. Our previous report shows that a DEAD box RNA helicase, DDX3, is targeted and regulated by hepatitis C virus (HCV) core protein, which implicates the involvement of DDX3 in HCV-related HCC development. In this study, the potential role of DDX3 in hepatocarcinogenesis is investigated by examining its expression in surgically excised human HCC specimens. Here we report the differential deregulation of DDX3 expression in hepatitis virus-associated HCC. A significant downregulation of DDX3 expression is found in HCCs from hepatitis B virus (HBV)-positive patients, but not from HCV-positive ones, compared to the corresponding nontumor tissues. The expression of DDX3 is differentially regulated by the gender and, moreover, there is a tendency that the downregulation of DDX3 expression in HCCs is more frequent in males than in females. Genetic knockdown of DDX3 with small interfering RNAs (siRNA) in a nontransformed mouse fibroblast cell line, NIH-3T3, results in a premature entry to S phase and an enhancement of cell growth. This enhanced cell cycle progression is linked to the upregulation of cyclin D1 and the downregulation of p21(WAF1) in the DDX3 knockdown cells. In addition, constitutive reduction of DDX3 expression increases the resistance of NIH-3T3 cells to serum depletion-induced apoptosis and enhances the ras-induced anchorage-independent growth, indicating the involvement of DDX3 in cell growth control. These findings together with the previous study suggest that the deregulation of DDX3, a DEAD box RNA helicase with cell growth-regulatory functions, is involved in HBV- and HCV-associated pathogenesis.
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Affiliation(s)
- P-C Chang
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei, Taiwan, Republic of China
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31
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Nakano M, Taura Y, Inoue M. Protein expression of Mdm2 and p53 in hyperplastic and neoplastic lesions of the canine circumanal gland. J Comp Pathol 2005; 132:27-32. [PMID: 15629477 DOI: 10.1016/j.jcpa.2004.06.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2004] [Accepted: 06/07/2004] [Indexed: 11/30/2022]
Abstract
Hyperplastic and neoplastic lesions of the circumanal gland in dogs were examined immunohistochemically for nuclear expression of Mdm2 and p53 proteins. Mdm2 nuclear labelling was detected in 64.3% of hyperplastic lesions and 70.7% of adenomas, the immunolabelling being stronger in the latter. Mdm2 reactivity in reserve-like cells in adenomas showed wide variation, the immunoreactive cells ranging from 4 to 80%. No reactivity was shown in 81.9% of adenocarcinomas. In contrast to Mdm2 reactivity, each of 14 hyperplastic lesions and 11 adenocarcinomas, and 60 of 65 adenomas (92.3%) failed to show nuclear p53 reactivity. These results suggest that increased expression of Mdm2 is an early event in circumanal gland tumorigenesis, and may be present in the absence of nuclear p53 protein accumulation.
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Affiliation(s)
- M Nakano
- The United Graduate School of Veterinary Sciences, Department of Veterinary Surgery, Faculty of Agriculture, Yamaguchi University, 1677-1 Yoshida, Yamaguchi 753-8515, Japan
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Qin HX, Nan KJ, Yang G, Jing Z, Ruan ZP, Li CL, Xu R, Guo H, Sui CG, Wei YC. Expression and clinical significance of TAp73α, p53, PCNA and apoptosis in hepatocellular carcinoma. World J Gastroenterol 2005; 11:2709-13. [PMID: 15884108 PMCID: PMC4305902 DOI: 10.3748/wjg.v11.i18.2709] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the prognostic role of TAp73α, p53, proliferating cell nuclear antigen (PCNA) and apoptosis in patients with hepatocellular carcinoma (HCC) after surgical tumor ablation.
METHODS: Forty-seven human resected HCC tissues and 42 adjacent non-cancerous tissues were studied with 10 normal liver tissues as control group. TAp73α, p53, and PCNA were detected with Elivision immunohistochemistry. Terminal deoxynucleotidyl transferase (TdT)-mediated d-UTP-biotin nick-end labeling (TUNEL) method was used to detect the apoptosis cells. All clinical and pathological materials were analyzed by SPSS10.0 statistical package.
RESULTS: TAp73α overexpressed in HCC tissues (36.2%) when compared with adjacent non-cancerous tissues (2.38%, P<0.005) and normal liver tissues (0, P<0.01). Mutant type p53 (mt-p53) overexpressed in HCC tissues (38.3%) when contracted with adjacent non-cancerous tissues (16.7%, P<0.05) and normal liver tissues (0, P<0.01). Proliferation index (PI) level in HCC tissues was significantly higher than that in adjacent non-cancerous tissues (30.34%±4.46% vs 27.88%±5.89%, t, P = 0.028). Apoptosis index (AI) level in HCC tissues was higher than that in adjacent non-cancerous tissues (8.62%±2.28% vs 7.38%±2.61%, t, P = 0.019). Expression of TAp73α was associated with lymph node metastasis and mt-p53, with r = 0.407 and 0.265, respectively. Expression of mt-p53 was associated with Edmondson’s stage and AFP, with r = 0.295 and -0.357, respectively. In Kaplan-Meier univariant analysis, TAp73α, AFP, TNM stage, portal vein invasion, liver membrane invasion and HBsAg correlated with prognosis (log rank, P = 0.039, 0.012, 0.002, 0.000, 0.014, 0.007, respectively). Multivariant Cox regression analysis showed that TAp73α, AFP, TNM stage, portal vein invasion, liver membrane invasion and age were independent factors of prognosis.
CONCLUSION: These results suggest that TAp73α can be used as a prognostic indicator of patients with HCC undergoing surgical tumor ablation. AFP, TNM, portal vein invasion, liver membrane invasion and age also have a potency of predicting the prognosis of HCC.
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Affiliation(s)
- Hai-Xia Qin
- Department of Medical Oncology, First Hospital of Xi'an Jiaotong University, 1 Jiankang Xilu, Xi'an 710061, Shaanxi Province, China.
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Wang H, Oliver P, Zhang Z, Agrawal S, Zhang R. Chemosensitization and radiosensitization of human cancer by antisense anti-MDM2 oligonucleotides: in vitro and in vivo activities and mechanisms. Ann N Y Acad Sci 2004; 1002:217-35. [PMID: 14751837 DOI: 10.1196/annals.1281.025] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
MDM2 oncogene is overexpressed in many human cancers including breast, colon, and prostate cancer, and MDM2 levels are associated with poor prognosis in patients with cancer. Here, we summarize the investigation of the functions of MDM2 oncogene in human cancer growth and the value of MDM2 as a drug target for prostate cancer therapy by using antisense to inhibit MDM2 expression. Antisense anti-human-MDM2 oligonucleotides and mismatch controls were tested in in vitro and in vivo human cancer models for antitumor activity. Targeted gene products and related proteins were analyzed and the antitumor activity was determined when the oligonucleotides were used alone or in combination with cancer chemotherapeutics and radiation therapy. The antisense oligonucleotide specifically inhibited MDM2 expression in a dose- and time-dependent manner, resulting in significant antitumor activity in vitro and in vivo. The antisense oligonucleotides also potentiated the effects of p53 activation and p21 induction by chemotherapeutic agents 10-hydroxycamptothecin, adriamycin, 5-fluorouracil, and paclitaxel. In a dose-dependent manner, the antisense oligonucleotide showed antitumor activity in nude mice bearing human cancer xenografts and increased therapeutic effectiveness of the chemotherapeutic agents irinotecan, paclitaxel, and Rituxan and radiation therapy. These results indicate that MDM2 has a role in various tumor growth through both p53-dependent and p53-independent mechanisms, indicating that MDM2 inhibitors have a broad spectrum of antitumor activities in human cancers regardless of p53 status. These results provide a basis for clinical evaluation of antisense anti-MDM2 oligonucleotides as chemosensitizer and radiosensitizer.
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Affiliation(s)
- Hui Wang
- Departments of Pharmacology and Toxicology, Division of Clinical Pharmacology, Comprehensive Cancer Center, and Gene Therapy Center, University of Alabama at Birmingham, Alabama 35294-0019, USA
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MESH Headings
- Carcinoma, Hepatocellular/etiology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/prevention & control
- Carcinoma, Hepatocellular/virology
- Cell Adhesion/genetics
- Cell Transformation, Neoplastic
- Cell Transformation, Viral
- Chronic Disease
- Genes, cdc
- Genes, p53
- Growth Substances/physiology
- Hepacivirus/pathogenicity
- Hepatitis B virus/pathogenicity
- Hepatitis B, Chronic/complications
- Hepatitis B, Chronic/virology
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/virology
- Humans
- Liver Diseases/complications
- Liver Diseases/pathology
- Liver Neoplasms/etiology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Liver Neoplasms/prevention & control
- Liver Neoplasms/virology
- Neoplasm Invasiveness/genetics
- Neoplasm Metastasis
- Neovascularization, Pathologic/genetics
- Precancerous Conditions/complications
- Precancerous Conditions/pathology
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Ikeguchi M, Ueda T, Fukuda K, Yamaguchi KI, Tsujitani SI, Kaibara N. Expression of the murine double minute gene 2 oncoprotein in esophageal squamous cell carcinoma as a novel marker for lack of response to chemoradiotreatment. Am J Clin Oncol 2002; 25:454-9. [PMID: 12393983 DOI: 10.1097/00000421-200210000-00006] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
The protein product of the murine double minute gene 2 (MDM2) negatively controls the work of the p53 protein and the retinoblastoma protein (pRB). Recent studies have found that MDM2 expression correlates with chemoresistance of tumor cells. In the present study, the correlation between MDM2 expression and chemoradioresistance was evaluated in patients with esophageal squamous cell carcinoma (ESCC). The immunoreactivities of p53, pRB, and MDM2 were evaluated in 148 surgically resected ESCC by using monoclonal antibodies. The disease-free survival of 107 surviving patients who underwent curative surgery was compared among groups with positive and negative expressions of p53, pRB, and MDM2. High immunoreactivities of p53, pRB, and MDM2 were detected in 47.3%, 64.2%, and 32.4% of cases, respectively. In 107 patients undergoing curative surgery, pRB losses and MDM2 overexpression were found to be poor prognostic factors by univariate analysis. In multivariate analysis, only MDM2 expression was determined to be a prognostic factor independent of the tumor stage. Moreover, we found that MDM2 expression correlates with short survival of patients undergoing postoperative adjuvant chemoradiotherapy. In patients without adjuvant therapy, however, the MDM2 status did not correlate with patient survival. The present results indicate that MDM2 expression may be not only a prognostic marker for patients with ESCC, but also a novel marker for predicting a lack of response to chemoradiotreatment.
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Affiliation(s)
- Masahide Ikeguchi
- Department of Surgery I, Faculty of Medicine, Tottori University, 36-1 Nishi-cho, Yonago 683-8504, Japan
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Zeng JZ, Wang HY, Chen ZJ, Ullrich A, Wu MC. Molecular cloning and characterization of a novel gene which is highly expressed in hepatocellular carcinoma. Oncogene 2002; 21:4932-43. [PMID: 12118372 DOI: 10.1038/sj.onc.1205652] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2002] [Revised: 05/09/2002] [Accepted: 05/09/2002] [Indexed: 11/08/2022]
Abstract
To gain new insight into the molecular mechanism underlying the pathogenesis of human primary hepatocellular carcinoma (HCC), we searched for HCC-specific molecules through screening genes that are differentially expressed between cancerous and noncancerous counterparts of liver and identified a novel HCC-associated gene, HCCA1 encoding a approximately 80 kDa cytoplasmic protein that contains several proline-rich motifs likely for SH3-binding. HCCA1 transcript, albeit present in some adult tissues, is up-regulated selectively in HCC but not in other tumor cells. High expression of HCCA1 occurs as a late event frequently (89.2%) in HCCs and correlated significantly with the degree of tumor progression. When treated with antisense oligonucleotides to HCCA1, HCCA1 expression in HCC cells (HuH-7) was effectively suppressed and cell growth was down-regulated in a time- and dose-dependent manner. Furthermore, HuH-7 cells harboring the HCCA1 antisense expression clone displayed a remarkably reduced efficiency in colony formation. Together, these data strongly suggest that HCCA1 is a positive effector in cell proliferation and contributes to HCC carcinogenesis and progression. We believe that this protein will serve as a novel useful marker for HCC and is a potential target for pharmaceutical intervention of this malignant disease.
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Affiliation(s)
- Jin-Zhang Zeng
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgical Institute, Secondary Military Medical University, Shanghai 200438, PR China
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Qin LX, Tang ZY. The prognostic molecular markers in hepatocellular carcinoma. World J Gastroenterol 2002; 8:385-92. [PMID: 12046056 PMCID: PMC4656407 DOI: 10.3748/wjg.v8.i3.385] [Citation(s) in RCA: 237] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2002] [Revised: 04/23/2002] [Accepted: 05/08/2002] [Indexed: 02/06/2023] Open
Abstract
The prognosis of hepatocellular carcinoma (HCC) still remains dismal, although many advances in its clinical study have been made. It is important for tumor control to identify the factors that predispose patients to death. With new discoveries in cancer biology, the pathological and biological prognostic factors of HCC have been studied quite extensively. Analyzing molecular markers (biomarkers) with prognostic significance is a complementary method. A large number of molecular factors have been shown to associate with the invasiveness of HCC, and have potential prognostic significance. One important aspect is the analysis of molecular markers for the cellular malignancy phenotype. These include alterations in DNA ploidy, cellular proliferation markers (PCNA, Ki-67, Mcm2, MIB1, MIA, and CSE1L/CAS protein), nuclear morphology, the p53 gene and its related molecule MD M2, other cell cycle regulators (cyclin A, cyclin D, cyclin E, cdc2, p27, p73), oncogenes and their receptors (such as ras, c-myc, c-fms, HGF, c-met, and erb-B receptor family members), apoptosis related factors (Fas and FasL), as well as telomerase activity. Another important aspect is the analysis of molecular markers involved in the process of cancer invasion and metastasis. Adhesion molecules (E-cadherin, catenins, serum intercellular adhesion molecule-1, CD44 variants), proteinases involved in the degradation of extracellular matrix (MMP-2, MMP-9, uPA, uPAR, PAI), as well as other molecules have been regarded as biomarkers for the malignant phenotype of HCC, and are related to prognosis and therapeutic outcomes. Tumor angiogenesis is critical to both the growth and metastasis of cancers including HCC, and has drawn much attention in recent years. Many angiogenesis-related markers, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), platelet-derived endothelial cell growth factor (PD-ECGF), thrombospondin (TSP), angiogenin, pleiotrophin, and endostatin (ES) levels, as well as intratumor microvessel density (MVD) have been evaluated and found to be of prognostic significance. Body fluid (particularly blood and urinary) testing for biomarkers is easily accessible and useful in clinical patients. The prognostic significance of circulating DNA in plasma or serum, and its genetic alterations in HCC are other important trends. More attention should be paid to these two areas in future. As the progress of the human genome project advances, so does a clearer understanding of tumor biology, and more and more new prognostic markers with high sensitivity and specificity will be found and used in clinical assays. However, the combination of some items, i.e., the pathological features and some biomarkers mentioned above, seems to be more practical for now.
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Affiliation(s)
- Lun-Xiu Qin
- Liver Cancer Institute and Zhongshan Hospital, Fudan university, 136 Yi Xue Yuan Road, Shanghai 200032, China
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Schlott T, Scharf JG, Gorzel C, Middel P, Spring H. Cirrhotic livers reveal genetic changes in the MDM2-P14ARF system of cell cycle regulators. Br J Cancer 2002; 86:1290-6. [PMID: 11953887 PMCID: PMC2375354 DOI: 10.1038/sj.bjc.6600238] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2001] [Revised: 01/07/2002] [Accepted: 02/19/2002] [Indexed: 12/27/2022] Open
Abstract
The genesis of hepatocellular carcinoma is promoted by changes in the regulatory MDM2-P14ARF system. The incidence of such changes has to date not been analysed in non-tumourous livers showing regenerative proliferation. In the present study, 24 cirrhotic livers of alcohol-, autoimmue disorder- or HCV-caused genesis were screened for MDM2-P14ARF alterations at the level of protein, DNA and mRNA. Using confocal laser scanning microscopy, the absence of MDM2 and P14ARF expression was detected in all samples except three HCV-infected livers (four livers) which contained hepatocytes overexpressing MDM2 (P14ARF) protein. In two of the samples lacking P14ARF expression, laser microdissection and PCR demonstrated deletion of the P14ARF gene. The P14ARF gene amplified from other specimens did not carry mutations. MDM2 splicing variants were present in tissues from alcohol- and autoimmune disorder-induced cirrhoses. Sequencing of full-size mRNA revealed a MDM2 mis-sense mutation in an alcohol-induced cirrhosis. One sample contained regenerative nodules with genetic instability occurring at MDM2 locus D12S83 according to the data of automatic PCR fragment analysis. In summary, this study gives first evidence for different types of MDM2 and P14ARF alterations in cirrhotic livers. We suggest that the changes impair the regulatory MDM2-P14ARF system, thus possibly favouring regenerative proliferation and transformation.
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Affiliation(s)
- T Schlott
- Department of Cytopathology, Georg-August-University, Robert-Koch-Strasse 40, D-37075 Goettingen, Germany.
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40
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Kersemaekers AMF, Mayer F, Molier M, van Weeren PC, Oosterhuis JW, Bokemeyer C, Looijenga LHJ. Role of P53 and MDM2 in treatment response of human germ cell tumors. J Clin Oncol 2002; 20:1551-61. [PMID: 11896104 DOI: 10.1200/jco.2002.20.6.1551] [Citation(s) in RCA: 64] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Testicular germ cell tumors (TGCTs) of adolescents and adults are very sensitive to systemic treatment. The exquisite chemosensitivity of these cancers has been attributed to a high level of wild-type P53. MATERIALS AND METHODS To clarify the role of P53 in treatment sensitivity and resistance of TGCTs, we performed immunohistochemistry and Western blotting analysis on a series of 39 fresh-frozen primary TGCTs before therapy (unselected series). In a series of formalin-fixed paraffin-embedded TGCTs of patients with fully documented clinical course, including treatment-sensitive (n = 17) and -resistant (n = 18) tumors, P53 status was assessed by immunohistochemistry and mutation analysis. In addition, the involvement of MDM2, a P53 antagonist, was investigated by immunohistochemistry, reverse transcriptase polymerase chain reaction, and in situ hybridization. RESULTS Immunohistochemistry demonstrated absence of staining for P53 in 36%, 41%, and 17% of the unselected, responding, and nonresponding TGCTs, respectively. Of the positive TGCTs, most tumors, ie, 49%, 41%, and 33%, showed 1% to 10% positive nuclei. This overall low level of P53 was confirmed by Western blotting. Mutation analysis revealed only one silent P53 mutation in one of the responding patients. All embryonal carcinomas were homogeneously positive for MDM2, encoded by the full length mRNA, while a heterogeneous pattern was found for the other histologic components. Amplification of MDM2 was detected in one out of 12 embryonal carcinomas. CONCLUSION Although our results are in line with previous findings of the presence of wild-type P53 in TGCTs, they show that a high level of P53 does not relate directly to treatment sensitivity of these tumors, and inactivation of P53 is not a common event in the development of cisplatin resistance.
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Affiliation(s)
- Anne-Marie F Kersemaekers
- Department of Pathology/Laboratory for Experimental Patho-Oncology, University Hospital Rotterdam/Daniel, Josephine Nefkens Institute, Erasmus University Rotterdam, Rotterdam, The Netherlands
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Goldenberg D, Ayesh S, Schneider T, Pappo O, Jurim O, Eid A, Fellig Y, Dadon T, Ariel I, de Groot N, Hochberg A, Galun E. Analysis of differentially expressed genes in hepatocellular carcinoma using cDNA arrays. Mol Carcinog 2002. [PMID: 11813304 DOI: 10.1002/mc.10027] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/02/2023]
Abstract
Hepatocellular carcinoma (HCC) is characterized by multiple somatic mutations, including DNA rearrangements, that affect many cell-growth regulatory pathways. Many genes differentially expressed in HCC have been reported previously, but the patterns of expression varied significantly between patients who bore different risk factors for HCC. To identify genes whose differential expression could serve as a "signature" for diagnosis and prognosis of HCC, we performed analyses of differentially expressed genes in three cases of HCC with different risk factors using the Atlas Human Cancer cDNA Expression Arrays. Among all 597 genes present on the array, only three were found to be coordinately differentially expressed in all three HCC cases, in agreement with published data. These three genes, Cu/Zn superoxide dismutase, osteonectin/secreted protein acidic and rich in cysteine, and matrix metalloproteinase 14, could serve as candidates for the HCC "signature." Ten genes were found to be coordinately differentially expressed in only two of three tested HCC cases. On the other hand, many genes that had been reported previously as differentially expressed in HCC failed to show the described pattern of expression in this group. The results of this study confirm the great variability in gene-expression patterns in HCC and establish the utility of the array technology for identifying both the HCC signature genes and individual gene-expression patterns for purposes of patient-oriented therapy.
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Affiliation(s)
- Daniel Goldenberg
- Goldyne Savad Institute of Gene Therapy, Hadassah University Hospital, Jerusalem, Israel
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Peng Y, Chen L, Li C, Lu W, Agrawal S, Chen J. Stabilization of the MDM2 oncoprotein by mutant p53. J Biol Chem 2001; 276:6874-8. [PMID: 11152666 DOI: 10.1074/jbc.c000781200] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022] Open
Abstract
MDM2 is a short-lived protein that regulates p53 degradation. We report here that transient coexpression of MDM2 and several p53 hotspot mutants resulted in stabilization and increased expression of MDM2. Ectopic expression of the mutant p53(175H) allele by recombinant adenovirus infection or stable transfection also stabilized endogenous MDM2 in p53-null cells. A panel of human tumor cell lines expressing different endogenous mutant p53 alleles also contained stabilized nuclear MDM2 at elevated levels when compared with p53-null cells. MDM2 was present in complexes with mutant p53 in tumor cells, and stabilization of MDM2 required direct binding to mutant p53. These results reveal a novel property of mutant p53 and a unique feature of tumors with p53 missense mutations. Accumulation of stable MDM2 may contribute to tumorigenesis through its p53-independent transforming functions.
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Affiliation(s)
- Y Peng
- Molecular Oncology Program, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida 33612, USA
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