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Iskandar M, Xiao Barbero M, Jaber M, Chen R, Gomez-Guevara R, Cruz E, Westerheide S. A Review of Telomere Attrition in Cancer and Aging: Current Molecular Insights and Future Therapeutic Approaches. Cancers (Basel) 2025; 17:257. [PMID: 39858038 PMCID: PMC11764024 DOI: 10.3390/cancers17020257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2024] [Revised: 01/09/2025] [Accepted: 01/11/2025] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES As cells divide, telomeres shorten through a phenomenon known as telomere attrition, which leads to unavoidable senescence of cells. Unprotected DNA exponentially increases the odds of mutations, which can evolve into premature aging disorders and tumorigenesis. There has been growing academic and clinical interest in exploring this duality and developing optimal therapeutic strategies to combat telomere attrition in aging and cellular immortality in cancer. The purpose of this review is to provide an updated overview of telomere biology and therapeutic tactics to address aging and cancer. METHODS We used the Rayyan platform to review the PubMed database and examined the ClinicalTrial.gov registry to gain insight into clinical trials and their results. RESULTS Cancer cells activate telomerase or utilize alternative lengthening of telomeres to escape telomere shortening, leading to near immortality. Contrarily, normal cells experience telomeric erosion, contributing to premature aging disorders, such as Werner syndrome and Hutchinson-Gilford Progeria, and (2) aging-related diseases, such as neurodegenerative and cardiovascular diseases. CONCLUSIONS The literature presents several promising therapeutic approaches to potentially balance telomere maintenance in aging and shortening in cancer. This review highlights gaps in knowledge and points to the potential of these optimal interventions in preclinical and clinical studies to inform future research in cancer and aging.
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Affiliation(s)
| | | | | | | | | | | | - Sandy Westerheide
- Department of Molecular Biosciences, University of South Florida, 4202 East Fowler Avenue, ISA2015, Tampa, FL 33620, USA; (M.I.); (M.X.B.); (M.J.); (R.C.); (R.G.-G.); (E.C.)
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Mouchtaris Michailidis T, De Saeger S, Khoueiry R, Odongo GA, Bader Y, Dhaenens M, Herceg Z, De Boevre M. The interplay of dietary mycotoxins and oncogenic viruses toward human carcinogenesis: a scoping review. Crit Rev Food Sci Nutr 2024:1-19. [PMID: 39422902 DOI: 10.1080/10408398.2024.2414828] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2024]
Abstract
BACKGROUND Mycotoxins, fungal metabolites prevalent in many foods, are recognized for their role in carcinogenesis, especially when interacting with oncogenic viruses. OBJECTIVES This scoping review synthesizes current evidence on the human cancer risk associated with mycotoxin exposure and oncogenic virus infections. METHODS Searches were conducted on PubMed, Embase, and Web of Science. Studies were selected based on the PECOS framework. Data extraction involved narrative and qualitative presentation of findings, with meta-analysis where feasible. Risk of bias and outcome quality were assessed using the OHAT tool and GRADE approach. RESULTS From 25 included studies, 18 focused on aflatoxins and hepatitis viruses in hepatocellular carcinoma (HCC). Four studies examined aflatoxin B1 (AFB1) and human papilloma virus (HPV) in cervical cancer, while three investigated AFB1 with Epstein-Barr virus (EBV) in lymphomagenesis. The review highlights a significant synergistic effect between AFB1 and hepatitis B and C viruses in HCC development. Significant interactions between AFB1 and HPV, as well as AFB1 and EBV, were observed, but further research is needed. CONCLUSIONS The synergistic impact of mycotoxins and oncogenic viruses is a critical public health concern. Future research, especially prospective cohort studies and investigations into molecular mechanisms, is essential to address this complex issue.
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Affiliation(s)
- Thanos Mouchtaris Michailidis
- Faculty of Pharmaceutical Sciences, Centre of Excellence in Mycotoxicology and Public Health, Ghent University, Ghent, Belgium
- CRIG, Cancer Research Institute Ghent, Ghent, Belgium
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France
| | - Sarah De Saeger
- Faculty of Pharmaceutical Sciences, Centre of Excellence in Mycotoxicology and Public Health, Ghent University, Ghent, Belgium
- CRIG, Cancer Research Institute Ghent, Ghent, Belgium
- Department of Biotechnology and Food Technology, Faculty of Science, University of Johannesburg, Johannesburg, South Africa
| | - Rita Khoueiry
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France
| | - Grace A Odongo
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France
- Institute of Cancer Research and Genomics Sciences, University of Birmingham, Birmingham, UK
| | - Yasmine Bader
- Faculty of Pharmaceutical Sciences, Centre of Excellence in Mycotoxicology and Public Health, Ghent University, Ghent, Belgium
- CRIG, Cancer Research Institute Ghent, Ghent, Belgium
| | - Maarten Dhaenens
- Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - Zdenko Herceg
- Epigenomics and Mechanisms Branch, International Agency for Research on Cancer/World Health Organization, Lyon, France
| | - Marthe De Boevre
- Faculty of Pharmaceutical Sciences, Centre of Excellence in Mycotoxicology and Public Health, Ghent University, Ghent, Belgium
- CRIG, Cancer Research Institute Ghent, Ghent, Belgium
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Xu X, Liu J, Li X, Feng Q, Su Y. Integrated network pharmacology and metabolomics to study the potential mechanism of Jiawei Yinchenhao decoction in chronic hepatitis B. Heliyon 2024; 10:e36267. [PMID: 39224343 PMCID: PMC11367511 DOI: 10.1016/j.heliyon.2024.e36267] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Revised: 08/01/2024] [Accepted: 08/13/2024] [Indexed: 09/04/2024] Open
Abstract
Chronic hepatitis B infection (CHB) is a major risk factor for the development of hepatocellular carcinoma (HCC) globally and continues to pose a significant global health challenge. Jiawei Yinchenhao decoction (JWYCH) is a modified version of Yinchenhao decoction (YCHD), which is widely used to treat liver diseases including icteric hepatitis, cholelithiasis, and hepatic ascites. However, the effectiveness and underlying mechanism of JWYCH on CHB are still unclear. This study aimed to investigate the impact of JWYCH on CHB and explore the underlying mechanism via network pharmacology and metabolomics. C57BL/6 mice were administered rAAV-HBV1.3 via hydrodynamic injection (HDI) to establish the CHB model. The infected mice were orally administered JWYCH for 4 weeks. HBsAg, HBeAg, HBV DNA, the serum liver function index, and histopathology were detected. In addition, network pharmacology was used to investigate potential targets, whereas untargeted metabolomics analysis was employed to explore the hepatic metabolic changes in JWYCH in CHB mice and identify relevant biomarkers and metabolic pathways. JWYCH was able to reduce HBeAg levels and improve liver pathological changes in mice with CHB. Additionally, metabolomics analysis indicated that JWYCH can influence 105 metabolites, including pipecolic acid, alpha-terpinene, adenosine, and L-phenylalanine, among others. Bile acid metabolism, arachidonic acid metabolism, and retinol metabolism are suggested to be potential targets of JWYCH in CHB. In conclusion, JWYCH demonstrated a hepatoprotective effect on a mouse model of CHB, suggesting a potential alternative therapeutic strategy for CHB. The effect of JWYCH is associated mainly with regulating the metabolism of bile acid, arachidonic acid, and retinol. These differentially abundant metabolites may serve as potential biomarkers and therapeutic targets for CHB.
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Affiliation(s)
- Xinyi Xu
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Jin Liu
- College of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xue Li
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - QuanSheng Feng
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yue Su
- College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
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Rezaei Z, Hamzeh Pour S, Ezati P, Akrami-Mohajeri F. Determination of aflatoxin M 1 and ochratoxin A in breast milk in rural centers of Yazd, Iran: Exposure assessment and risk characterization. Mycotoxin Res 2024; 40:211-221. [PMID: 38285127 DOI: 10.1007/s12550-024-00519-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 12/29/2023] [Accepted: 01/03/2024] [Indexed: 01/30/2024]
Abstract
Breast milk (BM) is considered as the best source of nutrition which could have prevention effects on various diseases in the first years of a child. Along with nutritive compounds, presence of contaminants such as mycotoxins in BM could be transmitted into neonate. The aim of this study was to determine the occurrence, levels, and factors associated with the presence of aflatoxin M1 (AFM1) and ocratoxin a (OTA) in BM samples of nursing mothers in rural centers of Yazd, Iran. The presence and average AFM1 and OTA concentration in 72 BM samples was measured by competitive ELISA. The demographic and diet parameters of nursing mothers were collected by a questionnaire and were analyzed using SPSS 18 software. AFM1 and OTA were detected in 63 (87.5%) and 47 (65.2%) samples with the mean concentration levels of 19.46 ± 13.26 ng/L (ranges from 5.1 to 53.9) and 200 ± 160 ng/L (ranges from 100 to 2460), respectively. Of these, 32 samples (50.7%) for AFM1 and 23 samples (48.9%) for OTA had values exceeding the limit set by the European Union regulation for infant foods (25 ng/L for AFM1 and 500 ng/L for OTA). It was also found that the risk of AFM1 and OTA occurrence in BM increased significantly with the consumption of beans, bread, cereals, fruit juice and crackers, and cream, respectively. This study showed that the estimated daily intake for AFM1 and OTA by 1 month of age infants was 2.7 and 28.5 ng/kg bw/day, respectively, while, as the age of the infant increased, the values were lower and close to 0.9 and 9.9 ng/kg bw/day for AFM1 and OTA in 12 months of age infants, respectively. The high occurrence and noticeable levels of AFM1 and OTA detected in this study indicated that some infants receive undesirable exposures to AFM1 and OTA with breast milk. Therefore, it is recommended that mothers are advised to avoid certain foods during pregnancy and breastfeeding that are likely sources of mycotoxins.
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Affiliation(s)
- Zeinab Rezaei
- Center of Cheshme noshan khorasan (Alis), University of Applied Science and Technology, Chanaran, Iran
| | - Siavash Hamzeh Pour
- Department of Pathobiology, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Parya Ezati
- BioNanocomposite Research Center, Department of Food and Nutrition, Kyung Hee University, 26 Kyungheedae‑Ro, Dongdaemun‑Gu, Seoul, 02447, Republic of Korea
| | - Fateme Akrami-Mohajeri
- Infectious Diseases Research Center, Shahid Sadoughi Hospital, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
- Department of Food Hygiene and Safety, School of Public Health, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
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Zeng Z, Liao X, Huang K, Han C, Qin W, Su H, Ye X, Yang C, Zhou X, Wei Y, Mo S, Liu J, Lan C, Huang X, Huang Z, Peng K, Gao Q, Peng T, Zhu G. Outer dynein arm docking complex subunit 2 polymorphism rs7893462 modulates hepatocellular carcinoma susceptibility and can serve as an overall survival biomarker for hepatitis B virus-related hepatocellular carcinoma after hepatectomy: a cohort study with a long-term follow-up. World J Surg Oncol 2023; 21:322. [PMID: 37833735 PMCID: PMC10571289 DOI: 10.1186/s12957-023-03205-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Accepted: 10/03/2023] [Indexed: 10/15/2023] Open
Abstract
BACKGROUND Genetic variants of outer dynein arm docking complex subunit 2 (ODAD2) have been reported to be closely associated with primary ciliary dyskinesia and colorectal cancer in previous studies, but the association of genetic variants of ODAD2 with hepatocellular carcinoma (HCC) has not been reported. METHODS We enrolled 80 healthy subjects and 468 Guangxi hepatitis B virus (HBV)-related HCC patients in this study. A case-control study method was used to explore the association of different ODAD2-rs7893462 genotypes with hepatocarcinogenesis. A comprehensive survival analysis was used to explore the association of rs7893462 with the prognosis of HBV-related HCC in Guangxi. RESULTS Through a case-control study, we observed that patients carrying the G allele of rs7893462 had a markedly increased susceptibility to hepatocarcinogenesis (odds ratio = 1.712, 95% confidence interval = 1.032-2.839, P = 0.037). We found that there were significant prognosis differences among three different genotypes of rs7893462. Nomogram analysis suggested that the contribution of rs7893462 polymorphisms to the prognosis of HBV-related HCC was second only to the BCLC stage. Stratified survival analysis suggested that the AG genotype of rs7893462 was an independent prognostic risk factor for HBV-related HCC. Joint effect survival analysis also observed that the AG genotype of rs7893462 combined with clinical parameters could significantly identify HBV-related HCC patients with different prognostic outcomes more accurately, and the AG genotype was also observed to be independent of clinical factors in HBV-related HCC survival. CONCLUSION The ODAD2-rs7893462 polymorphisms can be used as an independent prognostic indicator of HBV-related HCC overall survival and are significantly associated with susceptibility to hepatocarcinogenesis.
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Affiliation(s)
- Zhiming Zeng
- Department of Medical Oncology, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Yongguang Wei
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Shutian Mo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Junqi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Chenlu Lan
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Xinlei Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Zaida Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Kai Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Qiang Gao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China.
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China.
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China.
- Guangxi Key Laboratory of Enhanced Recovery After Surgery for Gastrointestinal Cancer, Guangxi Zhuang Autonomous Region, Nanning, 530021, People's Republic of China.
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Pan X, Hao L, Yang C, Lin H, Wu D, Chen X, Zhang M, Ma D, Wang Y, Fu W, Yao Y, Wang S, Zhuang Z. SWD1 epigenetically chords fungal morphogenesis, aflatoxin biosynthesis, metabolism, and virulence of Aspergillus flavus. JOURNAL OF HAZARDOUS MATERIALS 2023; 455:131542. [PMID: 37172387 DOI: 10.1016/j.jhazmat.2023.131542] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 04/17/2023] [Accepted: 04/28/2023] [Indexed: 05/14/2023]
Abstract
As the main producer of aflatoxins, Aspergillus flavus is also one of the most important causes of invasive and non-invasive aspergillosis. Therefore, it is crucial to unravel the regulatory mechanisms of growth, metabolism, and pathogenicity of A. flavus. SWD1 is highly conserved across species for maintaining COMPASS methyltransferase activity, but the bio-function of SWD1 in A. flavus has not been explored. Through genetic analysis, this study revealed that SWD1 is involved in fungal morphogenesis and AFB1 biosynthesis by regulating the orthodox pathways through H3K4me1-3. Stresses sensitivity and crop models analysis revealed that SWD1 is a key regulator for the resistance of A. flavus to adapt to extreme adverse environments and to colonize crop kernels. It also revealed that the WD40 domain and 25 aa highly conserved sequence are indispensable for SWD1 in the regulation of mycotoxin bio-synthesis and fungal virulence. Metabolomic analysis inferred that SWD1 is crucial for the biosynthesis of numerous primary and secondary metabolites, regulates biological functions by reshaping the whole metabolic process, and may inhibit fungal virulence by inducing the apoptosis of mycelia through the inducer sphingosine. This study elucidates the epigenetic mechanism of SWD1 in regulating fungal pathogenicity and mycotoxin biosynthesis, and provides a potential novel target for controlling the virulence of A. flavus.
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Affiliation(s)
- Xiaohua Pan
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Fujian Key Laboratory of Propagated Sensation along Meridian, Fujian Academy of Chinese Medical Sciences, Fuzhou 350003, China
| | - Ling Hao
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Chi Yang
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; Institute of Edible Mushroom, Fujian Academy of Agricultural Sciences, Fuzhou 350014, China
| | - Hong Lin
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Dandan Wu
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Xuan Chen
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Mengjuan Zhang
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Dongmei Ma
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China; College of Animal Sciences (College of Bee Science), Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Yu Wang
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Wangzhuo Fu
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Yanfang Yao
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China
| | - Shihua Wang
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
| | - Zhenhong Zhuang
- Key Laboratory of Pathogenic Fungi and Mycotoxins of Fujian Province, Key Laboratory of Biopesticide and Chemical Biology of Education Ministry, Proteomic Research Center, and School of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, China.
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Che L, Huang J, Lin JX, Xu CY, Wu XM, Du ZB, Wu JS, Lin ZN, Lin YC. Aflatoxin B1 exposure triggers hepatic lipotoxicity via p53 and perilipin 2 interaction-mediated mitochondria-lipid droplet contacts: An in vitro and in vivo assessment. JOURNAL OF HAZARDOUS MATERIALS 2023; 445:130584. [PMID: 37055989 DOI: 10.1016/j.jhazmat.2022.130584] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 11/17/2022] [Accepted: 12/07/2022] [Indexed: 06/19/2023]
Abstract
Aflatoxin B1 (AFB1) is one of the most toxic mycotoxins widely found in food contaminants, and its target organ is the liver. It poses a major food security and public health threat worldwide. However, the lipotoxicity mechanism of AFB1 exposure-induced liver injury remains unclear and requires further elucidation. Herein, we investigated the potential hepatic lipotoxicity of AFB1 exposure using in vitro and in vivo models to assess the public health hazards of high dietary AFB1 exposure. We demonstrated that low-dose of AFB1 (1.25 μM for 48 h, about one-fifth of the IC50 in HepG2 and HepaRG cells, IC50 are 5.995 μM and 5.266 μM, respectively) exposure significantly induced hepatic lipotoxicity, including abnormal lipid droplets (LDs) growth, mitochondria-LDs contacts increase, lipophagy disruption, and lipid accumulation. Mechanistically, we showed that AFB1 exposure promoted the mitochondrial p53 (mito-p53) and LDs-associated protein perilipin 2 (PLIN2) interaction-mediated mitochondria-LDs contacts, resulting in lipid accumulation in hepatocytes. Mito-p53-targeted inhibition, knockdown of PLIN2, and rapamycin application efficiently promoted the lysosome-dependent lipophagy and alleviated the hepatic lipotoxicity and liver injury induced by AFB1 exposure. Overall, our study found that mito-p53 and PLIN2 interaction mediates three organelles-mitochondria, LDs, and lysosomal networks to regulate lipid homeostasis in AFB1 exposure-induced hepatotoxicity, revealing how this unique trio of organelles works together and provides a novel insight into the targeted intervention in inter-organelle lipid sensing and trafficking for alleviating hazardous materials-induced hepatic lipotoxicity.
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Affiliation(s)
- Lin Che
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jing Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jin-Xian Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Chi-Yu Xu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Xin-Mou Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Ze-Bang Du
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Jia-Shen Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China
| | - Zhong-Ning Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
| | - Yu-Chun Lin
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen 361102, China.
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8
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Aflatoxins: Source, Detection, Clinical Features and Prevention. Processes (Basel) 2023. [DOI: 10.3390/pr11010204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
The most potent mycotoxin, aflatoxins are the secondary metabolite produced by fungi, especially Aspergillus, and have been found to be ubiquitous, contaminating cereals, crops, and even milk and causing major health and economic issues in some countries due to poor storage, substandard management, and lack of awareness. Different aspects of the toxin are reviewed here, including its structural biochemistry, occurrence, factors conducive to its contamination and intoxication and related clinical features, as well as suggested preventive and control strategies and detection methods.
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9
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Dai C, Tian E, Hao Z, Tang S, Wang Z, Sharma G, Jiang H, Shen J. Aflatoxin B1 Toxicity and Protective Effects of Curcumin: Molecular Mechanisms and Clinical Implications. Antioxidants (Basel) 2022; 11:antiox11102031. [PMID: 36290754 PMCID: PMC9598162 DOI: 10.3390/antiox11102031] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/09/2022] [Accepted: 10/10/2022] [Indexed: 11/26/2022] Open
Abstract
One of the most significant classes of mycotoxins, aflatoxins (AFTs), can cause a variety of detrimental outcomes, including cancer, hepatitis, aberrant mutations, and reproductive issues. Among the 21 identified AFTs, aflatoxin B1 (AFB1) is the most harmful to humans and animals. The mechanisms of AFB1-induced toxicity are connected to the generation of excess reactive oxygen species (ROS), upregulation of CYP450 activities, oxidative stress, lipid peroxidation, apoptosis, mitochondrial dysfunction, autophagy, necrosis, and inflammatory response. Several signaling pathways, including p53, PI3K/Akt/mTOR, Nrf2/ARE, NF-κB, NLRP3, MAPKs, and Wnt/β-catenin have been shown to contribute to AFB1-mediated toxic effects in mammalian cells. Curcumin, a natural product with multiple therapeutic activities (e.g., anti-inflammatory, antioxidant, anticancer, and immunoregulation activities), could revise AFB1-induced harmful effects by targeting these pathways. Therefore, the potential therapeutic use of curcumin against AFB1-related side effects and the underlying molecular mechanisms are summarized. This review, in our opinion, advances significant knowledge, sparks larger discussions, and drives additional improvements in the hazardous examination of AFTs and detoxifying the application of curcumin.
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Affiliation(s)
- Chongshan Dai
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
- Correspondence:
| | - Erjie Tian
- College of Animal Science and Technology, Henan University of Science and Technology, Luoyang 471023, China
| | - Zhihui Hao
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
- Key Biology Laboratory of Chinese Veterinary Medicine, Ministry of Agriculture and Rural Affairs, Beijing 100193, China
| | - Shusheng Tang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Zhanhui Wang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Gaurav Sharma
- Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Haiyang Jiang
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
| | - Jianzhong Shen
- Department of Veterinary Pharmacology and Toxicology, College of Veterinary Medicine, China Agricultural University, Beijing 100193, China
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10
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Terrell JR, Tang S, Faniyi OO, Jeong IH, Yin J, Nijampatnam B, Velu SE, Wang W, Zhang R, Luo M. Structural studies of antitumor compounds that target the RING domain of MDM2. Protein Sci 2022; 31:e4367. [PMID: 35900024 PMCID: PMC9301682 DOI: 10.1002/pro.4367] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/11/2022] [Accepted: 05/27/2022] [Indexed: 08/03/2023]
Abstract
Mouse double minute 2 homolog (MDM2) is an E3 ubiquitin-protein ligase that is involved in the transfer of ubiquitin to p53 and other protein substrates. The expression of MDM2 is elevated in cancer cells and inhibitors of MDM2 showed potent anticancer activities. Many inhibitors target the p53 binding domain of MDM2. However, inhibitors such as Inulanolide A and MA242 are found to bind the RING domain of MDM2 to block ubiquitin transfer. In this report, crystal structures of MDM2 RING domain in complex with Inulanolide A and MA242 were solved. These inhibitors primarily bind in a hydrophobic site centered at the sidechain of Tyr489 at the C-terminus of MDM2 RING domain. The C-terminus of MDM2 RING domain, especially residue Tyr489, is required for ubiquitin discharge induced by MDM2. The binding of these inhibitors at Tyr489 may interrupt interactions between the MDM2 RING domain and the E2-Ubiquitin complex to inhibit ubiquitin transfer, regardless of what the substrate is. Our results suggest a new mechanism of inhibition of MDM2 E3 activity for a broad spectrum of substrates.
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Affiliation(s)
- James Ross Terrell
- Center for Diagnostics and TherapeuticsGeorgia State UniversityAtlantaGeorgiaUSA
- Department of ChemistryGeorgia State UniversityAtlantaGeorgiaUSA
| | - Sijia Tang
- Institute for Biomedical SciencesGeorgia State UniversityAtlantaGeorgiaUSA
| | - Oluwafoyinsola Omobodunde Faniyi
- Center for Diagnostics and TherapeuticsGeorgia State UniversityAtlantaGeorgiaUSA
- Department of ChemistryGeorgia State UniversityAtlantaGeorgiaUSA
| | - In Ho Jeong
- Department of ChemistryGeorgia State UniversityAtlantaGeorgiaUSA
| | - Jun Yin
- Center for Diagnostics and TherapeuticsGeorgia State UniversityAtlantaGeorgiaUSA
- Department of ChemistryGeorgia State UniversityAtlantaGeorgiaUSA
| | | | - Sadanandan E. Velu
- Department of ChemistryUniversity of Alabama at BirminghamBirminghamAlabamaUSA
| | - Wei Wang
- Department of Pharmacological and Pharmaceutical Sciences, College of PharmacyUniversity of HoustonHoustonTexasUSA
- Drug Discovery InstituteUniversity of HoustonHoustonTexasUSA
| | - Ruiwen Zhang
- Department of Pharmacological and Pharmaceutical Sciences, College of PharmacyUniversity of HoustonHoustonTexasUSA
- Drug Discovery InstituteUniversity of HoustonHoustonTexasUSA
| | - Ming Luo
- Center for Diagnostics and TherapeuticsGeorgia State UniversityAtlantaGeorgiaUSA
- Department of ChemistryGeorgia State UniversityAtlantaGeorgiaUSA
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11
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Li W, Pei Y, Wang J. Development and analysis of a novel AF11-2 aptamer capable of enhancing the fluorescence of aflatoxin B1. CHINESE CHEM LETT 2022. [DOI: 10.1016/j.cclet.2022.01.040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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12
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Macias RI, Monte MJ, Serrano MA, González-Santiago JM, Martín-Arribas I, Simão AL, Castro RE, González-Gallego J, Mauriz JL, Marin JJ. Impact of aging on primary liver cancer: epidemiology, pathogenesis and therapeutics. Aging (Albany NY) 2021; 13:23416-23434. [PMID: 34633987 PMCID: PMC8544321 DOI: 10.18632/aging.203620] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Accepted: 09/28/2021] [Indexed: 01/18/2023]
Abstract
Aging involves progressive physiological and metabolic reprogramming to adapt to gradual deterioration of organs and functions. This includes mechanisms of defense against pre-malignant transformations. Thus, certain tumors are more prone to appear in elderly patients. This is the case of the two most frequent types of primary liver cancer, i.e., hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (iCCA). Accordingly, aging hallmarks, such as genomic instability, telomere attrition, epigenetic alterations, altered proteostasis, mitochondrial dysfunction, cellular senescence, exhaustion of stem cell niches, impaired intracellular communication, and deregulated nutrient sensing can play an important role in liver carcinogenesis in the elders. In addition, increased liver fragility determines a worse response to risk factors, which more frequently affect the aged population. This, together with the difficulty to carry out an early detection of HCC and iCCA, accounts for the late diagnosis of these tumors, which usually occurs in patients with approximately 60 and 70 years, respectively. Furthermore, there has been a considerable controversy on what treatment should be used in the management of HCC and iCCA in elderly patients. The consensus reached by numerous studies that have investigated the feasibility and safety of different curative and palliative therapeutic approaches in elders with liver tumors is that advanced age itself is not a contraindication for specific treatments, although the frequent presence of comorbidities in these individuals should be taken into consideration for their management.
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Affiliation(s)
- Rocio I.R. Macias
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maria J. Monte
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Maria A. Serrano
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Jesús M. González-Santiago
- Department of Gastroenterology and Hepatology, University Hospital of Salamanca, IBSAL, Salamanca, Spain
| | - Isabel Martín-Arribas
- Department of Gastroenterology and Hepatology, University Hospital of Salamanca, IBSAL, Salamanca, Spain
| | - André L. Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Rui E. Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Javier González-Gallego
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - José L. Mauriz
- Institute of Biomedicine (IBIOMED), University of León, León, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
| | - Jose J.G. Marin
- Experimental Hepatology and Drug Targeting (HEVEPHARM) Group, University of Salamanca, IBSAL, Salamanca, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Carlos III National Institute of Health, Madrid, Spain
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Dillon M, Lopez A, Lin E, Sales D, Perets R, Jain P. Progress on Ras/MAPK Signaling Research and Targeting in Blood and Solid Cancers. Cancers (Basel) 2021; 13:cancers13205059. [PMID: 34680208 PMCID: PMC8534156 DOI: 10.3390/cancers13205059] [Citation(s) in RCA: 64] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 09/30/2021] [Accepted: 10/06/2021] [Indexed: 12/18/2022] Open
Abstract
Simple Summary The Ras-Raf-MEK-ERK signaling pathway is responsible for regulating cell proliferation, differentiation, and survival. Overexpression and overactivation of members within the signaling cascade have been observed in many solid and blood cancers. Research often focuses on targeting the pathway to disrupt cancer initiation and progression. We aimed to provide an overview of the pathway’s physiologic role and regulation, interactions with other pathways involved in cancer development, and mutations that lead to malignancy. Several blood and solid cancers are analyzed to illustrate the impact of the pathway’s dysregulation, stemming from mutation or viral induction. Finally, we summarized different approaches to targeting the pathway and the associated novel treatments being researched or having recently achieved approval. Abstract The mitogen-activated protein kinase (MAPK) pathway, consisting of the Ras-Raf-MEK-ERK signaling cascade, regulates genes that control cellular development, differentiation, proliferation, and apoptosis. Within the cascade, multiple isoforms of Ras and Raf each display differences in functionality, efficiency, and, critically, oncogenic potential. According to the NCI, over 30% of all human cancers are driven by Ras genes. This dysfunctional signaling is implicated in a wide variety of leukemias and solid tumors, both with and without viral etiology. Due to the strong evidence of Ras-Raf involvement in tumorigenesis, many have attempted to target the cascade to treat these malignancies. Decades of unsuccessful experimentation had deemed Ras undruggable, but recently, the approval of Sotorasib as the first ever KRas inhibitor represents a monumental breakthrough. This advancement is not without novel challenges. As a G12C mutant-specific drug, it also represents the issue of drug target specificity within Ras pathway; not only do many drugs only affect single mutational profiles, with few pan-inhibitor exceptions, tumor genetic heterogeneity may give rise to drug-resistant profiles. Furthermore, significant challenges in targeting downstream Raf, especially the BRaf isoform, lie in the paradoxical activation of wild-type BRaf by BRaf mutant inhibitors. This literature review will delineate the mechanisms of Ras signaling in the MAPK pathway and its possible oncogenic mutations, illustrate how specific mutations affect the pathogenesis of specific cancers, and compare available and in-development treatments targeting the Ras pathway.
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Luo J, Lu C, Feng M, Dai L, Wang M, Qiu Y, Zheng H, Liu Y, Li L, Tang B, Xu C, Wang Y, Yang X. Cooperation between liver-specific mutations of pten and tp53 genetically induces hepatocarcinogenesis in zebrafish. J Exp Clin Cancer Res 2021; 40:262. [PMID: 34416907 PMCID: PMC8377946 DOI: 10.1186/s13046-021-02061-y] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 08/05/2021] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Liver cancer, mainly hepatocellular carcinoma, is one of the deadliest cancers worldwide and has a poor prognosis due to insufficient understanding of hepatocarcinogenesis. Previous studies have revealed that the mutations in PTEN and TP53 are the two most common genetic events in hepatocarcinogenesis. Here, we illustrated the crosstalk between aberrant Pten and Tp53 pathways during hepatocarcinogenesis in zebrafish. METHODS We used the CRISPR/Cas9 system to establish several transgenic zebrafish lines with single or double tissue-specific mutations of pten and tp53 to genetically induce liver tumorigenesis. Next, the morphological and histological determination were performed to investigate the roles of Pten and Tp53 signalling pathways in hepatocarcinogenesis in zebrafish. RESULTS We demonstrated that Pten loss alone induces hepatocarcinogenesis with only low efficiency, whereas single mutation of tp53 failed to induce tumour formation in liver tissue in zebrafish. Moreover, zebrafish with double mutations of pten and tp53 exhibits a much higher tumour incidence, higher-grade histology, and a shorter survival time than single-mutant zebrafish, indicating that these two signalling pathways play important roles in dynamic biological events critical for the initiation and progression of hepatocarcinogenesis in zebrafish. Further histological and pathological analyses showed significant similarity between the tumours generated from liver tissues of zebrafish and humans. Furthermore, the treatment with MK-2206, a specific Akt inhibitor, effectively suppressed hepatocarcinogenesis in zebrafish. CONCLUSION Our findings will offer a preclinical animal model for genetically investigating hepatocarcinogenesis and provide a useful platform for high-throughput anticancer drug screening.
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Affiliation(s)
- Juanjuan Luo
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
- Shantou University Medical College, Shantou, China
| | - Chunjiao Lu
- Shantou University Medical College, Shantou, China
| | - Meilan Feng
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Lu Dai
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Maya Wang
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Yang Qiu
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Huilu Zheng
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China
| | - Yao Liu
- Shantou University Medical College, Shantou, China
| | - Li Li
- Key Laboratory of Freshwater Fish Reproduction and Development, Ministry of Education, Key Laboratory of Aquatic Science of Chongqing, Laboratory of Molecular Developmental Biology, School of Life Sciences, Southwest University, Chongqing, China
| | - Bo Tang
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chuan Xu
- Integrative Cancer Center & Cancer Clinical Research Center, Cancer Center, Sichuan Cancer Hospital & Institute Sichuan, School of Medicine University of Electronic Science and Technology of China, Chengdu, 610041, China
| | - Yajun Wang
- Key laboratory of Bio-resources and Eco-environment of Ministry of Education, College of Life Science, Sichuan University, Chengdu, China.
| | - Xiaojun Yang
- Shantou University Medical College, Shantou, China.
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15
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Han C, Yu T, Qin W, Liao X, Huang J, Liu Z, Yu L, Liu X, Chen Z, Yang C, Wang X, Mo S, Zhu G, Su H, Li J, Qin X, Gui Y, Mo Z, Li L, Peng T. Genome-wide association study of the TP53 R249S mutation in hepatocellular carcinoma with aflatoxin B1 exposure and infection with hepatitis B virus. J Gastrointest Oncol 2020; 11:1333-1349. [PMID: 33457005 PMCID: PMC7807280 DOI: 10.21037/jgo-20-510] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 12/16/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Exposure to dietary aflatoxin B1 (AFB1) induces DNA damage and mutation in the TP53 gene at codon 249, known as the TP53 R249S mutation, and is a major risk factor for hepatocellular carcinoma (HCC). AFB1 and the hepatitis B virus (HBV) together exert synergistic effects that promote carcinogenesis and TP53 R249S mutation in HCC. METHODS A genome-wide association study (GWAS) of whole genome exons was conducted using 485 HCC patients with chronic HBV infection. This was followed by an independent replication study conducted using 270 patients with chronic HBV infection. Immunohistochemistry was used to evaluate TP53 expression in all samples. This showed a correlation between codon 249 mutations and TP53 expression. Susceptibility variants for the TP53 R249S mutation in HCC were identified based on both the GWAS and replication study. The associations between identified variants and the expression levels of their located genes were analyzed in 20 paired independent samples. RESULTS The likelihood of positive TP53 expression was found to be higher in HCC patients with the R249S mutation both in the GWAS (P<0.001) and the replication study (P=0.006). The combined analyses showed that the TP53 R249S mutation was significantly associated with three single nucleotide polymorphisms (SNPs): ADAMTS18 rs9930984 (adjusted P=4.84×10-6), WDR49 rs75218075 (adjusted P=7.36×10-5), and SLC8A3 rs8022091 (adjusted P=0.042). The TP53 R249S mutation was found to be highly associated with the TT genotypes of rs9930984 (additive model, P=0.01; dominant model, P=6.43×10-5) and rs75218075 (additive model, P=0.002; dominant model, P=2.16×10-4). Additionally, ADAMTS18 mRNA expression was significantly higher in HCC tissue compared with its expression in paired non-tumor tissue (P=0.041), and patients carrying the TT genotype at rs9930984 showed lower ADAMTS18 expression in non-tumor tissue compared with patients carrying the GT genotype (P=0.0028). WDR49 expression was markedly lower in HCC tissue compared with paired non-tumor tissue (P=0.0011). CONCLUSIONS TP53 expression is significantly associated with the R249S mutation in HCC. Our collective results suggest that rs9930984, rs75218075, and rs8022091 are associated with R249S mutation susceptibility in HCC patients exposed to AFB1 and HBV infection.
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Affiliation(s)
- Chuangye Han
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
- School of Basic Medical Sciences, Guangxi Medical University, Nanning, China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Wei Qin
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jianlu Huang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, the First Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China
| | - Long Yu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoguang Liu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Zhiwei Chen
- Department of General Surgery, Northern Jiangsu People’s Hospital, Yangzhou, China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Shutian Mo
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hao Su
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Jiaquan Li
- Medical Scientific Research Center, Guangxi Medical University, Nanning, China
| | - Xue Qin
- Department of Clinical Laboratory, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Ying Gui
- Department of Clinical Laboratory, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zengnan Mo
- Center for Genomics and Personalized Medicine, Guangxi Medical University, Nanning, China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
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Computational analysis of TP53 vs. CTNNB1 mutations in hepatocellular carcinoma suggests distinct cancer subtypes with differential gene expression profiles and chromatin states. Comput Biol Chem 2020; 89:107404. [PMID: 33096424 DOI: 10.1016/j.compbiolchem.2020.107404] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 09/09/2020] [Accepted: 10/11/2020] [Indexed: 12/24/2022]
Abstract
Genetic variations are important drivers of carcinogenesis. It is extremely important to identify molecular distinctions between patients of the same disease for effective cancer treatment. This study aims to understand cellular and molecular differences between hepatocellular carcinoma patients carrying TP53 or CTNNB1 mutations, which could possess clinical significance. For this purpose, DNA sequencing and mRNA expression data for hepatocellular carcinoma patients were analyzed. Differentially expressed genes and the cellular processes that they are involved in were determined for TP53/CTNNB1-altered patient groups. We found that the mutations of TP53/CTNNB1 genes in the patient cohort was almost mutually exclusive and gene expression profiling in these subgroups were unique. Gene Ontology (GO) enrichment analysis of the differentially expressed genes identified several important cellular processes. In line with this, selected histone variants, histone chaperons, as well as the binding partners of TP53/CTNNB1 showed distinct enrichment levels. TP53/CTNNB1-altered patient groups laso showed different prognostic outcomes and tumor infiltration levels. In conclusion, our results strongly imply differential chromatin states and transcriptional regulation in relation to the mutational status of TP53 vs. CTNNB1, suggesting that these genes might be inducing different cellular pathways involving distinct chromatin environments during the course of carcinogenesis.
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Taranu I, Hermenean A, Bulgaru C, Pistol GC, Ciceu A, Grosu IA, Marin DE. Diet containing grape seed meal by-product counteracts AFB1 toxicity in liver of pig after weaning. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2020; 203:110899. [PMID: 32678747 DOI: 10.1016/j.ecoenv.2020.110899] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/26/2020] [Revised: 06/11/2020] [Accepted: 06/14/2020] [Indexed: 06/11/2023]
Abstract
Liver is the earliest target for AFB1 toxicity in both human and animals. In the last decade, plant derived by-products have been used in animal feed to reduce AFB1 induced toxicity. In the present study we investigated whether the presence of 8% grape seed meal by-product is able to counteract the hepatotoxic effects produced by AFB1 in liver of pig after weaning exposed to the toxin through the contaminated feed for 28 days. Twenty four weaned cross-bred TOPIGS-40 piglets with an average body weight of 9.13±0.03 were allocated to the following experimentally treatments: control diet without AFB1 (normal compound feed for weaned pigs); contaminated diet with 320 mg kg-1 AFB1; GSM diet (compound feed plus 8% grape seed meal) and AFB1+GSM diet (320 mg kg-1 AFB1 contaminated feed plus 8% grape seed meal). Pigs fed AFB1 diet had altered performance, body weight decreasing with 25.1% (b.w.: 17.17 kg for AFB1 vs 22.92 kg for control). Exposure of piglets to AFB1 contaminated diet caused liver oxidative stress as well as liver histological damage, manly characterized by inflammatory infiltrate, fibrosis and parenchyma cells vacuolation when compared to control and GSM meal group. 94.12% of the total analysed genes (34) related to inflammation and immune response was up-regulated. The addition of GSM into the AFB1 diet diminished the gene overexpression and ameliorate histological liver injuries and oxidative stress. The protective effect of GSM diet in diminishing the AFB1 harmful effect was mediated through the decreasing of gene and protein expression of MAPKs and NF-κB signalling overexpressed by AFB1 diet. The inclusion of grape seed by-products in the diet of pigs after weaning might be used as a novel nutritional intervention to reduce aflatoxin toxicity.
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Affiliation(s)
- Ionelia Taranu
- Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, Balotesti, Ilfov, 077015, Romania.
| | - Anca Hermenean
- Aurel Ardelean Institute of Life Sciences, Vasile Goldis Western University of Arad, Arad, Romania
| | - Cristina Bulgaru
- Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, Balotesti, Ilfov, 077015, Romania
| | - Gina Cecilia Pistol
- Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, Balotesti, Ilfov, 077015, Romania
| | - Alina Ciceu
- Department of Biochemistry and Molecular Biology, University of Bucharest, Bucharest, Romania
| | - Iulian Alexandru Grosu
- Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, Balotesti, Ilfov, 077015, Romania
| | - Daniela Eliza Marin
- Laboratory of Animal Biology, National Institute for Research and Development for Biology and Animal Nutrition, Calea Bucuresti No. 1, Balotesti, Ilfov, 077015, Romania
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Ghazi T, Arumugam T, Foolchand A, Chuturgoon AA. The Impact of Natural Dietary Compounds and Food-Borne Mycotoxins on DNA Methylation and Cancer. Cells 2020; 9:E2004. [PMID: 32878338 PMCID: PMC7565866 DOI: 10.3390/cells9092004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 08/24/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022] Open
Abstract
Cancer initiation and progression is an accumulation of genetic and epigenetic modifications. DNA methylation is a common epigenetic modification that regulates gene expression, and aberrant DNA methylation patterns are considered a hallmark of cancer. The human diet is a source of micronutrients, bioactive molecules, and mycotoxins that have the ability to alter DNA methylation patterns and are thus a contributing factor for both the prevention and onset of cancer. Micronutrients such as betaine, choline, folate, and methionine serve as cofactors or methyl donors for one-carbon metabolism and other DNA methylation reactions. Dietary bioactive compounds such as curcumin, epigallocatechin-3-gallate, genistein, quercetin, resveratrol, and sulforaphane reactivate essential tumor suppressor genes by reversing aberrant DNA methylation patterns, and therefore, they have shown potential against various cancers. In contrast, fungi-contaminated agricultural foods are a source of potent mycotoxins that induce carcinogenesis. In this review, we summarize the existing literature on dietary micronutrients, bioactive compounds, and food-borne mycotoxins that affect DNA methylation patterns and identify their potential in the onset and treatment of cancer.
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Affiliation(s)
| | | | | | - Anil A. Chuturgoon
- Department of Medical Biochemistry, School of Laboratory Medicine and Medical Science, College of Health Sciences, University of KwaZulu-Natal, Durban 4041, South Africa; (T.G.); (T.A.); (A.F.)
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19
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Chang Y, Liu B, Niu H, Wang Z, Xia S, Li H. Value of anti-p53 antibody as a biomarker for hepatocellular carcinoma: Evidence from a meta-analysis. Medicine (Baltimore) 2020; 99:e21887. [PMID: 32846849 PMCID: PMC7447394 DOI: 10.1097/md.0000000000021887] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Revised: 07/15/2020] [Accepted: 07/21/2020] [Indexed: 12/19/2022] Open
Abstract
INTRODUCTION The incidence of hepatocellular carcinoma (HCC) ranks sixth in the world, but its mortality is the third highest due to the lack of early diagnostic markers. Nowadays, the increase of autoantibody levels has been found in many cancers, and many studies have begun to pay attention to the detection of anti-p53 antibodies in HCC. The purpose of this study is to quantitatively and comprehensively analyze the potential diagnostic value of anti-p53 autoantibodies in HCC METHODS:: English articles up to November 2019 were collected. The overall sensitivity and specificity were calculated. Besides, the positive likelihood ratio, negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and summary receiver operating characteristic curves of the overall diagnostic accuracy of anti-p53 antibody were calculated by STATA software. Finally, according to the heterogeneity of the results, the subgroup analysis, and the publication bias were performed. RESULTS A total of 16 eligible studies were incorporated into this meta-analysis, including 1323 patients with HCC and 1896 control. The pooled sensitivity was 0.28(0.17-0.41) and specificity was 0.98 (0.95-0.99). The pooled DOR was 10.44 (6.31-17.29) and the pooled NLR was 0.74 (0.63-0.86). The area under ROC curve of symmetrical ROC was 0.840. CONCLUSIONS The anti-p53 antibody has a high specificity for HCC, but the low sensitivity is not perfect and would limit the clinical application. The anti-p53 antibody would help rule out HCC but not help rule in HCC for early diagnosis. Whether combined as a diagnostic panel with other biomarkers or laboratory tests may prove useful requires further study.
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Affiliation(s)
- Yue Chang
- Department of Hepatopancreatobiliary and Splenic Medicine, Characteristic Medical Center of People's Armed Police Force
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis and Treatment
| | - Baiqing Liu
- Department of Hepatopancreatobiliary and Splenic Medicine, Characteristic Medical Center of People's Armed Police Force
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis and Treatment
| | - Haiyan Niu
- Department of Hepatopancreatobiliary and Splenic Medicine, Characteristic Medical Center of People's Armed Police Force
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis and Treatment
| | - Zhenguo Wang
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis and Treatment
| | - Shihai Xia
- Department of Hepatopancreatobiliary and Splenic Medicine, Characteristic Medical Center of People's Armed Police Force
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis and Treatment
| | - Hai Li
- Tianjin Key Laboratory of Hepatopancreatic Fibrosis and Molecular Diagnosis and Treatment
- Division of Gastroenterology and Hepatology, Tianjin Xiqing Hospital, Tianjin, China
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20
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Qin W, Han C, Mai R, Yu T, Shang L, Ye X, Zhu G, Su H, Liao X, Liu Z, Yu L, Liu X, Yang C, Wang X, Peng M, Peng T. Establishment of a prognostic model for predicting short-term disease-free survival in cases of hepatitis B-related hepatocellular carcinoma with the TP53 249Ser mutation in southern China. Transl Cancer Res 2020; 9:4517-4533. [PMID: 35117817 PMCID: PMC8798450 DOI: 10.21037/tcr-19-2788] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2019] [Accepted: 06/17/2020] [Indexed: 12/14/2022]
Abstract
Background Hepatitis B virus (HBV) infection and dietary aflatoxin exposure are two major and synergistic carcinogenic factors of hepatocellular carcinoma (HCC) in southern China. Mutation of the TP53 gene at codon 249 (TP53 249Ser) is recognized as a fingerprint of aflatoxin B1 (AFB1) exposure. Methods A total of 485 HCC patients positive for serum hepatitis B surface antigen were enrolled. The clinicopathological information and survival time were collected. TP53 249Ser mutations in HCC were detected by Sanger DNA sequencing after PCR amplification. Immunohistochemical staining was used to evaluate TP53 expression. Propensity score matching (PSM) and Cox proportional hazards regression (CPHR) were conducted to identify independent risk factors for prognosis that were incorporated into the nomogram. Univariate logistic regression analysis was used to compare differences in clinical factors between the TP53 249Ser mutation group and the non-mutation group. A Kaplan-Meier plot, univariate and multivariate Cox proportional hazards models were used to assess the association between clinicopathological characteristics and survival outcomes. Results After PSM, a total of 322 cases were included in the analysis of clinical prognosis. Results of CPHR showed that the mutation group had a relatively higher risk of tumor recurrence within 2 years after undergoing hepatectomy (P=0.039, HR =1.47, 95% CI: 1.02–2.18). The prognostic model performed better in terms of 2-year DFS prediction than BCLC stage. Patients who had a nomogram score of more than 160 were considered to have a higher risk of recurrence within 2 years. Conclusions Our study found that the TP53 249Ser mutation may be a high risk factor of HBV-related HCC recurrence in the short term. And we initially established a nomogram scoring system for predicting 2-year recurrence in HBV-related HCC patients in southern China.
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Affiliation(s)
- Wei Qin
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Rongyun Mai
- Department of Hepatobiliary & Pancreatic Surgery, Guangxi Medical University Cancer Hospital, Nanning, China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Liming Shang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Hao Su
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Zhengtao Liu
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
| | - Long Yu
- Department of Hepatobiliary and Pancreatic Surgery, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Xiaoguang Liu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Minhao Peng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Guangxi Medical University, Nanning, China
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21
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Hartwig A, Arand M, Epe B, Guth S, Jahnke G, Lampen A, Martus HJ, Monien B, Rietjens IMCM, Schmitz-Spanke S, Schriever-Schwemmer G, Steinberg P, Eisenbrand G. Mode of action-based risk assessment of genotoxic carcinogens. Arch Toxicol 2020; 94:1787-1877. [PMID: 32542409 PMCID: PMC7303094 DOI: 10.1007/s00204-020-02733-2] [Citation(s) in RCA: 93] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 03/31/2020] [Indexed: 12/16/2022]
Abstract
The risk assessment of chemical carcinogens is one major task in toxicology. Even though exposure has been mitigated effectively during the last decades, low levels of carcinogenic substances in food and at the workplace are still present and often not completely avoidable. The distinction between genotoxic and non-genotoxic carcinogens has traditionally been regarded as particularly relevant for risk assessment, with the assumption of the existence of no-effect concentrations (threshold levels) in case of the latter group. In contrast, genotoxic carcinogens, their metabolic precursors and DNA reactive metabolites are considered to represent risk factors at all concentrations since even one or a few DNA lesions may in principle result in mutations and, thus, increase tumour risk. Within the current document, an updated risk evaluation for genotoxic carcinogens is proposed, based on mechanistic knowledge regarding the substance (group) under investigation, and taking into account recent improvements in analytical techniques used to quantify DNA lesions and mutations as well as "omics" approaches. Furthermore, wherever possible and appropriate, special attention is given to the integration of background levels of the same or comparable DNA lesions. Within part A, fundamental considerations highlight the terms hazard and risk with respect to DNA reactivity of genotoxic agents, as compared to non-genotoxic agents. Also, current methodologies used in genetic toxicology as well as in dosimetry of exposure are described. Special focus is given on the elucidation of modes of action (MOA) and on the relation between DNA damage and cancer risk. Part B addresses specific examples of genotoxic carcinogens, including those humans are exposed to exogenously and endogenously, such as formaldehyde, acetaldehyde and the corresponding alcohols as well as some alkylating agents, ethylene oxide, and acrylamide, but also examples resulting from exogenous sources like aflatoxin B1, allylalkoxybenzenes, 2-amino-3,8-dimethylimidazo[4,5-f] quinoxaline (MeIQx), benzo[a]pyrene and pyrrolizidine alkaloids. Additionally, special attention is given to some carcinogenic metal compounds, which are considered indirect genotoxins, by accelerating mutagenicity via interactions with the cellular response to DNA damage even at low exposure conditions. Part C finally encompasses conclusions and perspectives, suggesting a refined strategy for the assessment of the carcinogenic risk associated with an exposure to genotoxic compounds and addressing research needs.
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Affiliation(s)
- Andrea Hartwig
- Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany.
| | - Michael Arand
- Institute of Pharmacology and Toxicology, University of Zurich, 8057, Zurich, Switzerland
| | - Bernd Epe
- Institute of Pharmacy and Biochemistry, University of Mainz, 55099, Mainz, Germany
| | - Sabine Guth
- Department of Toxicology, IfADo-Leibniz Research Centre for Working Environment and Human Factors, TU Dortmund, Ardeystr. 67, 44139, Dortmund, Germany
| | - Gunnar Jahnke
- Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany
| | - Alfonso Lampen
- Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589, Berlin, Germany
| | - Hans-Jörg Martus
- Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland
| | - Bernhard Monien
- Department of Food Safety, German Federal Institute for Risk Assessment (BfR), 10589, Berlin, Germany
| | - Ivonne M C M Rietjens
- Division of Toxicology, Wageningen University, Stippeneng 4, 6708 WE, Wageningen, The Netherlands
| | - Simone Schmitz-Spanke
- Institute and Outpatient Clinic of Occupational, Social and Environmental Medicine, University of Erlangen-Nuremberg, Henkestr. 9-11, 91054, Erlangen, Germany
| | - Gerlinde Schriever-Schwemmer
- Department of Food Chemistry and Toxicology, Institute of Applied Biosciences (IAB), Karlsruhe Institute of Technology (KIT), Adenauerring 20a, 76131, Karlsruhe, Germany
| | - Pablo Steinberg
- Max Rubner-Institut, Federal Research Institute of Nutrition and Food, Haid-und-Neu-Str. 9, 76131, Karlsruhe, Germany
| | - Gerhard Eisenbrand
- Retired Senior Professor for Food Chemistry and Toxicology, Kühler Grund 48/1, 69126, Heidelberg, Germany.
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22
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Jia W, Xie L, Wang X, Zhang Q, Wei B, Li H, Qin S, Chen S, Liu J, Tan Y, Zheng S, Liang X, Yang X. The impact of MCM6 on hepatocellular carcinoma in a Southern Chinese Zhuang population. Biomed Pharmacother 2020; 127:110171. [PMID: 32403044 DOI: 10.1016/j.biopha.2020.110171] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 04/04/2020] [Accepted: 04/13/2020] [Indexed: 12/21/2022] Open
Abstract
Minichromosome maintenance complex component 6 (MCM6) is involved in tumorigenesis of hepatocellular carcinoma (HCC). Because its effect on different populations remains unclear, this study investigated the impact of MCM6 on HCC in Southern Chinese Zhuang population. In addition to assessing the global mRNA levels of MCM6 based on The Cancer Genome Atlas database (TCGA) and The Gene Expression Omnibus database (GEO), associations between MCM6 mRNA levels and clinicopathological features were analyzed. High MCM6 levels were associated with high alpha-fetoprotein (AFP) (>20 ng/mL in serum) (P < 0.0001) and advanced clinical stage (III + IV) (P < 0.001). Higher MCM6 was associated with poorer outcomes (P < 0.01) in these databases. Furthermore, the mRNA and protein expression of MCM6 in the Guangxi Zhuang population was detected by quantitative polymerase chain reaction (qPCR), western blot, and immunohistochemistry (IHC). The results showed that MCM6 levels were up-regulated in the Zhuang population with HCC. Higher MCM6 protein levels were correlated with larger tumor size (>5 cm) (P = 0.038) and advanced clinical stage (III + IV) (p = 0.023). Bioinformatic enrichment analysis of MCM6 and its interacting proteins (CDT1,WEE1,TRIM28 and MKI67) suggested that in addition to being involved in the cell cycle process, these complexes could also be involved in protein binding, pre-replication complex assemble, and nucleus metabolism. Based on the protein-protein interaction (PPI) network with module screen, the interactions between MCM6 and its potential interacting proteins were further studied through protein docking with hot spot analysis. Additionally, the results of the algorithms combining the ROC of MCM6 and its interacting proteins showed that combination biomarker analysis has better HCC diagnosis ability than the single MCM6 test. The combination of MCM6 and TRIM28 was more suitable for the Guangxi Zhuang population. Overall, our study suggests that MCM6 plays an important role in the growth of HCC. MCM6 could be an optimal biomarker for diagnosing HCC and a potential molecular target for HCC therapy in the Zhuang population.
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Affiliation(s)
- Wenxian Jia
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China; Pharmaceutical College, Guangxi Medical University, Nanning, Guangxi, China
| | - Li Xie
- Department of Clinical Laboratory, The Second Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Xiao Wang
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China; Department of Orthopedic Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China
| | - Qinle Zhang
- Genetic and Metabolic Central Laboratory, The Maternal and Children Health Hospital of Guangxi, Guangxi, China
| | - Bing Wei
- College of International Education, Guilin Medical University, Guilin, Guangxi, China
| | - Hongwen Li
- Teaching and Researching Section of Human Anatomy, Guilin Medical University, Guilin, Guangxi, China
| | - Shouxu Qin
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Suixia Chen
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Jiayi Liu
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Yanjun Tan
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Shengfeng Zheng
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China
| | - Xiaonan Liang
- Department of Orthopedic Trauma and Hand Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi, China.
| | - Xiaoli Yang
- Scientific Research Center, Guilin Medical University, Guilin, Guangxi, China.
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23
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Wang X, Li L, Zhang G. Quercetin protects the buffalo rat liver (BRL-3A) cells from aflatoxin B1-induced cytotoxicity via activation of Nrf2-ARE pathway. WORLD MYCOTOXIN J 2020. [DOI: 10.3920/wmj2019.2465] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Aflatoxin B1 (AFB1) is the most toxic mycotoxin widely presented in agricultural products, and the protective effect of quercetin (QUE), a natural antioxidant, against AFB1-induced cytotoxicity to the buffalo rat liver (BRL-3A) cells was investigated. With an IC50 of 23 μM, AFB1 induced a significant oxidative stress to BRL-3A cells evidenced by a dose-dependent reduction of mitochondria membrane potential (MMP), ATP content, and activities of endogenous antioxidant enzymes along with increased levels of reactive oxygen species (ROS) and lipid peroxidation biomarker of malondialdehyde (MDA). The activity of CYP1A2, the key enzyme to convert AFB1 to reactive AFB1 exo-8,9- epoxide, was also increased, which, probably in together with ROS, led to cell apoptosis with DNA fragmentation, chromatin condensation and increased lactate dehydrogenase release. After the BRL cells were pre-treated by low level QUE (2.5 and/or 5 μM) for 24 h and then exposed to AFB1, the activities of antioxidant enzymes including haeme oxygenase-1, glutathione S-transferase, superoxide dismutase, and the ratio of reduced to oxidised glutathione were significantly increased whereas the levels of intracellular ROS and MDA were reduced. The QUE pre-treatment also increased the levels of MMP, ATP and DNA integrity, and reduced the expression of apoptosis related genes of Bax and Caspase-3. The Western blotting study revealed increased content of phosphorylated Akt and nuclear NF-E2-related factor 2 (Nrf2), indicating an activation of Nrf2-ARE pathway in counteracting oxidative stress and cytotoxicity of AFB1. Thus, the QUE pre-treatment enhanced the anti-stress capacity of the cells through the activation of the Nrf2-ARE pathway, and QUE-based measures could be developed to ameliorate the toxicity caused by AFB1.
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Affiliation(s)
- X. Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122 Jiangsu, China P.R
| | - L. Li
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122 Jiangsu, China P.R
| | - G. Zhang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, 1800 Lihu Avenue, Wuxi, 214122 Jiangsu, China P.R
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24
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Zhu GZ, Liao XW, Wang XK, Gong YZ, Liu XG, Yu L, Han CY, Yang CK, Su H, Huang KT, Yu TD, Huang JL, Li J, Zeng ZM, Qin W, Liu ZQ, Zhou X, Liu JQ, Lu L, Han QF, Shang LM, Ye XP, Peng T. Comprehensive investigation of p53, p21, nm23, and VEGF expression in hepatitis B virus-related hepatocellular carcinoma overall survival after hepatectomy. J Cancer 2020; 11:906-918. [PMID: 31949494 PMCID: PMC6959013 DOI: 10.7150/jca.33766] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 09/18/2019] [Indexed: 12/27/2022] Open
Abstract
Objective: The goal of our current study is to assess the immunohistochemical of p53, p21, nm23, and VEGF expression in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) prognosis after hepatectomy, as well as the prospective molecular mechanisms of prognostic indicator. Methods: There were 419 HBV-related HCC patients who were from southern China of Guangxi province and were used to evaluate the immunohistochemical expression for these biomarkers in prognosis. A genome-wide expression microarray dataset of HBV-related HCC were obtained from GSE14520. Results: In our study, the expression of p53, p21, and nm23 in cancer tissues of patients with hepatitis B-related hepatocellular carcinoma did not affected the clinical outcome of 2 years, 5 years or overall. Patients with high expression of VEGF had a worse overall survival after 2 years of surgery than patients with low expression (adjusted P=0.040, adjusted HR = 1.652, 95% CI = 1.024-2.665). Survival analysis of VEGF in GSE14520 cohort also demonstrated that VEGF mRNA expression also significantly associated with HBV-related HCC OS (adjusted P=0.035, adjusted HR =1.651, 95% CI =1.035-2.634). The prospective molecular mechanisms by co-expression analysis suggested that VEGF might be correlated to regulation of cell proliferation, cell growth and apoptotic process, Rap1 signaling pathway, HIF-1 signaling pathway, PPAR signaling pathway, cell cycle. Whereas the GSEA suggested that VEGF might involve in the regulation of HIF and HIF1A pathway, and TP53 regulation pathway. Conclusion: Our findings suggested that VEGF might be a prognostic indicator of HBV-related HCC, and we also identified the VEGF prospective molecular mechanisms through the whole genome co-expression and GSEA approaches.
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Affiliation(s)
- Guang-Zhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xi-Wen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiang-Kun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Yi-Zhen Gong
- Department of Colorectal and Anal Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xiao-Guang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Long Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Chuang-Ye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Cheng-Kun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Ke-Tuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Ting-Dong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Jian-Lu Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China.,Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Guangxi Medical University, Nanning, 530031, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Jia Li
- Department of Pathology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, People's Republic of China
| | - Zhi-Ming Zeng
- Department of Medical Oncology, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region 530021, People's Republic of China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Zheng-Qian Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xin Zhou
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Jun-Qi Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Lei Lu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Quan-Fa Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Li-Ming Shang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Xin-Ping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, People's Republic of China
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25
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Taghizadeh SF, Rezaee R, Badiebostan H, Giesy JP, Karimi G. Occurrence of mycotoxins in rice consumed by Iranians: a probabilistic assessment of risk to health. Food Addit Contam Part A Chem Anal Control Expo Risk Assess 2019; 37:342-354. [PMID: 31810432 DOI: 10.1080/19440049.2019.1684572] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Risks based on cancer and non-cancer endpoints, to Iranians from exposure to several mycotoxins (aflatoxin B1, ochratoxin, deoxynivalenol and T-2 toxin) following consumption of rice were evaluated. Point estimates of hazard were made for each mycotoxin and a hazard index (HI) and probabilistic estimates were based on results of Monte Carlo Simulations (MCS). All known 17 peer-reviewed studies, published in databases included in Science Direct, PubMed, Scopus and Web of Science, as well as grey literature published in Google Scholar from 2008 to 2017 were considered. The 95th and 50th centiles of Hazard Index (HI) in Iranians due to ingestion of rice were estimated to be 2.5 and 0.5, respectively. The 95th and 50th centiles of people with positive surface antigens for hepatitis B (HBsAg+) risk characterisation for AFB1 in Iranian consumers of rice were 81 and 79.1, respectively. The 95th and 50th centiles for risks of Iranians negative for the surface antigen of hepatitis B HBsAg (HBsAg-) were 4.4 and 2.6, respectively. Based on results of the MCS for risks to cancer effects, the 95th and 50th centiles of margins of exposure (MOE) were 233 and 231, respectively. Therefore, it is recommended to update agricultural approaches and storage methods and implement monitoring and regulations based on risks to health posed by consumption of rice by the Iranian population.
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Affiliation(s)
- Seyedeh Faezeh Taghizadeh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ramin Rezaee
- Clinical Research Unit, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.,Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Chemical Engineering, Environmental Engineering Laboratory, Aristotle University of Thessaloniki, Thessaloniki, Greece.,HERACLES Research Center on the Exposome and Health, Center for Interdisciplinary Research and Innovation, Balkan Center, Thessaloniki, Greece
| | - Hasan Badiebostan
- Department of Pharmacodynamics and Toxicology School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - John P Giesy
- Department of Veterinary Biomedical Sciences and Toxicology Centre, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.,Department of Zoology and Center for Integrative Toxicology, Michigan State University, East Lansing, MI, USA.,School of Biological Sciences, University of Hong Kong, Hong Kong, SAR, China
| | - Gholamreza Karimi
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmacodynamics and Toxicology School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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26
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Matumba L, Kimanya M, Chunga-Sambo W, Munthali M, Ayalew A. Probabilistic dietary based estimation of the burden of aflatoxin-induced hepatocellular carcinoma among adult Malawians. WORLD MYCOTOXIN J 2019. [DOI: 10.3920/wmj2018.2346] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The risk of aflatoxin-induced hepatocellular carcinoma (HCC) among adults (average body weight of 60 kg) in Malawi was assessed based on aflatoxin B1 (AFB1) exposure through groundnut and maize consumption, by Monte Carlo simulation. The risk (cases per year per 100,000 people) of aflatoxin-induced HCC was estimated based on the AFB1 exposures estimated by this study and hepatitis B virus infection prevalence published for Malawi. AFB1 exposures were estimated by probabilistically combining data of AFB1 contamination in 338 groundnut and 604 maize samples with data of per capita groundnut and maize consumption in 274 households. Aflatoxins in the samples were analysed using validated LC-MS/MS, HPLC and VICAM based methods. The groundnut and maize consumption survey was based on household expenditure technique. The simulated mean AFB1 exposures through consumption of groundnuts, maize, and combination thereof were 28±65, 42±174, and 71±211 ng/kg. body weight (bw)/day, respectively. The estimated HCC risks were 1.26±2.72, 1.86±6.66 and 3.10±6.85 cases per 100,000 persons per year, respectively. Further, hypothetical eradication of hepatitis B virus (HBV) reduced the risk of HCC by 78%. This reaffirms the need for integrating HBV vaccination in the fight of aflatoxin induced HCC.
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Affiliation(s)
- L. Matumba
- Food Technology and Nutrition Group, Lilongwe University of Agriculture and Natural Resources, (LUANAR), NRC campus, P.O. Box 143, Lilongwe, Malawi
| | - M. Kimanya
- The Partnership for Aflatoxin Control in Africa, Department of Rural Economy and Agriculture, P.O. Box 3243, Roosevelt Street, Addis Ababa, Ethiopia
- Department of Food Biotechnology and Nutritional Sciences, Nelson Mandela – African Institution of Science and Technology, Arusha, Tanzania
| | - W. Chunga-Sambo
- The Partnership for Aflatoxin Control in Africa, Department of Rural Economy and Agriculture, P.O. Box 3243, Roosevelt Street, Addis Ababa, Ethiopia
| | - M. Munthali
- Department of Agricultural Research Services, Chitedze Agricultural Research Station, P.O. Box 158, Lilongwe, Malawi
| | - A. Ayalew
- The Partnership for Aflatoxin Control in Africa, Department of Rural Economy and Agriculture, P.O. Box 3243, Roosevelt Street, Addis Ababa, Ethiopia
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Yang WY, Rao PS, Luo YC, Lin HK, Huang SH, Yang JM, Yuh CH. Omics-based Investigation of Diet-induced Obesity Synergized with HBx, Src, and p53 Mutation Accelerating Hepatocarcinogenesis in Zebrafish Model. Cancers (Basel) 2019; 11:cancers11121899. [PMID: 31795276 PMCID: PMC6966430 DOI: 10.3390/cancers11121899] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Revised: 11/17/2019] [Accepted: 11/25/2019] [Indexed: 12/19/2022] Open
Abstract
The primary type of liver cancer, hepatocellular carcinoma (HCC), has been associated with nonalcoholic steatohepatitis, diabetes, and obesity. Previous studies have identified some genetic risk factors, such as hepatitis B virus X antigens, overexpression of SRC oncogene, and mutation of the p53 tumor suppressor gene; however, the synergism between diet and genetic risk factors is still unclear. To investigate the synergism between diet and genetic risk factors in hepatocarcinogenesis, we used zebrafish with four genetic backgrounds and overfeeding or high-fat-diet-induced obesity with an omics-based expression of genes and histopathological changes. The results show that overfeeding and high-fat diet can induce obesity and nonalcoholic steatohepatitis in wild-type fish. In HBx, Src (p53-) triple transgenic zebrafish, diet-induced obesity accelerated HCC formation at five months of age and increased the cancer incidence threefold. We developed a global omics data analysis method to investigate genes, pathways, and biological systems based on microarray and next-generation sequencing (NGS, RNA-seq) omics data of zebrafish with four diet and genetic risk factors. The results show that two Kyoto Encyclopedia of Genes and Genomes (KEGG) systems, metabolism and genetic information processing, as well as the pathways of fatty acid metabolism, steroid biosynthesis, and ribosome biogenesis, are activated during hepatocarcinogenesis. This study provides a systematic view of the synergism between genetic and diet factors in the dynamic liver cancer formation process, and indicate that overfeeding or a high-fat diet and the risk genes have a synergistic effect in causing liver cancer by affecting fatty acid metabolism and ribosome biogenesis.
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Affiliation(s)
- Wan-Yu Yang
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 35053, Miaoli, Taiwan; (W.-Y.Y.); (P.-S.R.); (H.-K.L.)
| | - Pei-Shu Rao
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 35053, Miaoli, Taiwan; (W.-Y.Y.); (P.-S.R.); (H.-K.L.)
- Department of Life Science, National Tsing-Hua University, Hsinchu 30070, Taiwan
| | - Yong-Chun Luo
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 30010, Taiwan; (Y.-C.L.); (S.-H.H.)
| | - Hua-Kuo Lin
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 35053, Miaoli, Taiwan; (W.-Y.Y.); (P.-S.R.); (H.-K.L.)
| | - Sing-Han Huang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 30010, Taiwan; (Y.-C.L.); (S.-H.H.)
| | - Jinn-Moon Yang
- Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu 30010, Taiwan; (Y.-C.L.); (S.-H.H.)
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan
- Center for Intelligent Drug Systems and Smart Bio-devices, National Chiao Tung University, Hsinchu 30010, Taiwan
- Correspondence: (J.-M.Y.); (C.-H.Y.); Tel.: +011-886-03-5712121*56942 (J.-M.Y.); +011-886-37-206166*35338 (C.-H.Y.)
| | - Chiou-Hwa Yuh
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan 35053, Miaoli, Taiwan; (W.-Y.Y.); (P.-S.R.); (H.-K.L.)
- Department of Biological Science and Technology, National Chiao Tung University, Hsinchu 30010, Taiwan
- Institute of Bioinformatics and Structural Biology, National Tsing-Hua University, Hsinchu 30070, Taiwan
- Program in Environmental and Occupational Medicine, Kaohsiung Medical University, Kaohsiung 80708, Taiwan
- Correspondence: (J.-M.Y.); (C.-H.Y.); Tel.: +011-886-03-5712121*56942 (J.-M.Y.); +011-886-37-206166*35338 (C.-H.Y.)
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28
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Duan J, Wu Y, Liu J, Zhang J, Fu Z, Feng T, Liu M, Han J, Li Z, Chen S. Genetic Biomarkers For Hepatocellular Carcinoma In The Era Of Precision Medicine. J Hepatocell Carcinoma 2019; 6:151-166. [PMID: 31696097 PMCID: PMC6805787 DOI: 10.2147/jhc.s224849] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 09/18/2019] [Indexed: 12/24/2022] Open
Abstract
Being one of the most lethal cancers that exhibit high levels of heterogeneity, hepatocellular carcinoma (HCC) is associated with diverse oncogenic pathways underpinned by varied driver genes. HCC can be induced by different etiological factors including virus infection, toxin exposure or metabolic disorders. Consequently, patients may display varied genetic profiles, and may respond differently to the treatments involving inhibition of target pathways. These DNA/RNA mutations, copy number variations, chromatin structural changes, aberrant expression of non-coding RNAs and epigenetic modifications were considered as biomarkers in the application of precision medication. To explore how genetic testing could contribute to early diagnosis, prognosis, treatment and postoperative monitoring of HCC, we conducted a systematic review of genetic markers associated with different pathologies. Moreover, we summarized on-going clinical trials for HCC treatment, including the trials for multiple kinase inhibitors and immune checkpoint blockade (ICB). The efficacy of ICB treatment in HCC is not as good as what was observed in lung cancer and melanoma, which might be due to the heterogeneity of the microenvironment of the liver.
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Affiliation(s)
- Jingxian Duan
- Department of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China
| | - Yuling Wu
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Jikui Liu
- Department of Hepatobiliary and Pancreatic Surgery, Peking University Shenzhen Hospital, Shenzhen518036, People’s Republic of China
| | - Jiajia Zhang
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Zhichao Fu
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Tieshan Feng
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Ming Liu
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Jie Han
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
| | - Zhicheng Li
- Department of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China
| | - Shifu Chen
- Department of Biomedical and Health Engineering, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, People’s Republic of China
- Department of Oncology, HaploX Biotechnology Co. Ltd, Shenzhen518000, People’s Republic of China
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Zhou R, Liu M, Liang X, Su M, Li R. Clinical features of aflatoxin B1-exposed patients with liver cancer and the molecular mechanism of aflatoxin B1 on liver cancer cells. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2019; 71:103225. [PMID: 31376682 DOI: 10.1016/j.etap.2019.103225] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/16/2019] [Revised: 07/21/2019] [Accepted: 07/24/2019] [Indexed: 06/10/2023]
Abstract
Aflatoxin B1 (AFB1) induces hepatocellular carcinoma (HCC) through consumption of contaminated food in Southern China. Aldo-keto reductase-7A (AKR7A) functionally plays a potent role in the biodetoxification in the liver. In addition, hepatocellular lipid disorder has found to be closely linked to the development of HCC. This study was, therefore, designed to investigate the potent bioeffect of AKR7A on the lipid metabolism in AFB1-exposed hepatocellular carcinoma cells through assaying human cancerous samples and cell culture. In the baseline data, the HCC patients showed increased contents of AFB1 in sera and cancerous samples. In the clinical parameters, the HCC patients demonstrated changed lipid settings in sera. As revealed by immunostaining and immunoblotting, AFB1-elevated HCC sections showed marked down-regulation of AKR7A expression, accompanied with reduced ApoB expression and increased CD36, S6K1 expressions in the HCC. Studies in the human hepatocarcinoma line HepG2 also showed AFB1-exposure to increase ApoA1, LDL, TC, and TG contents; induce cell proliferation; and reduce hepatocellular AKR7A expression. Furthermore, AKR7A bioactivity was inactivated after treatment with perfluorooctane sulfonate (PFOS), an ApoB activator, in AFB1-dosed HepG2 cells. Collectively, our current findings suggest that hepatocellular AKR7A has a protective role against AFB1-induced cytotoxicity through the regulation of CD36, S6K1 and ApoB expression through the reduction of lipid utilization in malignant liver cells.
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Affiliation(s)
- Rui Zhou
- Department of Hepatobiliary Surgery, Guigang City People's Hospital, The Eighth Affiliated Hospital of Guangxi Medical University, Guigang 537100, Guangxi, PR China
| | - Meizhen Liu
- College of Pharmacy, Guangxi Medical University, Guangxi, Nanning 530021, PR China
| | - Xiaoliu Liang
- College of Pharmacy, Guangxi Medical University, Guangxi, Nanning 530021, PR China
| | - Min Su
- Key Laboratory of Tumour Immunology and Microenvironmental Regulation, Guilin Medical University, Guangxi, Guilin 541004, PR China
| | - Rong Li
- Key Laboratory of Tumour Immunology and Microenvironmental Regulation, Guilin Medical University, Guangxi, Guilin 541004, PR China.
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30
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Chen HQ, Zhao J, Li Y, Huang YJ, Chen DJ, He LX, Wang LQ, Zheng CF, Wang J, Cao J, Shu WQ, Liu JY, Liu WB. Epigenetic inactivation of LHX6 mediated microcystin-LR induced hepatocarcinogenesis via the Wnt/β-catenin and P53 signaling pathways. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2019; 252:216-226. [PMID: 31151060 DOI: 10.1016/j.envpol.2019.05.049] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 04/14/2019] [Accepted: 05/10/2019] [Indexed: 06/09/2023]
Abstract
Microcystins (MCs) have been shown to be carcinogenic by animal and cellular experiments and found to be associated with the development of human hepatocellular carcinoma (HCC) through epidemiological studies. However, the molecular mechanism of microcystin-LR (MC-LR) induced HCC is still unclear. This study is determined to clarify the role and mechanism of LHX6 in MC-LR-induced hepatocarcinogenesis. Using the previously established MC-LR-induced malignant transformation model in L02 cells, we screened out LHX6, homeobox gene that was significantly changed. We found that LHX6 was significantly down-regulated in MC-LR treated L02 cells and the liver tissue of rats treated for 35 weeks with 10 μg/kg body weight of MC-LR. Expression of LHX6 in human tumor tissue was significantly down-regulated in high MC-LR-exposure group. LHX6 was hypermethylated in MC-LR treated L02 cells and up-regulated after treatment with 10 μM of 5-aza-2'-deoxycytidine. Furthermore, overexpression of LHX6 inhibited proliferation, invasion and migration of malignantly transformed L02 cells in vitro and in vivo, while knockdown of LHX6 resulted in an opposite phenotype. In addition, we found that up-regulation of P53 and Bax resulted in apoptosis, and that down-regulation of CTNNB1 and MMP7 led to migration of MC-LR treated L02 cells. Blockade of P53 and CTNNB1 by its inhibitor significantly diminished the effect of LHX6. These genes were working together during the process of MC-LR-induced hepatocarcinogenesis. Our study demonstrated for the first time that LHX6 gene expression is regulated by DNA methylation and can inhibit the proliferation, invasion and migration through Wnt/β-catenin and P53 signaling pathways during the MC-LR-induced hepatocarcinogenesis. This result may suggest that LHX6 gene can be used as a potential target gene and a biomarker for liver cancer treatment.
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Affiliation(s)
- Hong-Qiang Chen
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Ji Zhao
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China; College of Public Health and Management, Ningxia Medical University, Yinchuan, 750004, PR China
| | - Yan Li
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China; The Calmette International Hospital, Kunming, 650224, PR China
| | - Yu-Jing Huang
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Dong-Jiao Chen
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China; College of Public Health and Management, Ningxia Medical University, Yinchuan, 750004, PR China
| | - Li-Xiong He
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Ling-Qiao Wang
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Chuan-Fen Zheng
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Jia Wang
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Jia Cao
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Wei-Qun Shu
- Department of Environmental Hygiene, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Jin-Yi Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China.
| | - Wen-Bin Liu
- Institute of Toxicology, College of Preventive Medicine, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China.
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31
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Qiu Z, Li H, Zhang Z, Zhu Z, He S, Wang X, Wang P, Qin J, Zhuang L, Wang W, Xie F, Gu Y, Zou K, Li C, Li C, Wang C, Cen J, Chen X, Shu Y, Zhang Z, Sun L, Min L, Fu Y, Huang X, Lv H, Zhou H, Ji Y, Zhang Z, Meng Z, Shi X, Zhang H, Li Y, Hui L. A Pharmacogenomic Landscape in Human Liver Cancers. Cancer Cell 2019; 36:179-193.e11. [PMID: 31378681 PMCID: PMC7505724 DOI: 10.1016/j.ccell.2019.07.001] [Citation(s) in RCA: 139] [Impact Index Per Article: 23.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2018] [Revised: 05/17/2019] [Accepted: 07/01/2019] [Indexed: 12/30/2022]
Abstract
Liver cancers are highly heterogeneous with poor prognosis and drug response. A better understanding between genetic alterations and drug responses would facilitate precision treatment for liver cancers. To characterize the landscape of pharmacogenomic interactions in liver cancers, we developed a protocol to establish human liver cancer cell models at a success rate of around 50% and generated the Liver Cancer Model Repository (LIMORE) with 81 cell models. LIMORE represented genomic and transcriptomic heterogeneity of primary cancers. Interrogation of the pharmacogenomic landscape of LIMORE discovered unexplored gene-drug associations, including synthetic lethalities to prevalent alterations in liver cancers. Moreover, predictive biomarker candidates were suggested for the selection of sorafenib-responding patients. LIMORE provides a rich resource facilitating drug discovery in liver cancers.
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MESH Headings
- Animals
- Antineoplastic Agents/pharmacology
- Asian People/genetics
- Biomarkers, Tumor/genetics
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/ethnology
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/pathology
- Cell Line, Tumor
- Clinical Decision-Making
- Databases, Genetic
- Drug Resistance, Neoplasm/genetics
- Female
- Genetic Heterogeneity
- Genetic Predisposition to Disease
- High-Throughput Nucleotide Sequencing
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/ethnology
- Liver Neoplasms/genetics
- Liver Neoplasms/pathology
- Male
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, Nude
- Mice, SCID
- Patient Selection
- Pharmacogenomic Testing
- Pharmacogenomic Variants
- Phenotype
- Precision Medicine
- Protein Kinase Inhibitors/pharmacology
- Sorafenib/pharmacology
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Zhixin Qiu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Hong Li
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhengtao Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhenfeng Zhu
- Department of Minimally Invasive Therapy, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Sheng He
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China
| | - Xujun Wang
- SJTU-Yale Joint Center for Biostatistics, Department of Bioinformatics and Biostatistics, Shanghai Jiaotong University, Shanghai 200240, China
| | - Pengcheng Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Jianjie Qin
- Liver Transplantation Center, Key Laboratory of Living Donor Liver Transplantation of Ministry of Public Health, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, China
| | - Liping Zhuang
- Department of Minimally Invasive Therapy, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Wei Wang
- Shanghai ChemPartner Co., Ltd., Shanghai 201203, China
| | - Fubo Xie
- Shanghai ChemPartner Co., Ltd., Shanghai 201203, China
| | - Ying Gu
- Shanghai ChemPartner Co., Ltd., Shanghai 201203, China
| | - Keke Zou
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chao Li
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chun Li
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Chenhua Wang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Jin Cen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Xiaotao Chen
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yajing Shu
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Zhao Zhang
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Lulu Sun
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Lihua Min
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China
| | - Yong Fu
- Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China
| | - Xiaowu Huang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Fudan University, Shanghai 200032, China
| | - Hui Lv
- SJTU-Yale Joint Center for Biostatistics, Department of Bioinformatics and Biostatistics, Shanghai Jiaotong University, Shanghai 200240, China
| | - He Zhou
- Shanghai ChemPartner Co., Ltd., Shanghai 201203, China
| | - Yuan Ji
- Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Zhigang Zhang
- Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Zhiqiang Meng
- Department of Minimally Invasive Therapy, Collaborative Innovation Center for Cancer Medicine, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiaolei Shi
- Department of Hepatobiliary Surgery, the Affiliated Drum Tower Hospital, Medical School of Nanjing University, Nanjing, Jiangsu 211166, China.
| | - Haibin Zhang
- Fifth Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai 200438, China.
| | - Yixue Li
- CAS Key Laboratory of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
| | - Lijian Hui
- State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, Shanghai Tech University, Shanghai 201210, China; Bio-Research Innovation Center Suzhou, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Suzhou, Jiangsu 215121, China.
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32
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Li S, Muhammad I, Yu H, Sun X, Zhang X. Detection of Aflatoxin adducts as potential markers and the role of curcumin in alleviating AFB1-induced liver damage in chickens. ECOTOXICOLOGY AND ENVIRONMENTAL SAFETY 2019; 176:137-145. [PMID: 30925330 DOI: 10.1016/j.ecoenv.2019.03.089] [Citation(s) in RCA: 81] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2018] [Revised: 02/23/2019] [Accepted: 03/20/2019] [Indexed: 06/09/2023]
Abstract
In this study, we identified AFB1 adducts as potential markers and investigated the role of curcumin in alleviating AFB1-induced liver damage by suppressing the production of AFB1 adducts and oxidative stress in AA broilers liver. A total of 64 one-day-old Arbor Acres (AA) broilers were randomly divided into four groups, including control group, AFB1 group (5 mg/kg AFB1), cur + AFB1 group (300 mg/kg curcumin+5 mg/kg AFB1) and curcumin group (300 mg/kg). Serum biochemical parameters, liver antioxidant abilities, AFB1 adducts and oxidative stress mechanism were studied in broilers. AFB1 administration accompany with signs of liver injury, including hepatic histological lesions, increased serum enzymes activities, decreased liver antioxidant enzymes activities and the suppression of ROS and 8-OHdG. Meanwhile, Nrf2/HO-1 pathway was depressed by AFB1 treatment. Immunohistochemistry and ELISA showed that AFB1 significantly increased AFB1-DNA adduct in liver (p < 0.05) and AFB1-lysine adduct in serum (p < 0.05). Importantly, supplementation of curcumin can ameliorate these alterations. Intriguingly, curcumin alleviated AFB1-induced toxicity and oxidative stress by inhibiting the generation of ROS, 8-OHdG and AFB1 adducts, and activated Nrf2 signaling pathway in broilers. Conclusively, our experiments suggest that curcumin could be considered as a potential agent for prevention of AFB1-induced toxicity and oxidative stress, and AFB1 adducts could be suitable therapeutic targets.
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Affiliation(s)
- Sihong Li
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, PR China
| | - Ishfaq Muhammad
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, PR China
| | - Hongxiao Yu
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, PR China
| | - Xiaoqi Sun
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, PR China
| | - Xiuying Zhang
- Heilongjiang Key Laboratory for Animal Disease Control and Pharmaceutical Development. Faculty of Basic Veterinary Science, College of Veterinary Medicine, Northeast Agricultural University, 600 Changjiang Road, Xiangfang District, Harbin, PR China.
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Zhang W, Chen J, Liu L, Wang L, Liu J, Su D. Prognostic value of preoperative computed tomography in HBV-related hepatocellular carcinoma patients after curative resection. Onco Targets Ther 2019; 12:3791-3804. [PMID: 31190879 PMCID: PMC6529036 DOI: 10.2147/ott.s199136] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Accepted: 03/05/2019] [Indexed: 12/12/2022] Open
Abstract
Background: Preoperative treatments are considered for patients with worse outcome to improve overall survival and reduce tumor relapse. This study developed a prognostic risk estimation for patients with hepatitis B virus (HBV)-related solitary hepatocellular carcinoma after curative resection, including preoperative computed tomography (CT) signatures. Methods: Preoperative multiphasic CTs for 166 patients with operable HCC were performed in our hospital from 15 November 2013 through 15 May 2015. Follow-up information, until 5 June 2017, included: CT, pathological and clinical characteristics, and recurrence and metastases of HCC confirmed by pathological or radiological diagnosis. The parameters were analyzed by the Kaplan-Meier method and Cox proportional hazards regression analysis. Results: In multivariate analyses, overall survival was not significantly associated with any of the analyzed prognostic risk factors, but did show that the following were significant prognostic risk factors for disease-free survival: larger tumor size, positive radiogenomic venous invasion, non-smooth tumor margin, and histological microvascular invasion. These were all incorporated into the nomogram. The calibration curves for predicting the probability of disease-free survival between the nomogram and actual observation showed good conformity. Conclusion: In patients with HBV-related HCC, CT signatures were a noninvasive significant indicator of disease-free survival. Thus, consideration of CT signatures may optimize preoperative treatment strategies for the individual patient.
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Affiliation(s)
| | - Jie Chen
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Zhuang Autonomous Region, People's Republic of China
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Wang H, Liao P, Zeng SX, Lu H. It takes a team: a gain-of-function story of p53-R249S. J Mol Cell Biol 2019; 11:277-283. [PMID: 30608603 PMCID: PMC6487778 DOI: 10.1093/jmcb/mjy086] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2018] [Revised: 11/03/2018] [Accepted: 01/03/2019] [Indexed: 12/11/2022] Open
Abstract
Gain-of-function (GOF), the most malicious oncogenic activity of a cancer-promoting protein, is well illustrated to three hotspot p53 mutations at R248, R175, and R273 with distinct molecular mechanisms. Yet, less is known about another hotspot p53 mutant, R249S (p53-R249S). p53-R249S is the sole hotspot mutation in hepatocellular carcinoma (HCC) that is highly associated with chronic hepatitis B virus (HBV) infection and dietary exposure to aflatoxin B1 (AFB1). Its GOF is suggested by the facts that this mutant is associated with earlier onset of HCC and poorer prognosis of cancer patients and that its overexpression drives HCC proliferation and tumorigenesis. By contrast, simply knocking in this mutant in normal mice did not show apparent GOF activity. Hence, the GOF activity for p53-R249S and its underlying mechanisms have been elusive until recent findings offered some new insights. This review will discuss these findings as well as their clinical significance and implications for the development of a strategy to target multiple molecules as a therapy for p53-R249S-harboring HCC.
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Affiliation(s)
- Huai Wang
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
- School of Public Health, Nanchang University, Nanchang, China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, Nanchang University, Nanchang, China
| | - Peng Liao
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
| | - Shelya X Zeng
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
| | - Hua Lu
- Department of Biochemistry and Molecular Biology, Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA, USA
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Qi LN, Xiang BD, Wu FX, Ye JZ, Zhong JH, Wang YY, Chen YY, Chen ZS, Ma L, Chen J, Gong WF, Han ZG, Lu Y, Shang JJ, Li LQ. Circulating Tumor Cells Undergoing EMT Provide a Metric for Diagnosis and Prognosis of Patients with Hepatocellular Carcinoma. Cancer Res 2018; 78:4731-4744. [PMID: 29915159 DOI: 10.1158/0008-5472.can-17-2459] [Citation(s) in RCA: 206] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2017] [Revised: 03/21/2018] [Accepted: 06/12/2018] [Indexed: 12/13/2022]
Abstract
To clarify the significance of circulating tumor cells (CTC) undergoing epithelial-mesenchymal transition (EMT) in patients with hepatocellular carcinoma (HCC), we used an advanced CanPatrol CTC-enrichment technique and in situ hybridization to enrich and classify CTC from blood samples. One hundred and one of 112 (90.18%) patients with HCC were CTC positive, even with early-stage disease. CTCs were also detected in 2 of 12 patients with hepatitis B virus (HBV), both of whom had small HCC tumors detected within 5 months. CTC count ≥16 and mesenchymal-CTC (M-CTC) percentage ≥2% prior to resection were significantly associated with early recurrence, multi-intrahepatic recurrence, and lung metastasis. Postoperative CTC monitoring in 10 patients found that most had an increased CTC count and M-CTC percentage before clinically detectable recurrence nodules appeared. Analysis of HCC with high CTC count and high M-CTC percentage identified 67 differentially expressed cancer-related genes involved in cancer-related biological pathways (e.g., cell adhesion and migration, tumor angiogenesis, and apoptosis). One of the identified genes, BCAT1, was significantly upregulated, and knockdown in Hepg2, Hep3B, and Huh7 cells reduced cell proliferation, migration, and invasion while promoting apoptosis. A concomitant increase in epithelial marker expression (EpCAM and E-cadherin) and reduced mesenchymal marker expression (vimentin and Twist) suggest that BCAT1 may trigger the EMT process. Overall, CTCs were highly correlated with HCC characteristics, representing a novel marker for early diagnosis and a prognostic factor for early recurrence. BCAT1 overexpression may induce CTC release by triggering EMT and may be an important biomarker of HCC metastasis.Significance: In liver cancer, CTC examination may represent an important "liquid biopsy" tool to detect both early disease and recurrent or metastatic disease, providing cues for early intervention or adjuvant therapy. Cancer Res; 78(16); 4731-44. ©2018 AACR.
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Affiliation(s)
- Lu-Nan Qi
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology research center, Nanning, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, Guangxi Province, China
| | - Bang-De Xiang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology research center, Nanning, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, Guangxi Province, China
| | - Fei-Xiang Wu
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology research center, Nanning, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, Guangxi Province, China
| | - Jia-Zhou Ye
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Jian-Hong Zhong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Yan-Yan Wang
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Yuan-Yuan Chen
- Department of Ultrasound, First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Zu-Shun Chen
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Liang Ma
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Jie Chen
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Wen-Feng Gong
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Ze-Guang Han
- China National Human Genome Center at Shanghai, Shanghai, Shanghai City, China
| | - Yan Lu
- SurExam Bio-Tech, Guangzhou Technology Innovation Base, Science City, Guangzhou, Guangdong Province, China
| | - Jin-Jie Shang
- Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, Nanjing, Jiangsu Province, China
| | - Le-Qun Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi Province, China.
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology research center, Nanning, Guangxi Province, China
- Key Laboratory of Early Prevention and Treatment for Regional High Frequency Tumor, Ministry of Education, Nanning, Guangxi Province, China
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Ramalho LN, Porta LD, Rosim RE, Petta T, Augusto MJ, Silva DM, Ramalho FS, Oliveira CA. Aflatoxin B 1 residues in human livers and their relationship with markers of hepatic carcinogenesis in São Paulo, Brazil. Toxicol Rep 2018; 5:777-784. [PMID: 30101081 PMCID: PMC6082919 DOI: 10.1016/j.toxrep.2018.07.005] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 05/10/2018] [Accepted: 07/25/2018] [Indexed: 01/15/2023] Open
Abstract
In this study, hepatic biopsies from autopsy cases in São Paulo, Brazil, showing hepatocellular carcinoma (HCC, n = 8), cirrhosis associated with viral hepatitis (VC, n = 20), cirrhosis associated with alcoholism (AC, n = 20), and normal livers (NL or controls, n = 10) were subjected to determination of aflatoxin B1 (AFB1) and its main metabolites, and of markers of hepatic carcinogenesis Only non-metabolized AFB1 was detected in 13 samples (27.1%, N = 48) of liver disorders (HCC, VC and AC), at levels between 10.0 and 418.0 pg/g (mean: 76.6 ± 107.7 pg/g). Immuno-labeling of p53, cyclin D1, p21, β-catenin, and Prohibitin (PB) increased mainly in HCC patients, in relation to the controls. AFB1+ samples of HCC presented higher expressions of p53, cyclin D1, p21, and β-catenin compared with AFB1-livers. In contrast, p27, p16, and Rb immuno-labeling decreased in HCC, VC, and AC samples, compared with NL, with lowest values in AFB1+ samples for all liver disorders. Compared with NL, gene expression of cyclin D1 and PB in AFB1+ samples of HCC and AC were also higher, along with higher gene expression of p21 in VC and AC AFB1+ livers. Results indicated that patients with liver disorders were exposed to dietary aflatoxins, and that residual AFB1 in liver negatively affected the p53 and protein Rb pathways in HCC. Moreover, the presence of AFB1 in cirrhotic livers warrants concern about the potential contribution of dietary aflatoxin to disease progression during VC and AC.
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Affiliation(s)
- Leandra N.Z. Ramalho
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Livia D. Porta
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Roice E. Rosim
- Department of Food Engineering, School of Animal Science and Food Engineering, University of São Paulo, Av. Duque de Caxias – Norte, 225, CEP 13635-900, Pirassununga, SP, Brazil
| | - Tânia Petta
- Department of Biochemistry and Immunology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Marlei J. Augusto
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Deisy M. Silva
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Fernando S. Ramalho
- Department of Pathology, School of Medicine at Ribeirão Preto, University of São Paulo, Av. do Café, s/n, CEP 14040-903, Ribeirão Preto, SP, Brazil
| | - Carlos A.F. Oliveira
- Department of Food Engineering, School of Animal Science and Food Engineering, University of São Paulo, Av. Duque de Caxias – Norte, 225, CEP 13635-900, Pirassununga, SP, Brazil
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Ilic Z, Mondal TK, Guest I, Crawford DR, Sell S. Participation of liver stem cells in cholangiocarcinogenesis after aflatoxin B1 exposure of glutathione S-transferase A3 knockout mice. Tumour Biol 2018; 40:1010428318777344. [DOI: 10.1177/1010428318777344] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Aflatoxin B1, arguably the most potent human carcinogen, induces liver cancer in humans, rats, trout, ducks, and so on, but adult mice are totally resistant. This resistance is because of a detoxifying enzyme, mouse glutathione S-transferase A3, which binds to and inactivates aflatoxin B1 epoxide, preventing the epoxide from binding to DNA and causing mutations. Glutathione S-transferase A3 or its analog has not been detected in any of the sensitive species, including humans. The generation of a glutathione S-transferase A3 knockout (represented as KO or -/-) mice has allowed us to study the induction of liver cancer in mice by aflatoxin B1. In contrast to the induction of hepatocellular carcinomas in other species, aflatoxin B1 induces cholangiocarcinomas in GSTA3-/- mice. In other species and in knockout mice, the induction of liver cancer is preceded by extensive proliferation of small oval cells, providing additional evidence that oval cells are bipolar stem cells and may give rise to either hepatocellular carcinoma or cholangiocarcinoma depending on the nature of the hepatocarcinogen and the species of animal. The recent development of mouse oval cell lines in our laboratory from aflatoxin B1-treated GSTA3-/- mice should provide a new venue for study of the properties and potential of putative mouse liver stem cells.
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Affiliation(s)
- Zoran Ilic
- Wadsworth Center, New York State Department of Health, Albany, NY, USA
| | - Tapan K Mondal
- Wadsworth Center, New York State Department of Health, Albany, NY, USA
| | - Ian Guest
- Wadsworth Center, New York State Department of Health, Albany, NY, USA
| | | | - Stewart Sell
- Wadsworth Center, New York State Department of Health, Albany, NY, USA
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Liao X, Yu L, Liu X, Han C, Yu T, Qin W, Yang C, Zhu G, Su H, Peng T. Genome-wide association pathway analysis to identify candidate single nucleotide polymorphisms and molecular pathways associated with TP53 expression status in HBV-related hepatocellular carcinoma. Cancer Manag Res 2018; 10:953-967. [PMID: 29760565 PMCID: PMC5937480 DOI: 10.2147/cmar.s163209] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background The aim of this investigation was to identify candidate single nucleotide polymorphisms (SNPs) and molecular pathways associated with tumor protein p53 (TP53) expression status in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC), clarify their potential mechanisms, and generate SNP-to-gene to pathway hypothesis. Materials and methods Identify candidate Causal SNPs and Pathways (ICSNPathway) was used to perform pathway analysis based on the results of our previous genome-wide association study of TP53 expression status in 387 HBV-related HCC patients. Results Through the ICSNPathway analysis, we identified 18 candidate SNPs and 10 candidate pathways that are associated with TP53 expression status in HBV-related HCC. The strongest mechanism involved the modulation of major histocompatibility complex, class II, DP beta 1 (human leukocyte antigen [HLA]-DPB1-rs1042153), major histocompatibility complex, class II, DQ beta 1 (HLA-DQB1-rs1130399, HLA-DQB1-rs1049056, HLA-DQB1-rs1049059, and HLA-DQB1-rs1049060), and major histocompatibility complex, class II, DR beta 1 (HLA-DRB1-rs35445101). SNPs consequently affected regulatory roles in all the candidate pathways except hematopoietic cell lineage pathways. Association analysis using the GSE14520 data set, Gene Multiple Association Network Integration Algorithm, and Search Tool for the Retrieval of Interacting Genes/Proteins suggests that all genes of the candidate SNPs were associated with TP53. Survival analysis showed that the collagen type VI alpha 3 chain (COL6A3) rs111231885 and COL6A3-rs113155945 and COL6A3 block 4 CC haplotypes with TP53 negative status may have protective effects in HBV-related HCC patients after hepatectomy. Conclusion Our pathway analysis identified 18 candidate SNPs and 10 candidate pathways that were associated with TP53 expression status in HBV-related HCC. Among these candidate SNPs, the genetic variation of COL6A3 may be a potential prognostic biomarker of HBV-related HCC.
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Affiliation(s)
- Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Long Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Xiaoguang Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China.,Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, People's Republic of China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, People's Republic of China
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Liao X, Han C, Qin W, Liu X, Yu L, Zhu G, Yu T, Lu S, Su H, Liu Z, Chen Z, Yang C, Huang K, Liu Z, Liang Y, Huang J, Dong J, Li L, Qin X, Ye X, Xiao K, Peng M, Peng T. PLCE1 polymorphisms and expression combined with serum AFP level predicts survival of HBV-related hepatocellular carcinoma patients after hepatectomy. Oncotarget 2018; 8:29202-29219. [PMID: 28418898 PMCID: PMC5438724 DOI: 10.18632/oncotarget.16346] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2016] [Accepted: 02/22/2017] [Indexed: 12/17/2022] Open
Abstract
Polymorphisms in the phospholipase C epsilon (PLCE) 1 gene play a crucial role in the development and progression of several types of cancer. The present study investigated the prognostic significance of PLCE1 gene polymorphisms and expression combined with serum α-fetoprotein (AFP) level in hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Single nucleotide polymorphisms were genotyped by sequencing DNA isolated from surgically resected tumor samples of 421 HBV-related HCC patients, and expression profiles were generated based on the GSE14520 dataset. A joint-effects analysis of PLCE1 haplotypes (Ars2274223Crs3765524; Grs2274223Trs3765524) with AFP level stratified at 20 ng/ml showed a significant association with overall survival(OS) of HBV-related HCC patients(log-rank P=0.0003). Patients with AC and GT haplotypes with AFP level ≥ 20 ng/ml had an increased risk of death as compared to those with the AC haplotype and AFP level < 20 ng/ml (adjusted P=0.029 and 0.041, respectively). Patients with the GT haplotype and AFP level < 20 ng/ml also had an increased risk of death, although with a non-significant P value (adjusted P=0.092). Joint-effects analysis of PLCE1 mRNA expression with serum AFP level stratified at 300 ng/ml was significantly associated with HBV-related HCC recurrence and OS. Our results demonstrate that PLCE1 haplotypes (including rs2274223 and rs3765524) and expression combined with serum AFP level may predict postoperative outcome of HBV-related HCC patients.
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Affiliation(s)
- Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Xiaoguang Liu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, 524001, Guangdong Province, China
| | - Long Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450000, Henan Province, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Sicong Lu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Zhen Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Zhiwei Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Zhengtao Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Yu Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Jianlu Huang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Guangxi Medical University, Nanning 530031, Guangxi Province, China
| | - Jiahong Dong
- Department of Hepato-Biliary-Pancreatic Surgery, Beijing Tsinghua Changgung Hospital, Beijing, 102218, China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Xue Qin
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi Province, China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Kaiyin Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Minhao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Province, China
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Soler L, Oswald I. The importance of accounting for sex in the search of proteomic signatures of mycotoxin exposure. J Proteomics 2018; 178:114-122. [DOI: 10.1016/j.jprot.2017.12.017] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2017] [Revised: 12/18/2017] [Accepted: 12/22/2017] [Indexed: 10/18/2022]
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Liao P, Zeng SX, Zhou X, Chen T, Zhou F, Cao B, Jung JH, Del Sal G, Luo S, Lu H. Mutant p53 Gains Its Function via c-Myc Activation upon CDK4 Phosphorylation at Serine 249 and Consequent PIN1 Binding. Mol Cell 2017; 68:1134-1146.e6. [PMID: 29225033 PMCID: PMC6204219 DOI: 10.1016/j.molcel.2017.11.006] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Revised: 08/24/2017] [Accepted: 11/07/2017] [Indexed: 12/15/2022]
Abstract
TP53 missense mutations significantly influence the development and progression of various human cancers via their gain of new functions (GOF) through different mechanisms. Here we report a unique mechanism underlying the GOF of p53-R249S (p53-RS), a p53 mutant frequently detected in human hepatocellular carcinoma (HCC) that is highly related to hepatitis B infection and aflatoxin B1. A CDK inhibitor blocks p53-RS's nuclear translocation in HCC, whereas CDK4 interacts with p53-RS in the G1/S phase of the cells, phosphorylates it, and enhances its nuclear localization. This is coupled with binding of a peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1) to p53-RS, but not the p53 form with mutations of four serines/threonines previously shown to be crucial for PIN1 binding. As a result, p53-RS interacts with c-Myc and enhances c-Myc-dependent rDNA transcription key for ribosomal biogenesis. These results unveil a CDK4-PIN1-p53-RS-c-Myc pathway as a novel mechanism for the GOF of p53-RS in HCC.
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Affiliation(s)
- Peng Liao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Shelya X Zeng
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Xiang Zhou
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Tianjian Chen
- Haywood Genetics Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Fen Zhou
- Center for Experimental Medicine, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Bo Cao
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Ji Hoon Jung
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Giannino Del Sal
- Laboratorio Nazionale CIB, Area Science Park Padriciano and Dipartimento di Scienze della Vita, Università degli Studi di Trieste, Trieste, Italy
| | - Shiwen Luo
- Center for Experimental Medicine, First Affiliated Hospital of Nanchang University, Nanchang, China
| | - Hua Lu
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, New Orleans, LA 70112, USA; Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA.
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42
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The mitochondrial and death receptor pathways involved in the thymocytes apoptosis induced by aflatoxin B1. Oncotarget 2017; 7:12222-34. [PMID: 26933817 PMCID: PMC4914280 DOI: 10.18632/oncotarget.7731] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Accepted: 02/05/2016] [Indexed: 01/05/2023] Open
Abstract
Aflatoxin B1 (AFB1) is a potent immunosuppressive agent in endotherms, which can be related to the up-regulated apoptosis of immune organs. In this study, we investigated the roles of the mitochondrial, death receptor, and endoplasmic reticulum pathways in Aflatoxin B1 induced thymocytes apoptosis. Chickens were fed an aflatoxin B1 containing diet (0.6 mg/kg AFB1) for 3 weeks. Our results showed that (1) AFB1 diet induced the decrease of T-cell subsets, morphological changes, and excessive apoptosis of thymus. (2) The excessive apoptosis involved the mitochondrial pathway (up-regulation of Bax, Bak, cytC and down-regulation of Bcl-2 and Bcl-xL) and death receptor pathway (up-regulation of FasL, Fas and FADD). (3) Oxidative stress, an apoptosis inducer, was confirmed in the thymus. In conclusion, this is the first study to demonstrate that mitochondrial and death receptor pathways involved in AFB1 induced thymocytes apoptosis in broilers.
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43
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Xiang X, Qin H, You X, Wang Y, Qi L, Ma L, Xiang B, Zhong J, Li L. Expression of P62 in hepatocellular carcinoma involving hepatitis B virus infection and aflatoxin B1 exposure. Cancer Med 2017; 6:2357-2369. [PMID: 28941211 PMCID: PMC5633547 DOI: 10.1002/cam4.1176] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2017] [Revised: 07/23/2017] [Accepted: 08/04/2017] [Indexed: 01/27/2023] Open
Abstract
This study aims to clarify the relationship and mechanism between expression of autophagy-related protein P62 and prognosis of patients with hepatocellular carcinoma (HCC) involving chronic hepatitis B virus (HBV) infection and aflatoxin B1 (AFB1) exposure. HCC patients who underwent resection were divided into three groups: HBV(+)/AFB1(+) (n = 26), HBV(+)/AFB1(-) (n = 68), and HBV(-)/AFB1(-) (n = 14). The groups were compared in terms of mRNA and protein levels of P62, disease-free survival (DFS), and overall survival (OS) and the expression of NRF2, Nqo1, and AKR7A3 in P62 high-expression and low-expression group. HBV(+)/AFB1(+) group has lower DFS and OS, and higher P62 expression than in the other two groups. P62 expression generally correlated with elevated NRF2 and Nqo1 expression, and reduced AKR7A3 expression. Patients expressing high levels of P62 showed significantly lower DFS and OS rates than patients expressing low levels. HCC involving HBV infection and AFB1 exposure is associated with relatively high risk of tumor recurrence, and this poor prognosis may relate to high P62 expression. High P62 expression activates the NRF2 pathway, promotes tumor recurrence. The downregulation of AKR7A3 also reduced liver detoxification of aflatoxin B1.
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Affiliation(s)
- Xiao Xiang
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
| | - Hong‐Gui Qin
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
| | - Xue‐Mei You
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Yan‐Yan Wang
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
| | - Lu‐Nan Qi
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Liang Ma
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Bang‐De Xiang
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Jian‐Hong Zhong
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
| | - Le‐Qun Li
- Department of Hepatobiliary SurgeryAffiliated Tumor Hospital of Guangxi Medical UniversityGuangxi Cancer InstituteHospital Oncology SchoolGuangxi Cancer CenterNanning530021China
- Guangxi Liver Cancer Diagnosis and Treatment Engineering and Technology Research CenterNanning530021China
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44
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Liu X, Xu J, Wang S, Yu X, Kou B, Chai M, Zang Y, Chen D. Synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 and oxaliplatin via p53-independent pathway in vitro and in vivo. Int J Oncol 2017; 51:1291-1299. [PMID: 28902369 DOI: 10.3892/ijo.2017.4105] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2017] [Accepted: 07/26/2017] [Indexed: 11/06/2022] Open
Abstract
The present study was designed to investigate the synergistic inhibitory effects on hepatocellular carcinoma with recombinant human adenovirus Aspp2 (Aspp2-ad) and oxaliplatin via p53-independent pathway in vitro and in vivo. After being treated with Aspp2-ad and/or oxaliplatin for 24-48 h, HepG2P53-/- and Hep3B cells showed a significant growth inhibition compared with vehicle control. Combination group showed a synergetic effect, the inhibitory rates were all above 80% at 48 h point in HepG2P53-/- and Hep3B cells. The apoptotic cell numbers of Aspp2-ad and/or oxaliplatin treatment groups were increased remarkably, especially for the combined therapy group in the liver cancer cells. The Hep3B xenograft experiment also showed similar inhibition of Aspp2-ad and/or oxaliplatin to the in vitro experiment. H&E results showed that combination group had the least mitotic indexes and the most necrosis. The immunohistochemistry results showed that PCNA, CD31 expression decreased greatly in treatment groups. These results suggested that Aspp2-ad might inhibit proliferation and vascular growth of hepatocarcinoma. Aspp2 induced apoptosis protein expression in Aspp2-ad and combination groups, the Aspp2, Bax and activation of caspase-3 expression increased greatly both in vitro and in vivo. But interestingly, the autophagy proteins showed different responses not only in HepG2P53-/- and Hep3B cells but also in vitro and in vivo. We found that Aspp2-ad downregulated the p-ERK, p-STAT3 expression, the synergistic effects were observed in combination group, while there was not response of mTOR to Aspp2-ad. In conclusion, Aspp2-ad, in P53-independent manner, regulated ERK and STAT3 signal moleculars to inhibit hepatocarcinoma in coordination with oxaliplatin by influencing the protein expression of proliferation, apoptosis, autophagy and vascular growth. Aspp2-ad has the potential to be developed in gene therapy for HCC, especially for P53 deletion or mutation in HCC.
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Affiliation(s)
- Xiaoni Liu
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Jianji Xu
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Shuang Wang
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Xiaoxiao Yu
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Boxin Kou
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Mengyin Chai
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Yunjin Zang
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
| | - Dexi Chen
- Beijing Institute of Hepatology and Beijing YouAn Hospital, Capital Medical University, Beijing 100069, P.R. China
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45
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Zhu G, Liao X, Han C, Liu X, Yu L, Qin W, Lu S, Su H, Chen Z, Liu Z, Liang Y, Huang J, Yu T, Yang C, Huang K, Shang L, Ye X, Li L, Qin X, Xiao K, Peng M, Peng T. ALDH1L1 variant rs2276724 and mRNA expression predict post-operative clinical outcomes and are associated with TP53 expression in HBV-related hepatocellular carcinoma. Oncol Rep 2017; 38:1451-1463. [PMID: 28714006 PMCID: PMC5549030 DOI: 10.3892/or.2017.5822] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2016] [Accepted: 06/29/2017] [Indexed: 12/24/2022] Open
Abstract
Aldehyde dehydrogenase 1 family member L1 (ALDH1L1) is downregulated in hepatocellular carcinoma (HCC) tumors, and its decreased expression is associated with the poor prognosis of HCC patients. We, therefore, evaluated the effect of single nucleotide polymorphisms (SNPs) of ALDH1L1, and its mRNA expression on the survival of hepatitis B virus (HBV)-related HCC patients and the association with tumor protein p53 (TP53) expression. ALDH1L1 SNPs in 415 HBV-related HCC patients were genotyped via direct sequencing. Expression profile chip datasets and survival information were obtained from GSE14520. The C allele (CT/CC) carriers of rs2276724 were significantly associated with a favorable prognosis [adjusted P=0.040; adjusted hazard ratio (HR)=0.725; 95% confidence interval (CI)=0.533–0.986]. Joint-effect analyses suggested that the CT/CC genotype of rs2276724 in TP53-negative patients was significantly associated with a decreased risk of death, compared to the TT genotype of rs2276724 in TP53-positive patients (adjusted P=0.037; adjusted HR=0.621; 95% CI=0.396–0.973). Furthermore, low expression of ALDH1L1 predicted a poor prognosis for the HBV-related HCC patients (adjusted P=0.04 for disease-free survival; adjusted P=0.001 for overall survival). Patients with high ALDH1L1 expression and low TP53 expression were significantly associated with a decreased risk of recurrence and death, and patients with a high TP53 expression were also significantly associated with a decreased risk of death in HBV-related HCC, compared with low ALDH1L1 and low TP53 expression. Our results suggest that ALDH1L1 may be a biomarker for predicting postoperative clinical outcomes. Moreover, ALDH1L1-rs2276724 and mRNA expression were associated with TP53 expression in HBV-related HCC patients.
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Affiliation(s)
- Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xiaoguang Liu
- Department of Hepatobiliary Surgery, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, P.R. China
| | - Long Yu
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450000, P.R. China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Sicong Lu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Zhiwei Chen
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Zhengtao Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Yu Liang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Jianlu Huang
- Department of Hepatobiliary Surgery, The Third Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530031, P.R. China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Ketuan Huang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Liming Shang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xinping Ye
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Xue Qin
- Department of Clinical Laboratory, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Kaiyin Xiao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Minhao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi 530021, P.R. China
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46
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Liu W, Wang L, Yang X, Zeng H, Zhang R, Pu C, Zheng C, Tan Y, Luo Y, Feng X, Tian Y, Xiao G, Wang J, Huang Y, Luo J, Feng L, Wang F, Yuan C, Yao Y, Qiu Z, Chen JA, Wu L, Nong Q, Lin H, Shu W. Environmental Microcystin Exposure Increases Liver Injury Risk Induced by Hepatitis B Virus Combined with Aflatoxin: A Cross-Sectional Study in Southwest China. ENVIRONMENTAL SCIENCE & TECHNOLOGY 2017; 51:6367-6378. [PMID: 28467052 DOI: 10.1021/acs.est.6b05404] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
Three liver hazards, two confirmed-hepatitis B virus (HBV) and aflatoxin (AFB), and one rarely studied in populations-microcystin (MC), simultaneously exist in tropical and humid areas; however, there are no epidemiological data on their risks in the same population. We conducted a community-based cross-sectional survey among 5493 adults in two rural towns and statistically analyzed the comparative and combinative effects of the three factors after detecting HBsAg and HBV DNA titers, determining estimated daily intakes (EDIs) of AFB1 and MC-LR and testing serum AST and ALT as liver injury markers for each participant. We observed a HBsAg(+) rate of 7.6%, a relatively high AFB1 exposure level (mean EDIAFB1 = 471.30 ng/d), and a relatively low MC-LR exposure level (mean EDIMC-LR = 228.25 ng/d). ORs for abnormal AST (2.42, 95%CI = 1.69-3.45) and ALT (2.87, 95%CI = 1.91-4.29) increased in HBV infections compared with HBV-unexposed participants but did not increase in participants with separate or combined exposure to AFB1 and MC-LR (EDIs ≥ mean). Meanwhile, after adjustment for confounding factors, means of AST and ALT and ORs of abnormal AST and ALT were successively elevated after exposure to HBV, HBV&AFB1 (or HBV&MC-LR), and HBV&AFB1&MC-LR, especially in the group with detectable HBV DNA (AST: OR = 11.38, 95%CI = 3.91-33.17; ALT: OR = 17.09, 95%CI = 5.36-54.53). Notably, ORs for abnormal AST and ALT in the HBV exposed group were not significantly different from those in HBV&AFB1 or in the HBV&MC-LR exposed group but were significantly higher in the HBV&AFB1&MC-LR exposed group (P = 0.029 and P = 0.037, respectively). Our study indicated that microcystin may have the potential to increase the risk of liver injury induced by combined exposure to HBV and aflatoxin. However, in consideration of the uncertainties in the detection of the toxins and evaluation of the EDIs, more epidemiological data are expected to determine the increasing toxic effects of microcystins.
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Affiliation(s)
| | | | | | | | - Renping Zhang
- The Center for Disease Control and Prevention in Fuling District, Chongqing 408000, China
| | - Chaowen Pu
- The Center for Disease Control and Prevention in Fuling District, Chongqing 408000, China
| | | | | | | | | | - Yingqiao Tian
- The Center for Disease Control and Prevention in Fuling District, Chongqing 408000, China
| | - Guosheng Xiao
- College of Life Science and Engineering, Chongqing Three Gorges University , Wanzhou, Chongqing 404100, China
| | | | | | | | - Lei Feng
- The Center for Disease Control and Prevention in Fuling District, Chongqing 408000, China
| | - Feng Wang
- The Township Central Hospital in Yihe Town, Fuling District, Chongqing 408104, China
| | - Changyou Yuan
- The Community Health Service Center in Lidu Town, Fuling District, Chongqing 408103, China
| | | | | | | | | | - Qingqing Nong
- Department of Environmental Health, School of Public Health, Guangxi Medical University , Nanning, Guangxi 530021, China
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47
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Liu X, Wang S, Guo X, Wei F, Yin J, Zang Y, Li N, Chen D. Exogenous p53 and ASPP2 expression enhances rAdV-TK/ GCV-induced death in hepatocellular carcinoma cells lacking functional p53. Oncotarget 2017; 7:18896-905. [PMID: 26934443 PMCID: PMC4951338 DOI: 10.18632/oncotarget.7749] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2015] [Accepted: 01/13/2016] [Indexed: 12/13/2022] Open
Abstract
Suicide gene therapy using herpes simplex virus-1 thymidine kinase (HSV-TK) in combination with ganciclovir (GCV) has emerged as a potential new method for treating cancer. We hypothesize that the efficacy of HSV-TK/GCV therapy is at least partially dependent on p53 status in hepatocellular carcinoma (HCC) patients. Using recombinant adenoviral vectors (rAdV), TK, p53, and ASPP2 were overexpressed individually and in combination in Hep3B (p53 null) and HepG2 (p53 wild-type) cell lines and in primary HCC tumor cells. p53 overexpression induced death in Hep3B cells, but not HepG2 cells. ASPP2 overexpression increased rAdV-TK/GCV-induced HepG2 cell death by interacting with endogenous p53. Similarly, ASPP2 reduced survival in rAdV-TK/GCV-treated primary HCC cells expressing p53 wild-type but not a p53 R249S mutant. Mutated p53 was unable to bind to ASPP2, suggesting that the increase in rAdV-TK/GCV-induced cell death resulting from ASPP2 overexpression was dependent on its interaction with p53. Additionally, γ-H2AX foci, ATM phosphorylation, Bax, and p21 expression increased in rAdV-TK/GCV-treated HepG2 cells as compared to Hep3B cells. This suggests that the combined use of HSV-TK, GCV, rAdV-p53 and rAdV-ASPP2 may improve therapeutic efficacy in HCC patients lacking functional p53.
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Affiliation(s)
- Xiuhong Liu
- Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China.,Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China
| | - Shuang Wang
- Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China.,Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China
| | - Xianghua Guo
- Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China
| | - Feili Wei
- Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China
| | - Jiming Yin
- Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China
| | - Yunjin Zang
- Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China
| | - Ning Li
- Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China
| | - Dexi Chen
- Beijing You'an Hospital Affiliated with Capital Medical University, Beijing 100069, China.,Beijing Institute of Hepatology, Capital Medical University, Beijing 100069, China
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48
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Zheng H, Yang Y, Han J, Jiang WH, Chen C, Wang MC, Gao R, Li S, Tian T, Wang J, Ma LJ, Ren H, Zhou WP. TMED3 promotes hepatocellular carcinoma progression via IL-11/STAT3 signaling. Sci Rep 2016; 6:37070. [PMID: 27901021 PMCID: PMC5128793 DOI: 10.1038/srep37070] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
Transmembrane p24 trafficking protein 3(TMED3) is a metastatic suppressor in colon cancer, but its function in the progression of hepatocellular carcinoma (HCC) is unknown. Here, we report that TMED3 was up-regulated in HCC and portal vein tumor thrombus. TMED3 up-regulation in HCC was significantly correlated with aggressive characteristics and predicted poor prognosis in HCC patients. TMED3 overexpression in HCC cell lines promoted cell migration and invasion. In contrast, TMED3 knockdown suppressed HCC metastasis both in vitro and in vivo. Gene microarray analysis revealed decreased IL-11 expression in TMED3-knockdown cells. We propose that TMED3 promotes HCC metastasis through IL-11/STAT3 signaling. Taken together, these findings demonstrate that TMED3 promotes HCC metastasis and is a potential prognostic biomarker in HCC.
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Affiliation(s)
- Hao Zheng
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Yuan Yang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.,Department of Health Statistics, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Jun Han
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China.,Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Wei-Hua Jiang
- Department of Oncology, Shanghai Tongren Hospital, Shanghai Jiaotong University, 1111 Xianxia Road, Shanghai 200336, China
| | - Cheng Chen
- Department of Medical Oncology, Jinling Hospital, 305 Zhongshan East Road, Nanjing, Jiangsu 210000, China
| | - Meng-Chao Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Rong Gao
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Shuai Li
- Department of Computer Science, Rensselaer Polytechnic Institute, 110 8th Street, Troy, NY, 12180, United States
| | - Tao Tian
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Jian Wang
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
| | - Li-Jun Ma
- Department of Oncology, Shanghai Tongren Hospital, Shanghai Jiaotong University, 1111 Xianxia Road, Shanghai 200336, China
| | - Hao Ren
- Department of Microbiology, Shanghai Key Laboratory of Medical Biodefense, Second Military Medical University, 800 Xiangyin Road, Shanghai 200433, China
| | - Wei-Ping Zhou
- The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, 225 Changhai Road, Shanghai 200438, China
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49
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Niu ZS, Niu XJ, Wang WH. Genetic alterations in hepatocellular carcinoma: An update. World J Gastroenterol 2016; 22:9069-9095. [PMID: 27895396 PMCID: PMC5107590 DOI: 10.3748/wjg.v22.i41.9069] [Citation(s) in RCA: 122] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Revised: 09/20/2016] [Accepted: 10/19/2016] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Although recent advances in therapeutic approaches for treating HCC have improved the prognoses of patients with HCC, this cancer is still associated with a poor survival rate mainly due to late diagnosis. Therefore, a diagnosis must be made sufficiently early to perform curative and effective treatments. There is a need for a deeper understanding of the molecular mechanisms underlying the initiation and progression of HCC because these mechanisms are critical for making early diagnoses and developing novel therapeutic strategies. Over the past decade, much progress has been made in elucidating the molecular mechanisms underlying hepatocarcinogenesis. In particular, recent advances in next-generation sequencing technologies have revealed numerous genetic alterations, including recurrently mutated genes and dysregulated signaling pathways in HCC. A better understanding of the genetic alterations in HCC could contribute to identifying potential driver mutations and discovering novel therapeutic targets in the future. In this article, we summarize the current advances in research on the genetic alterations, including genomic instability, single-nucleotide polymorphisms, somatic mutations and deregulated signaling pathways, implicated in the initiation and progression of HCC. We also attempt to elucidate some of the genetic mechanisms that contribute to making early diagnoses of and developing molecularly targeted therapies for HCC.
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MESH Headings
- Animals
- Biomarkers, Tumor/genetics
- Biomarkers, Tumor/metabolism
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Gene Expression Regulation, Neoplastic
- Genetic Predisposition to Disease
- Genomic Instability
- Humans
- Liver Neoplasms/drug therapy
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Molecular Diagnostic Techniques
- Molecular Targeted Therapy
- Mutation
- Patient Selection
- Phenotype
- Polymorphism, Single Nucleotide
- Precision Medicine
- Predictive Value of Tests
- Signal Transduction
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50
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Liu J, Li W, Deng M, Liu D, Ma Q, Feng X. Immunohistochemical Determination of p53 Protein Overexpression for Predicting p53 Gene Mutations in Hepatocellular Carcinoma: A Meta-Analysis. PLoS One 2016; 11:e0159636. [PMID: 27428001 PMCID: PMC4948819 DOI: 10.1371/journal.pone.0159636] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2016] [Accepted: 07/06/2016] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Whether increased expression of the tumor suppressor protein p53 indicates a p53 gene mutation in hepatocellular carcinoma (HCC) remains unclear. We conducted a meta-analysis to determine whether p53 protein overexpression detected by immunohistochemistry (IHC) offers a diagnostic prediction for p53 gene mutations in HCC patients. METHODS Systematic literature searches were conducted with an end date of December 2015. A meta-analysis was performed to estimate the diagnostic accuracy of IHC-determined p53 protein overexpression in the prediction of p53 gene mutations in HCC. Sensitivity, subgroup, and publication bias analyses were also conducted. RESULTS Thirty-six studies were included in the meta-analysis. The results showed that the overall sensitivity and specificity for IHC-determined p53 overexpression in the diagnostic prediction of p53 mutations in HCC were 0.83 (95% CI: 0.80-0.86) and 0.74 (95% CI: 0.71-0.76), respectively. The summary positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were 2.65 (95% CI: 2.21-3.18) and 0.36 (95% CI: 0.26-0.50), respectively. The diagnostic odds ratio (DOR) of IHC-determined p53 overexpression in predicting p53 mutations ranged from 0.56 to 105.00 (pooled, 9.77; 95% CI: 6.35-15.02), with significant heterogeneity between the included studies (I2 = 40.7%, P = 0.0067). Moreover, subgroup and sensitivity analyses did not alter the results of the meta-analysis. However, potential publication bias was present in the current meta-analysis. CONCLUSION The upregulation of the tumor suppressor protein p53 was indeed linked to p53 gene mutations. IHC determination of p53 overexpression can predict p53 gene mutations in HCC patients.
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Affiliation(s)
- Jiangbo Liu
- Department of General Surgery, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, PR China
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, PR China
- * E-mail: (JL); (XF)
| | - Wei Li
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, PR China
| | - Miao Deng
- Department of General Surgery, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, PR China
| | - Dechun Liu
- Department of General Surgery, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, PR China
| | - Qingyong Ma
- Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, PR China
| | - Xiaoshan Feng
- Henan Key Laboratory of Cancer Epigenetics, Cancer Institute, First Affiliated Hospital, College of Clinical Medicine, Henan University of Science and Technology, Luoyang, Henan, PR China
- * E-mail: (JL); (XF)
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