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1
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Gan CJ, Zheng Y, Yang B, Cao LM. Comprehensive prognostic and immune analysis of sterol O-acyltransferase 1 in patients with hepatocellular carcinoma. World J Hepatol 2024; 16:439-451. [PMID: 38577529 PMCID: PMC10989313 DOI: 10.4254/wjh.v16.i3.439] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 12/22/2023] [Accepted: 02/18/2024] [Indexed: 03/27/2024] Open
Abstract
BACKGROUND Sterol O-acyltransferase 1 (SOAT1) is an important target in the diagnosis and treatment of liver cancer. However, the prognostic value of SOAT1 in patients with hepatocellular carcinoma (HCC) is still not clear. AIM To investigate the correlation of SOAT1 expression with HCC, using RNA-seq and gene expression data of The Cancer Genome Atlas (TCGA)-liver hepatocellular carcinoma (LIHC) and pan-cancer. METHODS The correlation between SOAT1 expression and HCC was analyzed. Cox hazard regression models were conducted to investigate the prognostic value of SOAT1 in HCC. Overall survival and disease-specific survival were explored based on TCGA-LIHC data. Biological processes and functional pathways mediated by SOAT1 were characterized by gene ontology (GO) analysis and the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of differentially expressed genes. In addition, the protein-protein interaction network and co-expression analyses of SOAT1 in HCC were performed to better understand the regulatory mechanisms of SOAT1 in this malignancy. RESULTS SOAT1 and SOAT2 were highly expressed in unpaired samples, while only SOAT1 was highly expressed in paired samples. The area under the receiver operating characteristic curve of SOAT1 expression in tumor samples from LIHC patients compared with para-carcinoma tissues was 0.748, while the area under the curve of SOAT1 expression in tumor samples from LIHC patients compared with GTEx was 0.676. Patients with higher SOAT1 expression had lower survival rates. Results from GO/KEGG and gene set enrichment analyses suggested that the PI3K/AKT signaling pathway, the IL-18 signaling pathway, the calcium signaling pathway, secreted factors, the Wnt signaling pathway, the Jak/STAT signaling pathway, the MAPK family signaling pathway, and cell-cell communication were involved in such association. SOAT1 expression was positively associated with the abundance of macrophages, Th2 cells, T helper cells, CD56bright natural killer cells, and Th1 cells, and negatively linked to the abundance of Th17 cells, dendritic cells, and cytotoxic cells. CONCLUSION Our findings demonstrate that SOAT1 may serve as a novel target for HCC treatment, which is helpful for the development of new strategies for immunotherapy and metabolic therapy.
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Affiliation(s)
- Chang-Jiao Gan
- Development Research Department, National Medical Products Administration Institute of Executive Development, Beijing 100071, China
| | - Yue Zheng
- School of Medicine, Nankai University Affiliated Third Center Hospital, Tianjin 300070, China
| | - Bin Yang
- Tianjin Institute of Hepatobiliary Disease, The Third Central Hospital of Tianjin, Tianjin 300170, China
| | - Li-Min Cao
- Department of Science and Technology, Tianjin Third Central Hospital, Tianjin 300170, China.
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He XL, Guo HJ, Lei YR, Li J, Li JY, Li MH, Li N, Wang F, Mo CF. NAMPT promotes the malignant progression of HBV-associated hepatocellular carcinoma through activation of SREBP1-mediated lipogenesis. FASEB J 2024; 38:e23444. [PMID: 38252081 DOI: 10.1096/fj.202300070rrr] [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: 01/14/2023] [Revised: 12/26/2023] [Accepted: 01/09/2024] [Indexed: 01/23/2024]
Abstract
Metabolic reprogramming is a hallmark of cancer. The nicotinamide phosphoribosyltransferase (NAMPT)-mediated salvage pathway maintains sufficient cellular NAD levels and is required for tumorigenesis and development. However, the molecular mechanism by which NAMPT contributes to HBV-associated hepatocellular carcinoma (HCC) remains not fully understood. In the present study, our results showed that NAMPT protein was obviously upregulated in HBV-positive HCC tissues compared with HBV-negative HCC tissues. NAMPT was positively associated with aggressive HCC phenotypes and poor prognosis in HBV-positive HCC patients. NAMPT overexpression strengthened the proliferative, migratory, and invasive capacities of HBV-associated HCC cells, while NAMPT-insufficient HCC cells exhibited decreased growth and mobility. Mechanistically, we demonstrated that NAMPT activated SREBP1 (sterol regulatory element-binding protein 1) by increasing the expression and nuclear translocation of SREBP1, leading to the transcription of SREBP1 downstream lipogenesis-related genes and the production of intracellular lipids and cholesterol. Altogether, our data uncovered an important molecular mechanism by which NAMPT promoted HBV-induced HCC progression through the activation of SREBP1-triggered lipid metabolism reprogramming and suggested NAMPT as a promising prognostic biomarker and therapeutic target for HBV-associated HCC patients.
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Affiliation(s)
- Xian-Lu He
- Department of General Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
| | - Hui-Jie Guo
- Department of General Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Ya-Ruo Lei
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Jun Li
- Department of Gastroenterology, First Affiliated Hospital of Chengdu Medical College, Chengdu, China
| | - Jing-Yi Li
- The Second Affiliated Hospital of Chengdu Medical College Nuclear Industry 416 Hospital, Chengdu, China
| | - Min-Hui Li
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Na Li
- School of Public Health, Chengdu Medical College, Chengdu, China
| | - Fei Wang
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
| | - Chun-Fen Mo
- Department of General Surgery, Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, China
- Department of Immunology, School of Basic Medical Sciences, Chengdu Medical College, Chengdu, China
- Development and Regeneration Key Laboratory of Sichuan Province, Chengdu Medical College, Chengdu, China
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Lu Y, Yang X, Kuang Q, Wu Y, Tan X, Lan J, Qiang Z, Feng T. HBx induced upregulation of FATP2 promotes the development of hepatic lipid accumulation. Exp Cell Res 2023; 430:113721. [PMID: 37437769 DOI: 10.1016/j.yexcr.2023.113721] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2023] [Revised: 07/05/2023] [Accepted: 07/09/2023] [Indexed: 07/14/2023]
Abstract
The hepatitis B Virus X (HBx) protein plays a crucial role in the HBV-induced hepatic steatosis. Fatty acid transport protein 2 (FATP2) is a key protein that is involved in hepatic lipogenesis, and it was found to be highly expressed in various metabolic diseases. However, Whether FATP2 is a key factor in the pathogenesis of HBx-induced hepatic steatosis remains unclear. In this study, we found that FATP2 was up-regulated by HBx in vitro and in vivo and participated in HBx-induced hepatic lipid accumulation. Treatment of HBx-expressing cell lines and mice with FATP2 inhibitor (FATP2i) lipofermata ameliorated HBx-induced lipid accumulation and reduced oxidative stress and inflammation caused by lipid accumulation. Moreover, the liver injury of mouse was restored after FATP2i treatment. In summary, our results reveal that FATP2 is a key driver factor for HBx-induced hepatic lipid accumulation, and inhibition of FATP2 can ameliorates lipid accumulation caused by HBx. This study provides new insights into the mechanism of HBV-induced hepatic steatosis.
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Affiliation(s)
- Yang Lu
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, China
| | - Xinyue Yang
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, China
| | - Qin Kuang
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, China
| | - Yong Wu
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, China
| | - Xin Tan
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, China
| | - Jizhong Lan
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Key Laboratory of Biochemistry and Molecular Pharmacology of Chongqing, Chongqing Medical University, Chongqing, 400016, China
| | - Zhe Qiang
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Chongqing Academy of Chinese Materia Medica, Chongqing, 400065, China.
| | - Tao Feng
- College of Pharmacy, Chongqing Medical University, Chongqing, 400016, China; Molecular Medicine and Cancer Research Center, Chongqing Medical University, Chongqing, 400016, China.
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Zhang W, Zhao Y, He Q, Lang R. Therapeutically targeting essential metabolites to improve immunometabolism manipulation after liver transplantation for hepatocellular carcinoma. Front Immunol 2023; 14:1211126. [PMID: 37492564 PMCID: PMC10363744 DOI: 10.3389/fimmu.2023.1211126] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Accepted: 06/26/2023] [Indexed: 07/27/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most prevalent primary liver malignancy worldwide and is associated with a poor prognosis. Sophisticated molecular mechanisms and biological characteristics need to be explored to gain a better understanding of HCC. The role of metabolites in cancer immunometabolism has been widely recognized as a hallmark of cancer in the tumor microenvironment (TME). Recent studies have focused on metabolites that are derived from carbohydrate, lipid, and protein metabolism, because alterations in these may contribute to HCC progression, ischemia-reperfusion (IR) injury during liver transplantation (LT), and post-LT rejection. Immune cells play a central role in the HCC microenvironment and the duration of IR or rejection. They shape immune responses through metabolite modifications and by engaging in complex crosstalk with tumor cells. A growing number of publications suggest that immune cell functions in the TME are closely linked to metabolic changes. In this review, we summarize recent findings on the primary metabolites in the TME and post-LT metabolism and relate these studies to HCC development, IR injury, and post-LT rejection. Our understanding of aberrant metabolism and metabolite targeting based on regulatory metabolic pathways may provide a novel strategy to enhance immunometabolism manipulation by reprogramming cell metabolism.
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Affiliation(s)
- Wenhui Zhang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Yu Zhao
- Department of Urology Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Qiang He
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
| | - Ren Lang
- Department of Hepatobiliary Surgery, Beijing Chao-Yang Hospital Affiliated to Capital Medical University, Beijing, China
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5
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Gong Z, Yan Z, Liu W, Luo B. Oncogenic viruses and host lipid metabolism: a new perspective. J Gen Virol 2023; 104. [PMID: 37279154 DOI: 10.1099/jgv.0.001861] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/08/2023] Open
Abstract
As noncellular organisms, viruses do not have their own metabolism and rely on the metabolism of host cells to provide energy and metabolic substances for their life cycles. Increasing evidence suggests that host cells infected with oncogenic viruses have dramatically altered metabolic requirements and that oncogenic viruses produce substances used for viral replication and virion production by altering host cell metabolism. We focused on the processes by which oncogenic viruses manipulate host lipid metabolism and the lipid metabolism disorders that occur in oncogenic virus-associated diseases. A deeper understanding of viral infections that cause changes in host lipid metabolism could help with the development of new antiviral agents as well as potential new therapeutic targets.
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Affiliation(s)
- Zhiyuan Gong
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Zhiyong Yan
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Wen Liu
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
| | - Bing Luo
- Department of Pathogenic Biology, School of Basic Medicine, Qingdao University, Qingdao 266071, PR China
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6
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Lan W, Wang Y, Zhou Z, Sun X, Zhang Y, Zhang F. Metabolic Regulation of Hepatitis B Virus Infection in HBV-Transgenic Mice. Metabolites 2022; 12:287. [PMID: 35448475 PMCID: PMC9031567 DOI: 10.3390/metabo12040287] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/17/2022] [Accepted: 03/23/2022] [Indexed: 11/20/2022] Open
Abstract
Hepatitis B virus (HBV) infection is a worldwide health burden. Metabolomics analysis has revealed HBV-induced metabolism dysregulation in liver tissues and hepatocytes. However, as an infectious disease, the tissue-specific landscape of metabolic profiles of HBV infection remains unclear. To fill this gap, we applied untargeted nuclear magnetic resonance (NMR) metabolomic analysis of the heart, liver, spleen, lung, kidney, pancreas, and intestine (duodenum, jejunum, ileum) in HBV-transgenic mice and their wild-type littermates. Strikingly, we found systemic metabolic alterations induced by HBV in liver and extrahepatic organs. Significant changes in metabolites have been observed in most tissues of HBV-transgenic mice, except for ileum. The metabolic changes may provide novel therapeutic targets for the treatment of HBV infection. Moreover, tissue-specific metabolic profiles could speed up the study of HBV induced systemic metabolic reprogramming, which could help follow the progression of HBV infection and explain the underlying pathogenesis.
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Affiliation(s)
- Wenning Lan
- Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China;
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, China
- Ganjiang Innovation Academy, Chinese Academy of Sciences, Ganzhou 341001, China
| | - Yang Wang
- Institute of Immunotherapy, Fujian Medical University, Fuzhou 350122, China;
| | - Zixiong Zhou
- Department of Pathology, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China;
| | - Xia Sun
- Fujian Science and Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, China;
| | - Yun Zhang
- Xiamen Key Laboratory of Rare Earth Photoelectric Functional Materials, Xiamen Institute of Rare Earth Materials, Haixi Institute, Chinese Academy of Sciences, Xiamen 361021, China
- Fujian Science and Technology Innovation Laboratory for Optoelectronic Information of China, Fuzhou 350108, China;
- State Key Laboratory of Structural Chemistry, Fujian Institute of Research on the Structure of Matter, Chinese Academy of Sciences, Fuzhou 350002, China
| | - Fangrong Zhang
- Key Laboratory of Gastrointestinal Cancer, Ministry of Education, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China;
- Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou 350122, China
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7
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Paul B, Lewinska M, Andersen JB. Lipid alterations in chronic liver disease and liver cancer. JHEP Rep 2022; 4:100479. [PMID: 35469167 PMCID: PMC9034302 DOI: 10.1016/j.jhepr.2022.100479] [Citation(s) in RCA: 147] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2021] [Revised: 03/01/2022] [Accepted: 03/07/2022] [Indexed: 02/06/2023] Open
Abstract
Lipids are a complex and diverse group of molecules with crucial roles in many physiological processes, as well as in the onset, progression, and maintenance of cancers. Fatty acids and cholesterol are the building blocks of lipids, orchestrating these crucial metabolic processes. In the liver, lipid alterations are prevalent as a cause and consequence of chronic hepatitis B and C virus infections, alcoholic hepatitis, and non-alcoholic fatty liver disease and steatohepatitis. Recent developments in lipidomics have also revealed that dynamic changes in triacylglycerols, phospholipids, sphingolipids, ceramides, fatty acids, and cholesterol are involved in the development and progression of primary liver cancer. Accordingly, the transcriptional landscape of lipid metabolism suggests a carcinogenic role of increasing fatty acids and sterol synthesis. However, limited mechanistic insights into the complex nature of the hepatic lipidome have so far hindered the development of effective therapies.
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8
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Choe JW, Hyun JJ, Kim B, Han KD. Influence of Metabolic Syndrome on Cancer Risk in HBV Carriers: A Nationwide Population Based Study Using the National Health Insurance Service Database. J Clin Med 2021; 10:jcm10112401. [PMID: 34072289 PMCID: PMC8198770 DOI: 10.3390/jcm10112401] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 05/19/2021] [Accepted: 05/26/2021] [Indexed: 01/08/2023] Open
Abstract
PURPOSE Hepatitis B virus (HBV) infection and metabolic syndrome (MS) are known independent risk factors for hepatocellular carcinoma (HCC) and other extrahepatic organ malignancies. The purpose of this study was to investigate whether MS and HBV have synergistic effects on cancers and to examine whether increasing the number of MS components could lead to higher risk of cancer development. MATERIALS AND METHODS We evaluated data from 1,504,880 HBV-infected adults who underwent a regular HCC screening program provided by the Korean National Health Insurance Service between 2009 and 2016. RESULTS The prevalence of MS in Korean HBV patients was 38.7% (582,449/1,504,880). Among individuals with HBV infection, the presence of MS was associated with an increased risk for the majority of malignancies except for HCC (HR = 0.862, p-value < 0.05). The presence of a higher number of MS components was associated with a significantly increased risk of developing cancers in most organs; only HCC was negatively associated with an increasing number of MS components (p < 0.01). CONCLUSIONS Our data show that the presence of MS increases the risk for most malignancies, excluding HCC. Moreover, we found that as the number of MS components increased, the risk for most cancers also increased; this trend was reversed in HCC.
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Affiliation(s)
- Jung Wan Choe
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan 15355, Korea;
| | - Jong Jin Hyun
- Department of Internal Medicine, Korea University Ansan Hospital, Ansan 15355, Korea;
- Correspondence: (J.J.H.); (K.-D.H.)
| | - Bongseong Kim
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
| | - Kyung-Do Han
- Department of Biostatistics, College of Medicine, The Catholic University of Korea, Seoul 06591, Korea;
- Correspondence: (J.J.H.); (K.-D.H.)
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9
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Chen Y, Yang X, Chen Y, Chen G, Winkler CA, An P, Lyu J. Impacts of the SOAT1 genetic variants and protein expression on HBV-related hepatocellular carcinoma. BMC Cancer 2021; 21:615. [PMID: 34039309 PMCID: PMC8152151 DOI: 10.1186/s12885-021-08245-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 04/23/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remains a major public health problem and its pathogenesis remains unresolved. A recent proteomics study discovered a lipid enzyme Sterol O-acyltransferase (SOAT1) involvement in the progression of HCC. We aimed to explore the association between SOAT1 genetic variation and HCC. METHODS We genotyped three exonic SOAT1 variants (rs10753191, V323V; rs3753526, L475L; rs13306731, Q526R) tagging most variations in the gene, in 221 HCC patients and 229 healthy individuals, to assess the impact of SOAT1 gene variation on risk of HCC occurrence. We further conducted immunohistochemistry to compare SOAT1 protein expression levels in 42 paired tumor and adjacent non-tumor tissues. RESULTS We found that rs10753191 (Odds ratio (OR) = 0.58, P = 0.04) and a haplotype TGA (OR = 0.40, P = 0.01) were associated with reduced HCC risk after adjusting for lipid levels. In the immunohistochemistry experiment, we found that the protein expression of SOAT1 was significantly increased in the tumor compared with adjacent tissue (P < 0.001). CONCLUSION This study revealed for the first time SOAT1 genetic variation that associates with host susceptibility to HCC occurrence. Our results suggest a role of SOAT1 in the HCC development, which warrants further elucidation.
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Affiliation(s)
- Yulong Chen
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Xunjun Yang
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, China
- Department of Laboratory Medicine, The Second Affiliated Hospital & Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Yao Chen
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Guorong Chen
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Cheryl A Winkler
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Ping An
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA.
| | - Jianxin Lyu
- Key Laboratory of Laboratory Medicine, Ministry of Education, Zhejiang Provincial Key Laboratory of Medical Genetics, Wenzhou Medical University, Wenzhou, Zhejiang, China.
- Zhejiang Provincial People's Hospital, Affiliated Hospital of Hangzhou Medical College, Zhejiang, Hangzhou, China.
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10
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Magon KL, Parish JL. From infection to cancer: how DNA tumour viruses alter host cell central carbon and lipid metabolism. Open Biol 2021; 11:210004. [PMID: 33653084 PMCID: PMC8061758 DOI: 10.1098/rsob.210004] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Accepted: 02/01/2021] [Indexed: 02/06/2023] Open
Abstract
Infections cause 13% of all cancers globally, and DNA tumour viruses account for almost 60% of these cancers. All viruses are obligate intracellular parasites and hijack host cell functions to replicate and complete their life cycles to produce progeny virions. While many aspects of viral manipulation of host cells have been studied, how DNA tumour viruses manipulate host cell metabolism and whether metabolic alterations in the virus life cycle contribute to carcinogenesis are not well understood. In this review, we compare the differences in central carbon and fatty acid metabolism in host cells following infection, oncogenic transformation, and virus-driven cancer of DNA tumour viruses including: Epstein-Barr virus, hepatitis B virus, human papillomavirus, Kaposi's sarcoma-associated herpesvirus and Merkel cell polyomavirus.
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Affiliation(s)
- Kamini L. Magon
- Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
| | - Joanna L. Parish
- Institute of Cancer and Genomic Science, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK
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11
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Recent Advances of Microbiome-Associated Metabolomics Profiling in Liver Disease: Principles, Mechanisms, and Applications. Int J Mol Sci 2021; 22:ijms22031160. [PMID: 33503844 PMCID: PMC7865944 DOI: 10.3390/ijms22031160] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/17/2021] [Accepted: 01/22/2021] [Indexed: 02/06/2023] Open
Abstract
Advances in high-throughput screening of metabolic stability in liver and gut microbiota are able to identify and quantify small-molecule metabolites (metabolome) in different cellular microenvironments that are closest to their phenotypes. Metagenomics and metabolomics are largely recognized to be the “-omics” disciplines for clinical therapeutic screening. Here, metabolomics activity screening in liver disease (LD) and gut microbiomes has significantly delivered the integration of metabolomics data (i.e., a set of endogenous metabolites) with metabolic pathways in cellular environments that can be tested for biological functions (i.e., phenotypes). A growing literature in LD and gut microbiomes reports the use of metabolites as therapeutic targets or biomarkers. Although growing evidence connects liver fibrosis, cirrhosis, and hepatocellular carcinoma, the genetic and metabolic factors are still mainly unknown. Herein, we reviewed proof-of-concept mechanisms for metabolomics-based LD and gut microbiotas’ role from several studies (nuclear magnetic resonance, gas/lipid chromatography, spectroscopy coupled with mass spectrometry, and capillary electrophoresis). A deeper understanding of these axes is a prerequisite for optimizing therapeutic strategies to improve liver health.
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12
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Cao LL, Han Y, Wang Y, Pei L, Yue Z, Qin L, Liu B, Cui J, Jia M, Wang H. Metabolic Profiling Identified a Novel Biomarker Panel for Metabolic Syndrome-Positive Hepatocellular Cancer. Front Endocrinol (Lausanne) 2021; 12:816748. [PMID: 35154012 PMCID: PMC8826723 DOI: 10.3389/fendo.2021.816748] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 12/14/2021] [Indexed: 12/24/2022] Open
Abstract
Metabolic syndrome (MetS) is an independent risk factor for hepatocellular cancer (HCC). Currently, there is no highly sensitive and specific biomarkers for HCC surveillance in MetS population. Metabolomics has been reported as a powerful technology for biomarker discovery. In the present study, we aimed to explore novel biomarkers with high sensitivity and specificity for MetS-positive [MetS(+)] HCC by metabolomic analysis. At first, many serum metabolites were found dysregulated in MetS(+) HCC individuals. Validation of the dysregulated metabolites by targeted metabolite analyses revealed that serum L-glutamic acid (L-glu), pipecolic acid (PA) and 7-methylguanine (7-mG) were increased in MetS(+) HCC compared to MetS group. Then a biomarker panel including L-glu, PA and alpha-fetoprotein (AFP) was identified as a novel biomarker for the diagnosis of MetS(+) HCC. Receiver operating characteristic (ROC) curve was drawn and the area under the ROC curve (AUC) was 0.87 for discriminating MetS(+) HCC from MetS group. The biomarker panel was capable of detecting small (AUC = 0.82) and early-stage (AUC = 0.78) tumors as well. Moreover, it exhibited great diagnostic performance (AUC = 0.93) for discriminating MetS(+) HCC from other MetS-associated cancers, including colorectal cancer and gastric cancer. Collectively, our study establishes a novel diagnostic tool for MetS(+) HCC.
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Affiliation(s)
- Lin-Lin Cao
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China
- *Correspondence: Lin-Lin Cao,
| | - Yi Han
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China
| | - Yuanxiao Wang
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China
| | - Lin Pei
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China
| | - Zhihong Yue
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China
| | - Li Qin
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China
| | - Boyu Liu
- Department of Pharmacy, Peking University People’s Hospital, Beijing, China
| | - Jingwen Cui
- SCIEX Analytical Instrument Trading Co., Shanghai, China
| | - Mei Jia
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China
| | - Hui Wang
- Department of Clinical Laboratory, Peking University People’s Hospital, Beijing, China
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Lipid Metabolism in Development and Progression of Hepatocellular Carcinoma. Cancers (Basel) 2020; 12:cancers12061419. [PMID: 32486341 PMCID: PMC7352397 DOI: 10.3390/cancers12061419] [Citation(s) in RCA: 107] [Impact Index Per Article: 21.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2020] [Revised: 05/19/2020] [Accepted: 05/27/2020] [Indexed: 12/11/2022] Open
Abstract
: Metabolic reprogramming is critically involved in the development and progression of cancer. In particular, lipid metabolism has been investigated as a source of energy, micro-environmental adaptation, and cell signalling in neoplastic cells. However, the specific role of lipid metabolism dysregulation in hepatocellular carcinoma (HCC) has not been widely described yet. Alterations in fatty acid synthesis, β-oxidation, and cellular lipidic composition contribute to initiation and progression of HCC. The aim of this review is to elucidate the mechanisms by which lipid metabolism is involved in hepatocarcinogenesis and tumour adaptation to different conditions, focusing on the transcriptional aberrations with new insights in lipidomics and lipid zonation. This will help detect new putative therapeutic approaches in the second most frequent cause of cancer-related death.
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Nagai K, Uranbileg B, Chen Z, Fujioka A, Yamazaki T, Matsumoto Y, Tsukamoto H, Ikeda H, Yatomi Y, Chiba H, Hui S, Nakazawa T, Saito R, Koshiba S, Aoki J, Saigusa D, Tomioka Y. Identification of novel biomarkers of hepatocellular carcinoma by high-definition mass spectrometry: Ultrahigh-performance liquid chromatography quadrupole time-of-flight mass spectrometry and desorption electrospray ionization mass spectrometry imaging. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2020; 34 Suppl 1:e8551. [PMID: 31412144 PMCID: PMC7154627 DOI: 10.1002/rcm.8551] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/12/2019] [Revised: 07/26/2019] [Accepted: 08/06/2019] [Indexed: 05/13/2023]
Abstract
RATIONALE Hepatocellular carcinoma (HCC) is a highly malignant disease for which the development of prospective or prognostic biomarkers is urgently required. Although metabolomics is widely used for biomarker discovery, there are some bottlenecks regarding the comprehensiveness of detected features, reproducibility of methods, and identification of metabolites. In addition, information on localization of metabolites in tumor tissue is needed for functional analysis. Here, we developed a wide-polarity global metabolomics (G-Met) method, identified HCC biomarkers in human liver samples by high-definition mass spectrometry (HDMS), and demonstrated localization in cryosections using desorption electrospray ionization MS imaging (DESI-MSI) analysis. METHODS Metabolic profiling of tumor (n = 38) and nontumor (n = 72) regions in human livers of HCC was performed by an ultrahigh-performance liquid chromatography quadrupole time-of-flight MS (UHPLC/QTOFMS) instrument equipped with a mixed-mode column. The HCC biomarker candidates were extracted by multivariate analyses and identified by matching values of the collision cross section and their fragment ions on the mass spectra obtained by HDMS. Cryosections of HCC livers, which included both tumor and nontumor regions, were analyzed by DESI-MSI. RESULTS From the multivariate analysis, m/z 904.83 and m/z 874.79 were significantly high and low, respectively, in tumor samples and were identified as triglyceride (TG) 16:0/18:1(9Z)/20:1(11Z) and TG 16:0/18:1(9Z)/18:2(9Z,12Z) using the synthetic compounds. The TGs were clearly localized in the tumor or nontumor areas of the cryosection. CONCLUSIONS Novel biomarkers for HCC were identified by a comprehensive and reproducible G-Met method with HDMS using a mixed-mode column. The combination analysis of UHPLC/QTOFMS and DESI-MSI revealed that the different molecular species of TGs were associated with tumor distribution and were useful for characterizing the progression of tumor cells and discovering prospective biomarkers.
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Affiliation(s)
- Koshi Nagai
- Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | | | - Zhen Chen
- Faculty of Health ScienceHokkaido UniversityJapan
| | - Amane Fujioka
- Department of OphthalmologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
| | - Takahiro Yamazaki
- Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Yotaro Matsumoto
- Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Hiroki Tsukamoto
- Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Hitoshi Ikeda
- Department of Clinical Laboratory MedicineUniversity of TokyoJapan
| | - Yutaka Yatomi
- Department of Clinical Laboratory MedicineUniversity of TokyoJapan
| | | | - Shu‐Ping Hui
- Faculty of Health ScienceHokkaido UniversityJapan
| | - Toru Nakazawa
- Department of OphthalmologyTohoku University Graduate School of MedicineSendaiMiyagiJapan
- Tohoku University Advanced Research Center for Innovations in Next-Generation Medicine
| | - Ritsumi Saito
- Department of Integrative GenomicsTohoku University Tohoku Medical Megabank OrganizationSendaiJapan
- Medical BiochemistryTohoku University Graduate School of MedicineSendaiJapan
| | - Seizo Koshiba
- Tohoku University Advanced Research Center for Innovations in Next-Generation Medicine
- Department of Integrative GenomicsTohoku University Tohoku Medical Megabank OrganizationSendaiJapan
- Medical BiochemistryTohoku University Graduate School of MedicineSendaiJapan
| | - Junken Aoki
- Laboratory of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
| | - Daisuke Saigusa
- Department of Integrative GenomicsTohoku University Tohoku Medical Megabank OrganizationSendaiJapan
- Medical BiochemistryTohoku University Graduate School of MedicineSendaiJapan
| | - Yoshihisa Tomioka
- Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical SciencesTohoku UniversitySendaiJapan
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Abudula A, Rouzi N, Xu L, Yang Y, Hasimu A. Tissue-based metabolomics reveals potential biomarkers for cervical carcinoma and HPV infection. Bosn J Basic Med Sci 2020; 20:78-87. [PMID: 31465717 PMCID: PMC7029203 DOI: 10.17305/bjbms.2019.4359] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 08/27/2019] [Indexed: 12/18/2022] Open
Abstract
Aberrant metabolic regulation has been observed in human cancers, but the corresponding regulation in human papillomavirus (HPV) infection-associated cervical cancer is not well understood. Here, we explored potential biomarkers for the early prediction of cervical carcinoma based on the metabolic profile of uterine cervical tissue specimens that were positive for HPV16 infection. Fifty-two fresh cervical tissues were collected from women confirmed to have cervical squamous cell carcinoma (SCC; n = 21) or cervical intraepithelial neoplasia (CIN) stages II-III (n = 20). Eleven healthy women constituted the controls (negative controls [NCs]). Real-time polymerase chain reaction (PCR) was performed to detect HPV infection in the tissues. High-resolution magic angle spinning nuclear magnetic resonance was utilized for the analysis of the metabolic profile in the tissues. The expression of rate-limiting enzymes involved in key metabolic pathways was detected by reverse-transcription quantitative PCR. An independent immunohistochemical analysis was performed using 123 cases of paraffin-embedded cervical specimens. A profile of 17 small molecular metabolites that showed differential expression in HPV16-positive cervical SCC or CIN II-III compared with HPV-negative NC group was identified. According to the profile, the levels of α- and β-glucose decreased, those of lactate and low-density lipoproteins increased, and the expression of multiple amino acids was altered. Significantly increased transcript and protein levels of glycogen synthase kinase 3 beta (GSK3β) and glutamate decarboxylase 1 (GAD1) and decreased transcript and protein levels of pyruvate kinase muscle isozyme 2 (PKM2) and carnitine palmitoyltransferase 1A (CPT1A) were observed in the patient group (p < 0.05). HPV infection and cervical carcinogenesis drive metabolic modifications that might be associated with the aberrant regulation of enzymes related to metabolic pathways.
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Affiliation(s)
- Abulizi Abudula
- Department of Labour and Environmental Hygienics, School of Public Health, Xinjiang Medical University, Urumqi, China.
| | - Nuermanguli Rouzi
- Department of Labour and Environmental Hygienics, School of Public Health, Xinjiang Medical University, Urumqi, China.
| | - Lixiu Xu
- Department of Pathology, School of Basic Medicine, Xinjiang Medical University, Urumqi, China.
| | - Yun Yang
- Department of Pathology, School of Basic Medicine, Xinjiang Medical University, Urumqi, China.
| | - Axiangu Hasimu
- Department of Pathology, School of Basic Medicine, Xinjiang Medical University, Urumqi, China.
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Hu B, Lin JZ, Yang XB, Sang XT. Aberrant lipid metabolism in hepatocellular carcinoma cells as well as immune microenvironment: A review. Cell Prolif 2020; 53:e12772. [PMID: 32003505 PMCID: PMC7106960 DOI: 10.1111/cpr.12772] [Citation(s) in RCA: 94] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2019] [Revised: 12/23/2019] [Accepted: 01/15/2020] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a primary malignancy of the liver with a high worldwide prevalence and poor prognosis. Researches are urgently needed on its molecular pathogenesis and biological characteristics. Metabolic reprogramming for adaptation to the tumour microenvironment (TME) has been recognized as a hallmark of cancer. Dysregulation of lipid metabolism especially fatty acid (FA) metabolism, which involved in the alternations of the expression and activity of lipid‐metabolizing enzymes, is a hotspot in recent study, and it may be involved in HCC development and progression. Meanwhile, immune cells are also known as key players in the HCC microenvironment and show complicated crosstalk with cancer cells. Emerging evidence has shown that the functions of immune cells in TME are closely related to abnormal lipid metabolism. In this review, we summarize the recent findings of lipid metabolic reprogramming in TME and relate these findings to HCC progression. Our understanding of dysregulated lipid metabolism and associated signalling pathways may suggest a novel strategy to treat HCC by reprogramming cell lipid metabolism or modulating TME.
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Affiliation(s)
- Bo Hu
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Jian-Zhen Lin
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xiao-Bo Yang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Xin-Ting Sang
- Department of Liver Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Chemopreventive Effect of Phytosomal Curcumin on Hepatitis B Virus-Related Hepatocellular Carcinoma in A Transgenic Mouse Model. Sci Rep 2019; 9:10338. [PMID: 31316146 PMCID: PMC6637187 DOI: 10.1038/s41598-019-46891-5] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2018] [Accepted: 07/01/2019] [Indexed: 12/11/2022] Open
Abstract
Chronic hepatitis B virus (HBV) infection is a major risk factor for the development of hepatocellular carcinoma (HCC), a leading cause of cancer mortality worldwide. Hepatitis B X protein (HBx) and pre-S2 mutant have been proposed as the two most important HBV oncoproteins that play key roles in HCC pathogenesis. Curcumin is a botanical constituent displaying potent anti-inflammatory and anti-cancer properties without toxic side effects. Phytosomal formulation of curcumin has been shown to exhibit enhanced bioavailability, improved pharmacokinetics, and excellent efficacy against many human diseases. However, effectiveness of phytosomal curcumin for HCC treatment remains to be clarified. In this study, we evaluated chemopreventive effect of phytosomal curcumin on HBV-related HCC by using a transgenic mouse model specifically expressing both HBx and pre-S2 mutant in liver. Compared with unformulated curcumin, phytosomal curcumin exhibited significantly greater effects on suppression of HCC formation, improvement of liver histopathology, decrease of lipid accumulation and leukocyte infiltration, and reduction of total tumor volume in transgenic mice. Moreover, phytosomal curcumin exerted considerably stronger effects on activation of anti-inflammatory PPARγ as well as inhibition of pro-inflammatory NF-κB than unformulated curcumin. Furthermore, phytosomal curcumin showed a comparable effect on suppression of oncogenic mTOR activation to unformulated curcumin. Our data demonstrated that phytosomal curcumin has promise for HCC chemoprevention in patients with chronic HBV infection.
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Bharali D, Banerjee BD, Bharadwaj M, Husain SA, Kar P. Expression analysis of apolipoproteins AI & AIV in hepatocellular carcinoma: A protein-based hepatocellular carcinoma-associated study. Indian J Med Res 2018; 147:361-368. [PMID: 29998871 PMCID: PMC6057253 DOI: 10.4103/ijmr.ijmr_1358_16] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Background & objectives: Hepatocellular carcinoma (HCC) is one of the leading causes of cancer mortality. The objective of this study was to find out the differential expression of apolipoproteins (ApoAI and ApoAIV) in HCC and cases of liver cirrhosis and chronic hepatitis (controls) without HCC and to compare ApoAI and ApoAIV expression with alpha-foetoprotein (AFP), the conventional marker in HCC. Methods: Fifty patients with HCC and 50 controls comprising patients with liver cirrhosis (n=25) and chronic hepatitis (n=25) without HCC were included in this study. Total proteins were precipitated using acetone precipitation method followed by albumin and IgG depletion of precipitated protein using depletion kit. Proteins were separated by sodium dodecyl sulphate-polyacrylamide gel electrophoresis. The expression changes of ApoAI and ApoAIV were confirmed by western blotting using specific primary and secondary polyclonal antibodies followed by densitometric protein semi-quantitative estimation. ApoAI, ApoAIV and AFP were measured in the plasma samples by ELISA method. Results: Semi-quantitative densitometric image analysis of the western blot images and the comparison between HCC patients with those without HCC (control) revealed differential expression of ApoAI and ApoAIV. Levels of ApoAI were significantly higher in patients with HCC compared to controls without HCC (0.279±0.216 vs 0.171±0.091 and 0.199±0.014; P <0.001). Levels of ApoAIV were significantly lower in patients of HCC compared to controls without HCC (0.119±0.061 vs 0.208±0.07 and 0.171±0.16; P <0.01). ELISA assays of apolipoproteins (ApoAI and ApoAIV) revealed similar results of expression of ApoAI and ApoAIV as detected in western blotting densitometric image analysis. Interpretation & conclusions: Increased expression of ApoAI and decreased expression of ApoAIV in HCC patients compared to controls without HCC revealed the abnormalities in HCC. These molecules need to be studied further for their use as potential biomarkers in the future diagnostic tools along with other conventional biomarkers for screening of HCC cases. It needs further analysis in higher number of patient population.
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Affiliation(s)
- Dipu Bharali
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
| | - Basu Dev Banerjee
- Department of Biochemistry, University College of Medical Sciences, Delhi, India
| | - Mausumi Bharadwaj
- Division of Molecular Genetics & Biochemistry, ICMR-National Institute of Cancer Prevention & Research, Noida, India
| | - Syed Akhtar Husain
- Department of Biosciences, Jamia Milia Islamia University, New Delhi, India
| | - Premashis Kar
- Department of Medicine, Maulana Azad Medical College, University of Delhi, New Delhi, India
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Teng C, Chang H, Tsai H, Hsieh W, Kuo Y, Su I, Lin Y. Liver regeneration accelerates hepatitis B virus-related tumorigenesis of hepatocellular carcinoma. Mol Oncol 2018; 12:1175-1187. [PMID: 29729074 PMCID: PMC6026873 DOI: 10.1002/1878-0261.12318] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 04/16/2018] [Accepted: 04/23/2018] [Indexed: 12/15/2022] Open
Abstract
Although partial hepatectomy (PH) to remove tumors provides a potential cure of hepatocellular carcinoma (HCC), long-term survival of hepatitis B virus (HBV)-related HCC patients after PH remains a big challenge. Early recurrence within 2 years post-PH is associated with the dissemination of primary HCC. However, late recurrence after 2 years post-PH is supposed due to the de novo or a secondary tumor. Since PH initiates liver regeneration (LR), we hypothesize that LR may accelerate tumorigenesis through activation of pre-existing precancerous lesions in the remaining liver. In this study, we explored the potential role of several LR-related factors in the de novo recurrence in a HBV X protein (HBx) transgenic mouse model receiving PH to mimic human HCC development. Following PH, we observed that tumor development was significantly accelerated from 16.9 to 10.4 months in HBx transgenic mice. The expression of suppressor of cytokine signaling (SOCS) family proteins was remarkably suppressed in livers of HBx transgenic relative to non-transgenic mice from early to late stages after PH as compared with non-PH mice. The expression of transforming growth factor-β (TGF-β)/Smad pathway, hepatocyte growth factor (HGF), Myc, signal transducer and activator of transcription 3 (STAT3), and β-Catenin also showed a significant difference between livers of HBx transgenic and non-transgenic mice at variable time points after PH in comparison with non-PH mice. Taken together, our results provide an explanation for the high de novo recurrence of HBV-related HCC after PH, probably through induction of the sequential changes of LR-related SOCS family proteins, growth factors, and transcription factors, which may promote growth on the precancerous remnant liver.
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Affiliation(s)
- Chiao‐Fang Teng
- Graduate Institute of Biomedical SciencesChina Medical UniversityTaichungTaiwan
- Organ Transplantation CenterChina Medical University HospitalTaichungTaiwan
| | - Hong‐Yi Chang
- Department of BiotechnologySouthern Taiwan University of Science and TechnologyTainanTaiwan
| | - Hung‐Wen Tsai
- Department of PathologyNational Cheng Kung University HospitalTainanTaiwan
- Institute of Clinical MedicineCollege of MedicineNational Cheng Kung UniversityTainanTaiwan
| | - Wen‐Chuan Hsieh
- National Institute of Infectious Diseases and VaccinologyNational Health Research InstitutesTainanTaiwan
| | - Yu‐Hao Kuo
- Organ Transplantation CenterChina Medical University HospitalTaichungTaiwan
| | - Ih‐Jen Su
- Department of BiotechnologySouthern Taiwan University of Science and TechnologyTainanTaiwan
- Department of PathologyNational Cheng Kung University HospitalTainanTaiwan
- National Institute of Infectious Diseases and VaccinologyNational Health Research InstitutesTainanTaiwan
| | - Yih‐Jyh Lin
- Division of General and Transplant SurgeryDepartment of SurgeryNational Cheng Kung University HospitalTainanTaiwan
- Department of SurgeryCollege of MedicineNational Cheng Kung UniversityTainanTaiwan
- Liver Cancer Collaborative Oncology GroupNational Cheng Kung University HospitalTainanTaiwan
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Guo W, Tan HY, Wang N, Wang X, Feng Y. Deciphering hepatocellular carcinoma through metabolomics: from biomarker discovery to therapy evaluation. Cancer Manag Res 2018; 10:715-734. [PMID: 29692630 PMCID: PMC5903488 DOI: 10.2147/cmar.s156837] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of death from cancer, with increasing prevalence worldwide. The mortality rate of HCC is similar to its incidence rate, which reflects its poor prognosis. At present, the diagnosis of HCC is still mostly dependent on invasive biopsy, imaging methods, and serum α-fetoprotein (AFP) testing. Because of the asymptomatic nature of early HCC, biopsy and imaging methods usually detect HCC at the middle-late stages. AFP has limited sensitivity and specificity, as many other nonmalignant liver diseases can also result in a very high serum level of AFP. Therefore, better biomarkers with higher sensitivity and specificity at earlier stages are greatly needed. Since metabolic reprogramming is an essential hallmark of cancer and the liver is the metabolic hub of living systems, it is useful to investigate HCC from a metabolic perspective. As a noninvasive and nondestructive approach, metabolomics provides holistic information on dynamically metabolic responses of living systems to both endogenous and exogenous factors. Therefore, it would be conducive to apply metabolomics in investigating HCC. In this review, we summarize recent metabolomic studies on HCC cellular, animal, and clinicopathologic models with attention to metabolomics as a biomarker in cancer diagnosis. Recent applications of metabolomics with respect to therapeutic and prognostic evaluation of HCC are also covered, with emphasis on the potential of treatment by drugs from natural products. In the last section, the current challenges and trends of future development of metabolomics on HCC are discussed. Overall, metabolomics provides us with novel insight into the diagnosis, prognosis, and therapeutic evaluation of HCC.
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Affiliation(s)
- Wei Guo
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Hor Yue Tan
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
| | - Ning Wang
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
- Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China
| | - Xuanbin Wang
- Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
| | - Yibin Feng
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pokfulam, Hong Kong
- Shenzhen Institute of Research and Innovation, The University of Hong Kong, Shenzhen, China
- Laboratory of Chinese Herbal Pharmacology, Oncology Center, Renmin Hospital, Hubei University of Medicine, Shiyan, China
- Hubei Key Laboratory of Wudang Local Chinese Medicine Research, Hubei University of Medicine, Shiyan, China
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Lin HJ, Ku KL, Lin IH, Yeh CC. Naringenin attenuates hepatitis B virus X protein-induced hepatic steatosis. Altern Ther Health Med 2017; 17:505. [PMID: 29183361 PMCID: PMC5706293 DOI: 10.1186/s12906-017-2019-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 11/20/2017] [Indexed: 12/19/2022]
Abstract
BACKGROUND Naringenin (Nar), a common dietary flavonoid abundantly present in fruits, vegetables, and Chinese herbs, is believed to possess strong anti-inflammatory properties and to modulate hepatic apolipoprotein and lipid synthesis. However, there are no reports describing Nar's effects on the hepatitis B virus protein X (HBx) -induced hepatic steatosis, and the detailed molecular mechanisms of the compound's effects are still unclear. METHODS Nar was administered by oral gavage to HBx-transgenic mice from 4 to 6 weeks of age. Mice were sacrificed after 14 days of once-daily naringenin administration. Liver tissues and sera were collected for histopathology and biochemical analysis. RESULTS Nar counteracted hepatic lipid accumulation and liver dysfunction in HBx-transgenic mice. In addition, Nar significantly decreased expression of adipogenic and lipogenic genes in mice, suggesting that the compound may have therapeutic effects in the early stages of HBx-mediated hepatic steatosis. These results indicated that naringenin inhibits HBx-induced expression of hepatic adipogenic and lipogenic genes through suppression of HBx-induced gene expression, including decreases in the transcriptional activity of SREBP1c, LXRα, and PPARγ in HBx-trangenic mice and HBx-transfected HepG2 cells. CONCLUSIONS Results from this study suggested that Nar may serve as a therapeutic agent for preventing HBx-infected hepatic steatosis in humans.
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22
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Bai P, Xia N, Sun H, Kong Y. Pleiotrophin, a target of miR-384, promotes proliferation, metastasis and lipogenesis in HBV-related hepatocellular carcinoma. J Cell Mol Med 2017; 21:3023-3043. [PMID: 28557334 PMCID: PMC5661149 DOI: 10.1111/jcmm.13213] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2016] [Accepted: 03/29/2017] [Indexed: 12/27/2022] Open
Abstract
Hepatitis B virus (HBV) infection plays a crucial role and is a major cause of hepatocellular carcinoma (HCC) in China. microRNAs (miRNAs) have emerged as key players in hepatic steatosis and carcinogenesis. We found that down-regulation of miR-384 expression was a common event in HCC, especially HBV-related HCC. However, the possible function of miR-384 in HBV-related HCC remains unclear. The oncogene pleiotrophin (PTN) was a target of miR-384. HBx inhibited miR-384, increasing PTN expression. The PTN receptor N-syndecan was highly expressed in HCC. PTN induced by HBx acted as a growth factor via N-syndecan on hepatocytes and further promoted cell proliferation, metastasis and lipogenesis. PTN up-regulated sterol regulatory element-binding protein 1c (SREBP-1c) through the N-syndecan/PI3K/Akt/mTORC1 pathway and the expression of lipogenic genes, including fatty acid synthesis (FAS). PTN-mediated de novo lipid synthesis played an important role in HCC proliferation and metastasis. PI3K/AKT and an mTORC1 inhibitor diminished PTN-induced proliferation, metastasis and lipogenesis. Taken together, these data strongly suggest that the dysregulation of miR-384 could play a crucial role in HBV related to HCC, and the target gene of miR-384, PTN, represents a new potential therapeutic target for the prevention of hepatic steatosis and further progression to HCC after chronic HBV infection.
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Affiliation(s)
- Pei‐song Bai
- Department of OncologyFirst Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Nan Xia
- Institute of Cancer Prevention and ControlPeking University Cancer HospitalBei'jingChina
| | - Hong Sun
- Department of OncologyFirst Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
| | - Ying Kong
- Department of OncologyFirst Hospital of Xi'an Jiaotong UniversityXi'anShaanxiChina
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23
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Simillion C, Semmo N, Idle JR, Beyoğlu D. Robust Regression Analysis of GCMS Data Reveals Differential Rewiring of Metabolic Networks in Hepatitis B and C Patients. Metabolites 2017; 7:metabo7040051. [PMID: 28991180 PMCID: PMC5746731 DOI: 10.3390/metabo7040051] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2017] [Revised: 09/30/2017] [Accepted: 10/05/2017] [Indexed: 12/17/2022] Open
Abstract
About one in 15 of the world’s population is chronically infected with either hepatitis virus B (HBV) or C (HCV), with enormous public health consequences. The metabolic alterations caused by these infections have never been directly compared and contrasted. We investigated groups of HBV-positive, HCV-positive, and uninfected healthy controls using gas chromatography-mass spectrometry analyses of their plasma and urine. A robust regression analysis of the metabolite data was conducted to reveal correlations between metabolite pairs. Ten metabolite correlations appeared for HBV plasma and urine, with 18 for HCV plasma and urine, none of which were present in the controls. Metabolic perturbation networks were constructed, which permitted a differential view of the HBV- and HCV-infected liver. HBV hepatitis was consistent with enhanced glucose uptake, glycolysis, and pentose phosphate pathway metabolism, the latter using xylitol and producing threonic acid, which may also be imported by glucose transporters. HCV hepatitis was consistent with impaired glucose uptake, glycolysis, and pentose phosphate pathway metabolism, with the tricarboxylic acid pathway fueled by branched-chain amino acids feeding gluconeogenesis and the hepatocellular loss of glucose, which most probably contributed to hyperglycemia. It is concluded that robust regression analyses can uncover metabolic rewiring in disease states.
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Affiliation(s)
- Cedric Simillion
- Interfaculty Bioinformatics Unit and SIB Swiss Institute of Bioinformatics, University of Bern, Baltzerstrasse 6, 3012 Bern, Switzerland.
- Department of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland.
| | - Nasser Semmo
- Department of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland.
- Department of Visceral Surgery and Medicine, Department of Hepatology, Inselspital, University Hospital of Bern, 3010 Bern, Switzerland.
| | - Jeffrey R Idle
- Department of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland.
- Department of Visceral Surgery and Medicine, Department of Hepatology, Inselspital, University Hospital of Bern, 3010 Bern, Switzerland.
- Division of Systems Pharmacology and Pharmacogenomics, Samuel J. and Joan B. Williamson Institute, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, 11201 New York, NY, USA.
| | - Diren Beyoğlu
- Department of BioMedical Research, University of Bern, Murtenstrasse 35, 3008 Bern, Switzerland.
- Division of Systems Pharmacology and Pharmacogenomics, Samuel J. and Joan B. Williamson Institute, Arnold & Marie Schwartz College of Pharmacy and Health Sciences, Long Island University, Brooklyn, 11201 New York, NY, USA.
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Ivanov AV, Valuev-Elliston VT, Tyurina DA, Ivanova ON, Kochetkov SN, Bartosch B, Isaguliants MG. Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis. Oncotarget 2017; 8:3895-3932. [PMID: 27965466 PMCID: PMC5354803 DOI: 10.18632/oncotarget.13904] [Citation(s) in RCA: 120] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 12/05/2016] [Indexed: 12/11/2022] Open
Abstract
Virally induced liver cancer usually evolves over long periods of time in the context of a strongly oxidative microenvironment, characterized by chronic liver inflammation and regeneration processes. They ultimately lead to oncogenic mutations in many cellular signaling cascades that drive cell growth and proliferation. Oxidative stress, induced by hepatitis viruses, therefore is one of the factors that drives the neoplastic transformation process in the liver. This review summarizes current knowledge on oxidative stress and oxidative stress responses induced by human hepatitis B and C viruses. It focuses on the molecular mechanisms by which these viruses activate cellular enzymes/systems that generate or scavenge reactive oxygen species (ROS) and control cellular redox homeostasis. The impact of an altered cellular redox homeostasis on the initiation and establishment of chronic viral infection, as well as on the course and outcome of liver fibrosis and hepatocarcinogenesis will be discussed The review neither discusses reactive nitrogen species, although their metabolism is interferes with that of ROS, nor antioxidants as potential therapeutic remedies against viral infections, both subjects meriting an independent review.
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Affiliation(s)
- Alexander V. Ivanov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | | | - Daria A. Tyurina
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Olga N. Ivanova
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Sergey N. Kochetkov
- Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia
| | - Birke Bartosch
- Inserm U1052, Cancer Research Center Lyon, University of Lyon, Lyon, France
- DevWeCan Laboratories of Excellence Network, France
| | - Maria G. Isaguliants
- Riga Stradins University, Riga, Latvia
- Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
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25
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Xie J, Zhang A, Wang X. Metabolomic applications in hepatocellular carcinoma: toward the exploration of therapeutics and diagnosis through small molecules. RSC Adv 2017. [DOI: 10.1039/c7ra00698e] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC), a complex public health issue that is the most common primary hepatic malignancy, remains the highest incidence in developing countries and is showing sustained growth across the developed world.
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Affiliation(s)
- Jing Xie
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Chinmedomics Research Center of State Administration of TCM
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
| | - Aihua Zhang
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Chinmedomics Research Center of State Administration of TCM
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
| | - Xijun Wang
- Sino-America Chinmedomics Technology Collaboration Center
- National TCM Key Laboratory of Serum Pharmacochemistry
- Chinmedomics Research Center of State Administration of TCM
- Metabolomics Laboratory
- Department of Pharmaceutical Analysis
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26
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Schoeman JC, Hou J, Harms AC, Vreeken RJ, Berger R, Hankemeier T, Boonstra A. Metabolic characterization of the natural progression of chronic hepatitis B. Genome Med 2016; 8:64. [PMID: 27286979 PMCID: PMC4902991 DOI: 10.1186/s13073-016-0318-8] [Citation(s) in RCA: 64] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 05/17/2016] [Indexed: 02/07/2023] Open
Abstract
Background Worldwide, over 350 million people are chronically infected with the hepatitis B virus (HBV) and are at increased risk of developing progressive liver diseases. The confinement of HBV replication to the liver, which also acts as the central hub for metabolic and nutritional regulation, emphasizes the interlinked nature of host metabolism and the disease. Still, the metabolic processes operational during the distinct clinical phases of a chronic HBV infection—immune tolerant, immune active, inactive carrier, and HBeAg-negative hepatitis phases—remains unexplored. Methods To investigate this, we conducted a targeted metabolomics approach on serum to determine the metabolic progression over the clinical phases of chronic HBV infection, using patient samples grouped based on their HBV DNA, alanine aminotransferase, and HBeAg serum levels. Results Our data illustrate the strength of metabolomics to provide insight into the metabolic dysregulation experienced during chronic HBV. The immune tolerant phase is characterized by the speculated viral hijacking of the glycerol-3-phosphate–NADH shuttle, explaining the reduced glycerophospholipid and increased plasmalogen species, indicating a strong link to HBV replication. The persisting impairment of the choline glycerophospholipids, even during the inactive carrier phase with minimal HBV activity, alludes to possible metabolic imprinting effects. The progression of chronic HBV is associated with increased concentrations of very long chain triglycerides together with citrulline and ornithine, reflective of a dysregulated urea cycle peaking in the HBV envelope antigen-negative phase. Conclusions The work presented here will aid in future studies to (i) validate and understand the implication of these metabolic changes using a thorough systems biology approach, (ii) monitor and predict disease severity, as well as (iii) determine the therapeutic value of the glycerol-3-phosphate–NADH shuttle. Electronic supplementary material The online version of this article (doi:10.1186/s13073-016-0318-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Johannes C Schoeman
- Department of Analytical Biosciences, Leiden Academic Center for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands.,Netherlands Metabolomics Centre, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands
| | - Jun Hou
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Wytemaweg 80, Room Na-1011, 3015, CE, Rotterdam, The Netherlands
| | - Amy C Harms
- Department of Analytical Biosciences, Leiden Academic Center for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands.,Netherlands Metabolomics Centre, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands
| | - Rob J Vreeken
- Department of Analytical Biosciences, Leiden Academic Center for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands.,Netherlands Metabolomics Centre, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands.,Present address: Discovery Sciences, Janssen R&D, Turnhoutseweg 30, 2340, Beerse, Belgium
| | - Ruud Berger
- Department of Analytical Biosciences, Leiden Academic Center for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands.,Netherlands Metabolomics Centre, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands
| | - Thomas Hankemeier
- Department of Analytical Biosciences, Leiden Academic Center for Drug Research, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands.,Netherlands Metabolomics Centre, Leiden University, Einsteinweg 55, 2333, CC, Leiden, The Netherlands
| | - Andre Boonstra
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center Rotterdam, Wytemaweg 80, Room Na-1011, 3015, CE, Rotterdam, The Netherlands.
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27
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Teng YC, Shen ZQ, Kao CH, Tsai TF. Hepatocellular carcinoma mouse models: Hepatitis B virus-associated hepatocarcinogenesis and haploinsufficient tumor suppressor genes. World J Gastroenterol 2016; 22:300-325. [PMID: 26755878 PMCID: PMC4698494 DOI: 10.3748/wjg.v22.i1.300] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 10/14/2015] [Accepted: 11/24/2015] [Indexed: 02/06/2023] Open
Abstract
The multifactorial and multistage pathogenesis of hepatocellular carcinoma (HCC) has fascinated a wide spectrum of scientists for decades. While a number of major risk factors have been identified, their mechanistic roles in hepatocarcinogenesis still need to be elucidated. Many tumor suppressor genes (TSGs) have been identified as being involved in HCC. These TSGs can be classified into two groups depending on the situation with respect to allelic mutation/loss in the tumors: the recessive TSGs with two required mutated alleles and the haploinsufficient TSGs with one required mutated allele. Hepatitis B virus (HBV) is one of the most important risk factors associated with HCC. Although mice cannot be infected with HBV due to the narrow host range of HBV and the lack of a proper receptor, one advantage of mouse models for HBV/HCC research is the numerous and powerful genetic tools that help investigate the phenotypic effects of viral proteins and allow the dissection of the dose-dependent action of TSGs. Here, we mainly focus on the application of mouse models in relation to HBV-associated HCC and on TSGs that act either in a recessive or in a haploinsufficient manner. Discoveries obtained using mouse models will have a great impact on HCC translational medicine.
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