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1
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Zhang H, Sheng S, Qiao W, Sun Y, Jin R. Nomogram built based on machine learning to predict recurrence in early-stage hepatocellular carcinoma patients treated with ablation. Front Oncol 2024; 14:1395329. [PMID: 38800405 PMCID: PMC11116608 DOI: 10.3389/fonc.2024.1395329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Accepted: 04/29/2024] [Indexed: 05/29/2024] Open
Abstract
Introduction To analyze the risk factors affecting recurrence in early-stage hepatocellular carcinoma (HCC) patients treated with ablation and then establish a nomogram to provide a clear and accessible representation of the patients' recurrence risk. Methods Collect demographic and clinical data of 898 early-stage HCC patients who underwent ablation treatment at Beijing You'an Hospital, affiliated with Capital Medical University from January 2014 to December 2022. Patients admitted from 2014 to 2018 were included in the training cohort, while 2019 to 2022 were in the validation cohort. Lasso and Cox regression was used to screen independent risk factors for HCC patients recurrence, and a nomogram was then constructed based on the screened factors. Results Age, gender, Barcelona Clinic Liver Cancer (BCLC) stage, tumor size, globulin (Glob) and γ-glutamyl transpeptidase (γ-GT) were finally incorporated in the nomogram for predicting the recurrence-free survival (RFS) of patients. We further confirmed that the nomogram has optimal discrimination, consistency and clinical utility by the C-index, Receiver Operating Characteristic Curve (ROC), calibration curve and Decision Curve Analysis (DCA). Moreover, we divided the patients into different risk groups and found that the nomogram can effectively identify the high recurrence risk patients by the Kaplan-Meier curves. Conclusion This study developed a nomogram using Lasso-Cox regression to predict RFS in early-stage HCC patients following ablation, aiding clinicians in identifying high-risk groups for personalized follow-up treatments.
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Affiliation(s)
- Honghai Zhang
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Shugui Sheng
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
| | - Wenying Qiao
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Changping Laboratory, Beijing, China
| | - Yu Sun
- Interventional Therapy Center for Oncology, Beijing You’an Hospital, Capital Medical University, Beijing, China
| | - Ronghua Jin
- Beijing Key Laboratory of Emerging Infectious Diseases, Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical University, Beijing, China
- Changping Laboratory, Beijing, China
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2
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Xu X, Huang A, Guo DZ, Wang YP, Zhang SY, Yan JY, Wang XY, Cao Y, Fan J, Zhou J, Fu XT, Shi YH. Integration of Inflammation-Immune Factors to Build Prognostic Model Predictive of Prognosis and Minimal Residual Disease for Hepatocellular Carcinoma. Front Oncol 2022; 12:893268. [PMID: 35756674 PMCID: PMC9213691 DOI: 10.3389/fonc.2022.893268] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/17/2022] [Indexed: 12/24/2022] Open
Abstract
Background Tumor recurrence after hepatectomy is high for hepatocellular carcinoma (HCC), and minimal residual disease (MRD) could be the underlying mechanism. A predictive model for recurrence and presence of MRD is needed. Methods Common inflammation-immune factors were reviewed and selected to construct novel models. The model consisting of preoperative aspartate aminotransferase, C-reactive protein, and lymphocyte count, named ACLR, was selected and evaluated for clinical significance. Results Among the nine novel inflammation-immune models, ACLR showed the highest accuracy for overall survival (OS) and time to recurrence (TTR). At the optimal cutoff value of 80, patients with high ACLR (> 80) had larger tumor size, higher Edmondson’s grade, more vascular invasion, advanced tumor stage, and poorer survival than those with low ACLR (≤ 80) in the training cohort (5-year OS: 43.3% vs. 80.1%, P < 0.0001; 5-year TTR: 74.9% vs. 45.3%, P < 0.0001). Multivariate Cox analysis identified ACLR as an independent risk factor for OS [hazard ratio (HR) = 2.22, P < 0.001] and TTR (HR = 2.36, P < 0.001). Such clinical significance and prognostic value were verified in validation cohort. ACLR outperformed extant models, showing the highest area under receiver operating characteristics curve for 1-, 3-, and 5-year OS (0.737, 0.719, and 0.708) and 1-, 3-, and 5-year TTR (0.696, 0.650, and 0.629). High ACLR correlated with early recurrence (P < 0.001) and extremely early recurrence (P < 0.001). In patients with high ACLR, wide resection margin might confer survival benefit by decreasing recurrence (median TTR, 25.5 vs. 11.4 months; P = 0.037). Conclusions The novel inflammation-immune model, ACLR, could effectively predict prognosis, and the presence of MRD before hepatectomy and might guide the decision on resection margin for patients with HCC.
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Affiliation(s)
- Xin Xu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Oncology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ao Huang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - De-Zhen Guo
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yu-Peng Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shi-Yu Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Jia-Yan Yan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Xin-Yu Wang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ya Cao
- Cancer Research Institute, Xiangya School of Medicine, Central South University; Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Xiangya Hospital, Central South University, Changsha, China
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Jian Zhou
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China.,Institute of Biomedical Sciences, Fudan University, Shanghai, China.,State Key Laboratory of Genetic Engineering, Fudan University, Shanghai, China
| | - Xiu-Tao Fu
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying-Hong Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University and Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, China.,Department of Liver Surgery and Transplantation, Zhongshan Hospital, Fudan University, Shanghai, China
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3
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Sun G, Hou X, Zhang L, Zhang H, Shao C, Li F, Zong C, Li R, Shi J, Yang X, Zhang L. 3,5,3'-Triiodothyronine-Loaded Liposomes Inhibit Hepatocarcinogenesis Via Inflammation-Associated Macrophages. Front Oncol 2022; 12:877982. [PMID: 35646705 PMCID: PMC9135096 DOI: 10.3389/fonc.2022.877982] [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: 02/17/2022] [Accepted: 04/04/2022] [Indexed: 11/19/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is inflammation-related cancer. Persistent inflammatory injury of the liver is an important factor mediating the occurrence and development of liver cancer. Hepatic macrophages play an important role in the inflammatory microenvironment, which mediates tumor immune escape, tumor growth, and metastasis. Previous studies have suggested that L-3,5,3-triiodothyronine (T3) can regulate inflammation; however, its use is associated with serious cardiac side effects, and its role in hepatocarcinogenesis remains unclear. In this study, we aimed to develop an effective T3 delivery system with reduced cardiac toxicity and to explore its effects on HCC occurrence. Methods T3 liposomes (T3-lipo) were prepared using the thin-film hydration method, and their characteristics, including particle size, polydispersity index, zeta potential, encapsulation efficiency, drug loading, drug release, and stability, were evaluated in vitro. We assessed the effect of T3-lipo on hepatocarcinogenesis in diethylnitrosamine (DEN)–induced primary HCC in rats and examined the biodistribution of T3 and T3-lipo by high-performance liquid chromatography–mass spectrometry. Furthermore, we explored the potential molecular mechanism of T3-lipo in hepatocarcinogenesis by immunohistochemistry and immunofluorescence analyses, Bio-Plex assays, real-time polymerase chain reaction analysis, and Western blotting assays. Results Compared with T3, T3-lipo had an enhanced inhibitory effect on hepatocarcinogenesis and reduced cardiac side effects in DEN-induced primary HCC in rats. Mechanistically, T3-lipo were absorbed by hepatic macrophages and regulated the secretion of inflammatory cytokines in macrophages by inhibiting inflammatory signaling pathways. Conclusions T3-lipo may suppress hepatocarcinogenesis by regulating the inflammatory microenvironment in the liver and reduce the cardiac side effects meanwhile.
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Affiliation(s)
- Gangqi Sun
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China.,Department of Phase I Clinical Trial, Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xiaojuan Hou
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China.,Department of Tumor Immunity and Metabolism,The National Center for Liver Cancer, Shanghai, China
| | - Luyao Zhang
- Department of Phase I Clinical Trial, Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China.,School of Pharmacy, Anhui Medical University, Hefei, China
| | - Hengyan Zhang
- Department of Phase I Clinical Trial, Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Changchun Shao
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Fengwei Li
- Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Naval Medical University, Shanghai, China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China.,Department of Tumor Immunity and Metabolism,The National Center for Liver Cancer, Shanghai, China
| | - Rong Li
- Laboratory Zone, Eastern Hepatobiliary Clinical Research Institute, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Junxia Shi
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China.,Department of Tumor Immunity and Metabolism,The National Center for Liver Cancer, Shanghai, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Second Military Medical University, Shanghai, China.,Department of Tumor Immunity and Metabolism,The National Center for Liver Cancer, Shanghai, China
| | - Li Zhang
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China.,Department of Phase I Clinical Trial, Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China
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4
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Hu Y, Zhang H, Xie N, Liu D, Jiang Y, Liu Z, Ye D, Liu S, Chen X, Li C, Wang Q, Huang X, Liu Y, Shi Y, Zhang X. Bcl-3 promotes TNF-induced hepatocyte apoptosis by regulating the deubiquitination of RIP1. Cell Death Differ 2022; 29:1176-1186. [PMID: 34853447 PMCID: PMC9177694 DOI: 10.1038/s41418-021-00908-7] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2020] [Revised: 11/16/2021] [Accepted: 11/16/2021] [Indexed: 11/09/2022] Open
Abstract
Tumor necrosis factor-α (TNF) is described as a main regulator of cell survival and apoptosis in multiple types of cells, including hepatocytes. Dysregulation in TNF-induced apoptosis is associated with many autoimmune diseases and various liver diseases. Here, we demonstrated a crucial role of Bcl-3, an IκB family member, in regulating TNF-induced hepatic cell death. Specifically, we found that the presence of Bcl-3 promoted TNF-induced cell death in the liver, while Bcl-3 deficiency protected mice against TNF/D-GalN induced hepatoxicity and lethality. Consistently, Bcl-3-depleted hepatic cells exhibited decreased sensitivity to TNF-induced apoptosis when stimulated with TNF/CHX. Mechanistically, the in vitro results showed that Bcl-3 interacted with the deubiquitinase CYLD to synergistically switch the ubiquitination status of RIP1 and facilitate the formation of death-inducing Complex II. This complex further resulted in activation of the caspase cascade to induce apoptosis. By revealing this novel role of Bcl-3 in regulating TNF-induced hepatic cell death, this study provides a potential therapeutic target for liver diseases caused by TNF-related apoptosis.
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Affiliation(s)
- Yiming Hu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Haohao Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Ningxia Xie
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
| | - Dandan Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Yuhang Jiang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Zhi Liu
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Deji Ye
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Sanhong Liu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, 201203, Shanghai, China
| | - Xi Chen
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Cuifeng Li
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Qi Wang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Xingxu Huang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China
| | - Yongzhong Liu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, 200032, Shanghai, China
| | - Yufang Shi
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China
| | - Xiaoren Zhang
- Affiliated Cancer Hospital and Institute of Guangzhou Medical University; Key Laboratory for Cell Homeostasis and Cancer Research of Guangdong Higher Education Institutes; State Key Laboratory of Respiratory Disease, 510000, Guangzhou, China.
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Shanghai Institutes for Biological Sciences, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 200031, Shanghai, China.
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Fernandes SM, Watanabe M, Vattimo MDFF. Inflammation: improving understanding to prevent or ameliorate kidney diseases. J Venom Anim Toxins Incl Trop Dis 2021; 27:e20200162. [PMID: 34712277 PMCID: PMC8525891 DOI: 10.1590/1678-9199-jvatitd-2020-0162] [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: 12/01/2020] [Accepted: 04/12/2021] [Indexed: 11/21/2022] Open
Abstract
Inflammatory processes are believed to play an important role in immune response to maintain tissue homeostasis by activating cellular signaling pathways and releasing inflammatory mediators in the injured tissue. Although acute inflammation can be considered protective, an uncontrolled inflammation may evolve to tissue damage, leading to chronic inflammatory diseases. Inflammation can be considered the major factor involved in the pathological progression of acute and chronic kidney diseases. Functional characteristics of this organ increase its vulnerability to developing various forms of injuries, including acute kidney injury (AKI) and chronic kidney disease (CKD). In view of translational research, several discoveries should be considered regarding the pathogenesis of the inflammatory process, which results in the validation of biomarkers for early detection of kidney diseases. Biomarkers enable the identification of proinflammatory mediators in kidney affections, based on laboratory research applied to clinical practice. Some inflammatory molecules can be useful biomarkers for the detection and diagnosis of kidney diseases, such as neutrophil gelatinase-associated lipocalin, kidney injury molecule-1 and interleukin 18.
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Affiliation(s)
- Sheila Marques Fernandes
- Animal Model Experimental Laboratory (LEMA), School of Nursing (EEUSP), University of São Paulo (USP), São Paulo, SP, Brazil
| | - Mirian Watanabe
- Animal Model Experimental Laboratory (LEMA), School of Nursing (EEUSP), University of São Paulo (USP), São Paulo, SP, Brazil.,Health Sciences and Wellbeing (CISBEM), University Center of United Metropolitan Colleges, São Paulo, SP, Brazil
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Tan L, Xu SL, Mo ZS, Liu JR, Gan WQ, Chen JH, Gao ZL, Wu ZQ. The clinical value of serum hepatic parenchyma cell volume-normalized hepatitis B surface antigen levels in hepatitis B e antigen -positive and -negative chronic hepatitis B patients. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:1431. [PMID: 34733983 PMCID: PMC8506748 DOI: 10.21037/atm-21-3846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/02/2021] [Indexed: 11/10/2022]
Abstract
BACKGROUND While serum hepatitis B surface antigens (HBsAg) play an important role in the diagnosis and assessment of treatment results of hepatitis B virus (HBV) infections, it remains unclear whether HBsAg levels normalized to hepatic parenchymal cell volume (HPCV) is a superior indicator of disease state. This study compared the absolute and HPCV-normalized serum HBsAg levels in hepatitis B e antigen (HBeAg)-positive and HBeAg-negative patients with chronic hepatitis B (CHB). METHODS Patients admitted to our institution with CHB were retrospectively included and categorized into the HBeAg-positive and HBeAg-negative groups. HPCV was calculated based on pathological examination of liver biopsy specimens and theory of sphere geometry. The difference between HBsAg levels and HBsAg normalized to HPCV, and also correlation between HBsAg levels and liver inflammation and fibrosis was analyzed. RESULTS Absolute HBsAg levels (P=0.004), but not HPCV-normalized HBsAg levels (P=0.071) were significantly higher in HBeAg-positive patients compared to HBeAg-negative patients. In HBeAg-positive CHB patients, absolute HBsAg levels were positively correlated with liver inflammation grade (R=0.285, P=0.001) and hepatic fibrosis stage (R=0.351, P<0.001), as were HPCV-normalized HBsAg levels (R=0.640 and 0.742, both, P<0.001). However, in HBeAg-negative CHB patients, only HPCV-normalized HBsAg level were correlated with liver inflammation grade and hepatic fibrosis stage (R=0.640 and 0.785, both, P<0.001). CONCLUSIONS HPCV-normalized serum HBsAg levels, rather than absolute HBsAg levels, were positively correlated with liver inflammation grade and hepatic fibrosis stage in both HBeAg-positive and HBeAg-negative CHB patients. Thus, HPCV-normalized HBsAg levels may more accurately reflect the pathological progress of CHB patients compared to absolute HBsAg levels.
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Affiliation(s)
- Lei Tan
- Department of Medical Ultrasonic, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Shi-Lei Xu
- Department of General Surgery, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Zhi-Shuo Mo
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Topical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Jian-Rong Liu
- Surgical and Transplant Intensive Care Unit, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Wei-Qiang Gan
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Topical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Jie-Huan Chen
- Department of Ultrasound, Binhaiwan Central Hospital of Dongguan, Dongguan, China
| | - Zhi-Liang Gao
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Topical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
| | - Ze-Qian Wu
- Department of Infectious Diseases, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- Key Laboratory of Topical Disease Control, Sun Yat-sen University, Ministry of Education, Guangzhou, China
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7
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Castro‐Gil MP, Sánchez‐Rodríguez R, Torres‐Mena JE, López‐Torres CD, Quintanar‐Jurado V, Gabiño‐López NB, Villa‐Treviño S, del‐Pozo‐Jauner L, Arellanes‐Robledo J, Pérez‐Carreón JI. Enrichment of progenitor cells by 2-acetylaminofluorene accelerates liver carcinogenesis induced by diethylnitrosamine in vivo. Mol Carcinog 2021; 60:377-390. [PMID: 33765333 PMCID: PMC8251613 DOI: 10.1002/mc.23298] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 02/24/2021] [Accepted: 03/15/2021] [Indexed: 02/06/2023]
Abstract
The potential role of hepatocytes versus hepatic progenitor cells (HPC) on the onset and pathogenesis of hepatocellular carcinoma (HCC) has not been fully clarified. Because the administration of 2-acetylaminofluorene (2AAF) followed by a partial hepatectomy, selectively induces the HPC proliferation, we investigated the effects of chronic 2AAF administration on the HCC development caused by the chronic administration of the carcinogen diethylnitrosamine (DEN) for 16 weeks in the rat. DEN + 2AAF protocol impeded weight gain of animals but promoted prominent hepatomegaly and exacerbated liver alterations compared to DEN protocol alone. The tumor areas detected by γ-glutamyl transferase, prostaglandin reductase-1, and glutathione S-transferase Pi-1 liver cancer markers increased up to 80% as early as 12 weeks of treatment, meaning 6 weeks earlier than DEN alone. This protocol also increased the number of Ki67-positive cells and those of CD90 and CK19, two well-known progenitor cell markers. Interestingly, microarray analysis revealed that DEN + 2AAF protocol differentially modified the global gene expression signature and induced the differential expression of 30 genes identified as HPC markers as early as 6 weeks of treatment. In conclusion, 2AAF induces the early appearance of HPC markers and as a result, accelerates the hepatocarcinogenesis induced by DEN in the rat. Thus, since 2AAF simultaneously administrated with DEN enriches HPC during hepatocarcinogenesis, we propose that DEN + 2AAF protocol might be a useful tool to investigate the cellular origin of HCC with progenitor features.
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Affiliation(s)
| | - Ricardo Sánchez‐Rodríguez
- Foundation Istituto di Ricerca Pediatrica‐Città della SperanzaPadovaItaly
- Department of Biomedical SciencesUniversity of PadovaPadovaItaly
| | | | | | | | | | - Saúl Villa‐Treviño
- Department of Cell BiologyCenter for Research and Advanced Studies of the National Polytechnic InstituteCiudad de MéxicoMexico
| | | | - Jaime Arellanes‐Robledo
- Laboratory of Liver DiseasesNational Institute of Genomic MedicineCiudad de MéxicoMexico
- Directorate of CátedrasNational Council of Science and TechnologyCiudad de MéxicoMexico
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Wisteria floribunda agglutinin-positive Mac-2-binding protein as a diagnostic biomarker in liver cirrhosis: an updated meta-analysis. Sci Rep 2020; 10:10582. [PMID: 32601332 PMCID: PMC7324360 DOI: 10.1038/s41598-020-67471-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Accepted: 06/04/2020] [Indexed: 02/05/2023] Open
Abstract
Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) had been suggested as a possible glycobiomarker for assessing liver fibrosis. Here, we conducted this updated meta-analysis to systematically investigate the predictive accuracy of WFA+-M2BP for diagnosing liver fibrosis and hepatocellular carcinoma (HCC) by comparing with multiple non-invasive indicators. We searched relevant literatures from Pubmed, Web of Science, EMBASE and Cochrane Library and enrolled 36 eligible studies involving 7,362 patients. Summary results were calculated using bivariate random effects model. The pooled sensitivities, specificities and areas under the summary receiver operating characteristic curves (AUSROCs) of WFA+-M2BP for identifying mild fibrosis, significant fibrosis, advanced fibrosis, cirrhosis, and HCC were 0.70/0.68/0.75, 0.71/0.75/0.79, 0.75/0.76/0.82, 0.77/0.86/0.88, and 0.77/0.80/0.85, respectively. The accuracy of WFA+-M2BP was strongly affected by etiology and it was not better than other non-invasive indicators for predicting early fibrosis. It showed similar diagnostic performance to hyaluronic acid and FibroScan for cirrhosis, but was equivalent to α-fetoprotein for HCC. In conclusion, WFA+-M2BP was suitable to diagnose late stage of liver fibrosis, especially cirrhosis. Individual cutoff value of WFA+-M2BP could be used to grade liver fibrosis in different etiology. Combined diagnostic model was suggested to improve its predictive accuracy for HCC.
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9
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Hepatocyte-specific TAK1 deficiency drives RIPK1 kinase-dependent inflammation to promote liver fibrosis and hepatocellular carcinoma. Proc Natl Acad Sci U S A 2020; 117:14231-14242. [PMID: 32513687 DOI: 10.1073/pnas.2005353117] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Transforming growth factor β-activated kinase1 (TAK1) encoded by the gene MAP3K7 regulates multiple important downstream effectors involved in immune response, cell death, and carcinogenesis. Hepatocyte-specific deletion of TAK1 in Tak1 ΔHEP mice promotes liver fibrosis and hepatocellular carcinoma (HCC) formation. Here, we report that genetic inactivation of RIPK1 kinase using a kinase dead knockin D138N mutation in Tak1 ΔHEP mice inhibits the expression of liver tumor biomarkers, liver fibrosis, and HCC formation. Inhibition of RIPK1, however, has no or minimum effect on hepatocyte loss and compensatory proliferation, which are the recognized factors important for liver fibrosis and HCC development. Using single-cell RNA sequencing, we discovered that inhibition of RIPK1 strongly suppresses inflammation induced by hepatocyte-specific loss of TAK1. Activation of RIPK1 promotes the transcription of key proinflammatory cytokines, such as CCL2, and CCR2+ macrophage infiltration. Our study demonstrates the role and mechanism of RIPK1 kinase in promoting inflammation, both cell-autonomously and cell-nonautonomously, in the development of liver fibrosis and HCC, independent of cell death, and compensatory proliferation. We suggest the possibility of inhibiting RIPK1 kinase as a therapeutic strategy for reducing liver fibrosis and HCC development by inhibiting inflammation.
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10
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Lian J, Zou Y, Huang L, Cheng H, Huang K, Zeng J, Chen L. Hepatitis B virus upregulates cellular inhibitor of apoptosis protein 2 expression via the PI3K/AKT/NF-κB signaling pathway in liver cancer. Oncol Lett 2020; 19:2043-2052. [PMID: 32194701 DOI: 10.3892/ol.2020.11267] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2019] [Accepted: 11/01/2019] [Indexed: 12/30/2022] Open
Abstract
Activation of antiapoptotic genes has been indicated as one of the factors that contributes to hepatitis B virus (HBV) infection-induced liver cancer. The cellular inhibitor of apoptosis protein 2 (cIAP2), a member of the IAP family, is upregulated in various types of cancer and serves as a potential treatment target. However, to the best of our knowledge, the importance of cIAP2 in HBV-induced liver cancer has not been investigated. In the present study, cIAP2 expression in liver cells in response to HBV infection and the underlying mechanism involved was investigated. Western blot analysis of clinical liver samples showed that higher cIAP2 expression was detected in HBV-positive non-cancerous tissue compared with that in HBV-negative non-cancerous tissue, and the expression was further increased in HBV-positive liver cancer tissue. Reverse transcription-quantitative PCR and western blot experiments performed on two liver cell lines also confirmed that cIAP2 expression was increased upon HBV infection at both the mRNA and protein levels. Promoter analysis revealed that HBV could activate cIAP2 promoter in an infection dose-dependent manner, and this activation involved a NF-κB-binding site in the cIAP2 promoter. Further analysis demonstrated that HBV enhanced NF-κB phosphorylation and nuclear translocation via the PI3K/AKT signaling pathway, leading to the binding and activation of cIAP2 promoter. The present data demonstrates that HBV-infection induces cIAP2 expression in the liver by activation of the PI3K/AKT/NF-κB signaling pathway through promoting the binding of NF-κB to cIAP2 promoter, which may lead to carcinogenesis. The findings from the present study provide more information for understanding HBV-induced liver cancer and also offer a potential target for treatment or diagnosis of this disease.
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Affiliation(s)
- Jianping Lian
- Department of Radiation Oncology, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong 510515, P.R. China.,Department of Oncology, The Affiliated Hospital of Jinggangshan University, Ji'an, Jiangxi 343000, P.R. China
| | - Yuanhua Zou
- Department of Rehabilitation, The Affiliated Hospital of Jinggangshan University, Ji'an, Jiangxi 343000, P.R. China
| | - Ling Huang
- Department of Oncology, The Affiliated Hospital of Jinggangshan University, Ji'an, Jiangxi 343000, P.R. China
| | - Hao Cheng
- Department of Nasopharyngeal Carcinoma, The First People's Hospital of Chenzhou, Southern Medical University, Chenzhou, Hunan 423000, P.R. China
| | - Kai Huang
- Department of Gastrointestinal Surgery, Jiangxi Provincial Cancer Hospital, Nanchang, Jiangxi 330029, P.R. China
| | - Junquan Zeng
- Department of Rehabilitation, The Affiliated Hospital of Jinggangshan University, Ji'an, Jiangxi 343000, P.R. China
| | - Longhua Chen
- Department of Radiation Oncology, Nanfang Hospital of Southern Medical University, Guangzhou, Guangdong 510515, P.R. China
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11
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Luo CL, Rong Y, Chen H, Zhang WW, Wu L, Wei D, Wei XQ, Mei LJ, Wang FB. A Logistic Regression Model for Noninvasive Prediction of AFP-Negative Hepatocellular Carcinoma. Technol Cancer Res Treat 2019; 18:1533033819846632. [PMID: 31106685 PMCID: PMC6535757 DOI: 10.1177/1533033819846632] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
α-Fetoprotein is commonly used in the diagnosis of hepatocellular carcinoma. However, the diagnostic significance of α-fetoprotein has been questioned because a number of patients with hepatocellular carcinoma are α-fetoprotein negative. It is therefore necessary to develop novel noninvasive techniques for the early diagnosis of hepatocellular carcinoma, particularly when α-fetoprotein level is low or negative. The current study aimed to evaluate the diagnostic efficiency of hematological parameters to determine which can act as surrogate markers in α-fetoprotein-negative hepatocellular carcinoma. Therefore, a retrospective study was conducted on a training set recruited from Zhongnan Hospital of Wuhan University-including 171 α-fetoprotein-negative patients with hepatocellular carcinoma and 102 healthy individuals. The results show that mean values of mean platelet volume, red blood cell distribution width, mean platelet volume-PC ratio, neutrophils-lymphocytes ratio, and platelet count-lymphocytes ratio were significantly higher in patients with hepatocellular carcinoma in comparison to the healthy individuals. Most of these parameters showed moderate area under the curve in α-fetoprotein-negative patients with hepatocellular carcinoma, but their sensitivities or specificities were not satisfactory enough. So, we built a logistic regression model combining multiple hematological parameters. This model presented better diagnostic efficiency with area under the curve of 0.922, sensitivity of 83.0%, and specificity of 93.1%. In addition, the 4 validation sets from different hospitals were used to validate the model. They all showed good area under the curve with satisfactory sensitivities or specificities. These data indicate that the logistic regression model combining multiple hematological parameters has better diagnostic efficiency, and they might be helpful for the early diagnosis for α-fetoprotein-negative hepatocellular carcinoma.
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Affiliation(s)
- Chang-Liang Luo
- 1 Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Yuan Rong
- 1 Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Hao Chen
- 2 Department of Pathology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Wu-Wen Zhang
- 1 Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Long Wu
- 3 Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Diao Wei
- 4 Department of Blood Transfusion, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Xiu-Qi Wei
- 5 Department of Laboratory Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, People's Republic of China
| | - Lie-Jun Mei
- 6 Department of Radiology, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
| | - Fu-Bing Wang
- 1 Department of Laboratory Medicine, Zhongnan Hospital of Wuhan University, Wuhan, People's Republic of China
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12
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Ponziani FR, Nicoletti A, Gasbarrini A, Pompili M. Diagnostic and therapeutic potential of the gut microbiota in patients with early hepatocellular carcinoma. Ther Adv Med Oncol 2019; 11:1758835919848184. [PMID: 31205505 PMCID: PMC6535703 DOI: 10.1177/1758835919848184] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2019] [Accepted: 04/12/2019] [Indexed: 12/16/2022] Open
Abstract
The gut microbiota is involved in the maintenance of the homeostasis of the human body and its alterations are associated with the development of different pathological conditions. The liver is the organ most exposed to the influence of the gut microbiota, and recently important connections between the intestinal flora and hepatocellular carcinoma (HCC) have been described. In fact, HCC is commonly associated with liver cirrhosis and develops in a microenvironment where inflammation, immunological alterations, and cellular aberrations are dramatically evident. Prevention and diagnosis in the earliest stages are still the most effective weapons in fighting this tumor. Animal models show that the gut microbiota can be involved in the promotion and progression of HCC directly or through different pathogenic mechanisms. Recent data in humans have confirmed these preclinical findings, shedding new light on HCC pathogenesis. Limitations due to the different experimental design, the ethnic and hepatological setting make it difficult to compare the results and draw definitive conclusions, but these studies lay the foundations for a pathogenetic redefinition of HCC. Therefore, it is evident that the characterization of the gut microbiota and its modulation can have an enormous diagnostic, preventive, and therapeutic potential, especially in patients with early stage HCC.
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Affiliation(s)
- Francesca Romana Ponziani
- Division of Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Largo Agostino Gemelli 8, Rome, 00168, Italy
| | - Alberto Nicoletti
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Antonio Gasbarrini
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
| | - Maurizio Pompili
- Internal Medicine, Gastroenterology and Hepatology, Fondazione Policlinico Agostino Gemelli IRCCS, Rome, Italy
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13
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Liu WT, Jing YY, Gao L, Li R, Yang X, Pan XR, Yang Y, Meng Y, Hou XJ, Zhao QD, Han ZP, Wei LX. Lipopolysaccharide induces the differentiation of hepatic progenitor cells into myofibroblasts constitutes the hepatocarcinogenesis-associated microenvironment. Cell Death Differ 2019; 27:85-101. [PMID: 31065105 DOI: 10.1038/s41418-019-0340-7] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 04/05/2019] [Accepted: 04/16/2019] [Indexed: 12/23/2022] Open
Abstract
Hepatocellular carcinoma (HCC) generally occurs in the presence of chronic liver injury, often as a sequela of liver fibrosis. Hepatic progenitor cells (HPCs) are known to be capable of forming both hepatocytes and cholangiocytes in chronic liver injury, which are also considered a source of myofibroblasts and tumor-initiating cells, under carcinogenic circumstances. However, the underlying mechanisms that activate HPCs to give rise to HCC are still unclear. In current study, the correlation between HPCs activation and liver fibrosis and carcinogenesis was investigated in rats and human specimens. We analyzed the role of HPCs in tumorigenesis, by transplanting exogenous HPCs in a diethylnitrosamine-induced rat HCC model. Our data indicated that HPC activation correlated with hepatic fibrosis and hepatocarcinogenesis. We further found that exogenous HPC infusion promoted liver fibrosis and hepatocarcinogenesis, while lipopolysaccharides (LPS) played an important role in this process. However, results of our study indicated that LPS did not induce HPCs to form tumor in nude mice directly. Rather, LPS induced myofibroblast-like morphology in HPCs, which enhanced the tumorigenic potential of HPCs. Further experiments showed that LPS/Toll-like receptor 4 (TLR4) signaling mediated the differentiation of HPCs into myofibroblasts and enhanced the production of interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), which led to the aberrant expression of Ras and p53 signaling pathways in HPCs, and finally, promoted the proliferation and malignant transformation of HPCs, by long non-coding RNA regulation. Besides, examination of HCC clinical samples demonstrated that IL-6 and TNF-α production correlated with HPC activation, hepatic fibrosis, and HCC recurrence. Our study indicates that both myofibroblasts and tumor cells are derived from HPCs. HPC-derived myofibroblasts create tumor microenvironment and contribute to the proliferation and malignant transformation of HPCs. Furthermore, LPS present in the chronic liver inflammation microenvironment might play an important role in hepatocarcinogenesis, by regulating the plastic potential of HPCs.
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Affiliation(s)
- Wen-Ting Liu
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Ying-Ying Jing
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Lu Gao
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xue Yang
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiao-Rong Pan
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yang Yang
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Yan Meng
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Xiao-Juan Hou
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Qiu-Dong Zhao
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China
| | - Zhi-Peng Han
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
| | - Li-Xin Wei
- Tumor Immunology and Gene Therapy Center, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, China.
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14
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Transcriptomic profiles of tumor-associated neutrophils reveal prominent roles in enhancing angiogenesis in liver tumorigenesis in zebrafish. Sci Rep 2019; 9:1509. [PMID: 30728369 PMCID: PMC6365535 DOI: 10.1038/s41598-018-36605-8] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Accepted: 10/31/2018] [Indexed: 12/12/2022] Open
Abstract
We have previously demonstrated the pro-tumoral role of neutrophils using a kras-induced zebrafish hepatocarcinogenesis model. To further illustrate the molecular basis of the pro-tumoral role, Tumor-associated neutrophils (TANs) were isolated by fluorescence-activated cell sorting (FACS) and transcriptomic analyses were carried out by RNA-Seq. Differentially expressed gene profiles of TANs from larvae, male and female livers indicate great variations during liver tumorigenesis, but the common responsive canonical pathways included an immune pathway (Acute Phase Response Signaling), a liver metabolism-related pathway (LXR/RXR Activation) and Thrombin Signaling. Consistent with the pro-tumoral role of TANs, gene module analysis identified a consistent down-regulation of Cytotoxicity module, which may allow continued proliferation of malignant cells. Gene Set Enrichment Analysis indicated up-regulation of several genes promoting angiogenesis. Consistent with this, we found decreased density of blood vessels accompanied with decreased oncogenic liver sizes in neutrophil-depleted larvae. Collectively, our study has indicated some molecular mechanisms of the pro-tumoral roles of TANs in hepatocarcinogenesis, including weakened immune clearance against tumor cells and enhanced function in angiogenesis.
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15
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Mazmishvili K, Jayant K, Janikashvili N, Kikodze N, Mizandari M, Pantsulaia I, Paksashvili N, Sodergren MH, Reccia I, Pai M, Habib N, Chikovani T. Study to evaluate the immunomodulatory effects of radiofrequency ablation compared to surgical resection for liver cancer. J Cancer 2018; 9:3187-3195. [PMID: 30210642 PMCID: PMC6134816 DOI: 10.7150/jca.25084] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Accepted: 04/05/2018] [Indexed: 12/13/2022] Open
Abstract
Introduction: Hepatic cancer is a highly lethal tumour with increasing worldwide incidence. These tumours are characterized by the proliferation of malignant cells, generalised immunosuppression and chronic inflammation marked with an increase in inflammatory markers as a neutrophil-to-lymphocyte ratio (NLR), the platelet-to-lymphocyte ratio (PLR) and overexpression of CD4+CD39+ on T lymphocytes. The studies have outlined immunomodulatory changes in liver cancer patients as the plausible explanation for the better survival. The aim of this pilot study was understand the possible immunomodulatory effect of radiofrequency (RF) energy and liver resection (non-radiofrequency based devices; non-RF device) in relation to NLR, PLR and expression of CD4+CD39+ T lymphocytes and compare the magnitude of these changes. Material and Methods: In the present study, 17 patients with hepatic cancer were prospectively divided into treatment groups radiofrequency ablation (RFA group) and Liver resection using non-RF devices (LR group). A blood sample was collected from each patient, one month before and after the procedure and compared with the blood samples of age-matched healthy volunteers for group wise comparison. The Mann-Whitney U test, Mc Nemar test and Wilcoxon rank test were used for statistical comparisons as appropriate. Results: A decrease in NLR was reported after RFA from 4.7±3.3 to 3.8±1.8 (P=0.283), in contrary to an increase from 3.5±2.8 to 4.5±3.2 (P=0.183) in LR group. Likewise, a decrease was discerned in PLR following RFA from 140.5±79.5 to 137±69.2 respectively (P=0.386) and increase in the LR group from 116±42.2 to 120.8±29 respectively (P=0.391). A significant decrease in CD4+CD39+ lymphocytes from 55.8±13.8 to 24.6±21.1 (P=0.03) was observed in RFA group whilst a significant increase was reported in LR group from 47.6±8.8 to 55.7±33.2 (P=0.38). Conclusion: Studies have shown that decrease in the NLR, PLR and expression of CD4+CD39+ on T lymphocytes as the marker of better survival in hepatic cancer patients and our findings have confirmed that these changes can be induced following application of RF energy. Moreover, this could be the explanation of better survival observed in different studies using RFA or other RF-based devices in comparison to non-RF based liver resection techniques. However, further larger studies are needed to confirm these findings.
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Affiliation(s)
- Ketevan Mazmishvili
- Department of Immunology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Kumar Jayant
- Department of Surgery and Cancer, Hammersmith Hospital, Imperial College London, DuCane Road, W120HS, UK
| | - Nona Janikashvili
- Department of Immunology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Nino Kikodze
- Department of Immunology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Malkhaz Mizandari
- Department of Interventional Radiology, Tbilisi State Medical University, High Technology University Clinic, 0144 Tbilisi, Georgia
| | - Ia Pantsulaia
- Department of Immunology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
| | - Natela Paksashvili
- Department of Immunology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
- Department of Interventional Radiology, Tbilisi State Medical University, High Technology University Clinic, 0144 Tbilisi, Georgia
| | - Mikael H Sodergren
- Department of Surgery and Cancer, Hammersmith Hospital, Imperial College London, DuCane Road, W120HS, UK
| | - Isabella Reccia
- Department of Surgery and Cancer, Hammersmith Hospital, Imperial College London, DuCane Road, W120HS, UK
| | - Madhava Pai
- Department of Surgery and Cancer, Hammersmith Hospital, Imperial College London, DuCane Road, W120HS, UK
| | - Nagy Habib
- Department of Surgery and Cancer, Hammersmith Hospital, Imperial College London, DuCane Road, W120HS, UK
| | - Tinatin Chikovani
- Department of Immunology, Tbilisi State Medical University, 0186 Tbilisi, Georgia
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16
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Choiniere J, Lin MJ, Wang L, Wu J. Deficiency of pyruvate dehydrogenase kinase 4 sensitizes mouse liver to diethylnitrosamine and arsenic toxicity through inducing apoptosis. LIVER RESEARCH 2018; 2:100-107. [PMID: 31815032 PMCID: PMC6896988 DOI: 10.1016/j.livres.2018.05.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIM Pyruvate dehydrogenase kinase 4 (PDK4) is a metabolism switch that regulates glucose oxidation and the tricarboxylic acid cycle (TCA cycle) in the mitochondria. Liver detoxifies xenobiotics and is constantly challenged by various injuries. This study aims at understanding how the loss of the metabolism regulator PDK4 contributes to liver injuries. METHODS Wild-type (WT) and Pdk4 knockout (Pdk4 -/-) mice of different ages were examined for spontaneous hepatic apoptosis. Juvenile or adult mice of two genotypes were insulted by diethylnitrosamine (DEN), arsenic, galactosamine (GalN)/lipopolysaccharide (LPS), anti-CD95 (Jo2) antibody or carbon tetrachloride (CCl4). Liver injury was monitored by blood biochemistry test. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, poly (ADP-ribose) polymerase (PARP) cleavage, and caspase activity assay. Inflammatory response was determined by nuclear factor (NF)-κB activation and the activation of NF-κB target genes. Primary hepatocytes were isolated and cell viability was evaluated by MTS assay. RESULTS We showed that systematic Pdk4 -/- in mice resulted in age-dependent spontaneous hepatic apoptosis. PDK4-deficiency increased the toxicity of DEN in juvenile mice, which correlated with a lethal consequence and massive hepatic apoptosis. Similarly, chronic arsenic administration induced more severe hepatic apoptosis in Pdk4 -/- mice compared to WT control mice. An aggravated hepatic NF-κB mediated-inflammatory response was observed in Pdk4 -/- mice livers. In vitro, Pdk4-deficient primary hepatocytes were more vulnerable to DEN and arsenic challenges and displayed higher caspase activity than wild type cells. Notably, hepatic PDK4 mRNA level was remarkably reduced during acute liver failure induced by GalN/LPS or Jo2 antibody. The diminished PDK4 expression was also observed in CCl4-induced acute liver injury. CONCLUSIONS PDK4 may contribute to the protection from apoptotic injury in mouse liver.
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Affiliation(s)
- Jonathan Choiniere
- Department of Physiology and Neurobiology, Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA
| | - Matthew Junda Lin
- Department of Physiology and Neurobiology, Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA
| | - Li Wang
- Department of Physiology and Neurobiology, Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA
- Veterans Affairs Connecticut Healthcare System, West Haven, CT, USA
- Department of Internal Medicine, Section of Digestive Diseases, Yale University, New Haven, CT, USA
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, China
| | - Jianguo Wu
- Department of Physiology and Neurobiology, Institute for Systems Genomics, University of Connecticut, Storrs, CT, USA
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17
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Shang N, Bank T, Ding X, Breslin P, Li J, Shi B, Qiu W. Caspase-3 suppresses diethylnitrosamine-induced hepatocyte death, compensatory proliferation and hepatocarcinogenesis through inhibiting p38 activation. Cell Death Dis 2018; 9:558. [PMID: 29752472 PMCID: PMC5948202 DOI: 10.1038/s41419-018-0617-7] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Accepted: 04/19/2018] [Indexed: 02/07/2023]
Abstract
It is critical to understand the molecular mechanisms of hepatocarcinogenesis in order to prevent or treat hepatocellular carcinoma (HCC). The development of HCC is commonly associated with hepatocyte death and compensatory proliferation. However, the role of Caspase-3, a key apoptotic executor, in hepatocarcinogenesis is unknown. In this study, we used Caspase-3-deficient mice to examine the role of Caspase-3 in hepatocarcinogenesis in a chemical (diethylnitrosamine, DEN)-induced HCC model. We found that Caspase-3 deficiency significantly increased DEN-induced HCC. Unexpectedly, Caspase-3 deficiency increased apoptosis induced by DEN and the subsequent compensatory proliferation. Intriguingly, we discovered that Caspase-3 deficiency increased the activation of p38 with and without DEN treatment. Moreover, we demonstrated that TNFα and IL1α stimulated increased activation of p38 in Caspase-3 KO hepatocytes compared with wild-type hepatocytes. Finally, we found that inhibition of p38 by SB202190 abrogated enhanced hepatocyte death, compensatory proliferation and HCC induced by DEN in Caspase-3-deficient mice. Overall, our data suggest that Caspase-3 inhibits chemical-induced hepatocarcinogenesis by suppressing p38 activation and hepatocyte death.
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Affiliation(s)
- Na Shang
- Department of Surgery and Oncology Institute, Loyola University Chicago Stritch School of Medicine, 2160 South 1st Avenue, Maywood, IL, 60153, USA
| | - Thomas Bank
- Department of Surgery and Oncology Institute, Loyola University Chicago Stritch School of Medicine, 2160 South 1st Avenue, Maywood, IL, 60153, USA
| | - Xianzhong Ding
- Department of Pathology, Loyola University Chicago Stritch School of Medicine, 2160 South 1st Avenue, Maywood, IL, 60153, USA
| | - Peter Breslin
- Department of Surgery and Oncology Institute, Loyola University Chicago Stritch School of Medicine, 2160 South 1st Avenue, Maywood, IL, 60153, USA
- Department of Molecular/Cellular Physiology, Loyola University Chicago Stritch School of Medicine, 2160 South 1st Avenue, Maywood, IL, 60153, USA
| | - Jun Li
- Department of Applied and Computational Mathematics and Statistics, University of Notre Dame, Notre Dame, IN, USA
| | - Baomin Shi
- Department of General Surgery Tongji Hospital, Tongji University Medical School, Shanghai, PR, 200065, China.
| | - Wei Qiu
- Department of Surgery and Oncology Institute, Loyola University Chicago Stritch School of Medicine, 2160 South 1st Avenue, Maywood, IL, 60153, USA.
- Department of General Surgery Tongji Hospital, Tongji University Medical School, Shanghai, PR, 200065, China.
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18
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Yang C, Su H, Liao X, Han C, Yu T, Zhu G, Wang X, Winkler CA, O'Brien SJ, Peng T. Marker of proliferation Ki-67 expression is associated with transforming growth factor beta 1 and can predict the prognosis of patients with hepatic B virus-related hepatocellular carcinoma. Cancer Manag Res 2018; 10:679-696. [PMID: 29692627 PMCID: PMC5901156 DOI: 10.2147/cmar.s162595] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent malignancy of the liver. Transforming growth factor beta 1 (TGFB1) and marker of proliferation Ki-67 (MKI67) regulate cell proliferation, differentiation, and growth. The association between MKI67 and TGFB1 expression and its clinical implications in HCC remain unknown.
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Affiliation(s)
- Chengkun Yang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Hao Su
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Cheryl Ann Winkler
- Basic Research Laboratory, CCR, NCI, Leidos Biomedical Research, Frederick National Laboratory, Frederick, MD, USA
| | - Stephen J O'Brien
- Laboratory of Genomic Diversity, National Cancer Institute, NIH, Frederick, MD, USA.,Theodosius Dobzhansky Center for Genome Bioinformatics, St. Petersburg State University, St Petersburg, Russia.,Guy Harvey Oceanographic Center, Halmos College of Natural Sciences and Oceanography, Nova Southeastern University, Fort Lauderdale, FL, USA
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
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19
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Eun HS, Cho SY, Joo JS, Kang SH, Moon HS, Lee ES, Kim SH, Lee BS. Gene expression of NOX family members and their clinical significance in hepatocellular carcinoma. Sci Rep 2017; 7:11060. [PMID: 28894215 PMCID: PMC5593889 DOI: 10.1038/s41598-017-11280-3] [Citation(s) in RCA: 44] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2017] [Accepted: 08/22/2017] [Indexed: 11/09/2022] Open
Abstract
Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-derived reactive oxygen species (ROS) promote chronic liver inflammation and remodeling that can drive hepatocellular carcinoma development. The role of NOX expression in hepatocellular carcinoma (HCC) has been partially investigated; however, the clinical relevance of collective or individual NOX family member expression for HCC survival remains unclear. Here, we obtained NOX mRNA expression data for 377 HCC samples and 21 normal liver controls from the TCGA data portal and performed Kaplan-Meier survival, gene ontology functional enrichment, and gene set enrichment analyses. Although most NOX genes exhibited little change, some were significantly induced in HCC compared to that in normal controls. In addition, HCC survival analyses indicated better overall survival in patients with high NOX4 and DUOX1 expression, whereas patients with high NOX1/2/5 expression showed poor prognoses. Gene-neighbour and gene set enrichment analyses revealed that NOX1/2/5 were strongly correlated with genes associated with cancer cell survival and metastasis, whereas increased NOX4 and DUOX1 expression was associated with genes that inhibit tumour progression. On the basis of these data, NOX family gene expression analysis could be a predictor of survival and identify putative therapeutic targets in HCC.
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Affiliation(s)
- Hyuk Soo Eun
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, 282, Munwha-ro, Jung-gu, Daejeon, Republic of Korea.,Department of Internal Medicine, School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, Republic of Korea
| | - Sang Yeon Cho
- School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, Republic of Korea
| | - Jong Seok Joo
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, 282, Munwha-ro, Jung-gu, Daejeon, Republic of Korea.,Department of Internal Medicine, School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, Republic of Korea
| | - Sun Hyung Kang
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, 282, Munwha-ro, Jung-gu, Daejeon, Republic of Korea.,Department of Internal Medicine, School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, Republic of Korea
| | - Hee Seok Moon
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, 282, Munwha-ro, Jung-gu, Daejeon, Republic of Korea.,Department of Internal Medicine, School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, Republic of Korea
| | - Eaum Seok Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, 282, Munwha-ro, Jung-gu, Daejeon, Republic of Korea.,Department of Internal Medicine, School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, Republic of Korea
| | - Seok Hyun Kim
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, 282, Munwha-ro, Jung-gu, Daejeon, Republic of Korea.,Department of Internal Medicine, School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, Republic of Korea
| | - Byung Seok Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Chungnam National University Hospital, 282, Munwha-ro, Jung-gu, Daejeon, Republic of Korea. .,Department of Internal Medicine, School of Medicine, Chungnam National University, 266, Munwha-ro, Jung-gu, Daejeon, Republic of Korea.
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20
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Chen CT, Liao WY, Hsu CC, Hsueh KC, Yang SF, Teng YH, Yu YL. FUT2 genetic variants as predictors of tumor development with hepatocellular carcinoma. Int J Med Sci 2017; 14:885-890. [PMID: 28824326 PMCID: PMC5562196 DOI: 10.7150/ijms.19734] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/20/2017] [Accepted: 05/20/2017] [Indexed: 01/10/2023] Open
Abstract
Lewis antigens related to the ABO blood group are fucosylated oligosaccharides and are synthesized by specific glycosyltransferases (FUTs). FUTs are involved in various biological processes including cell adhesion and tumor progression. The fucosyltransferase-2 gene (FUT2) encodes alpha (1,2) fucosyltransferase, which is responsible for the addition of the alpha (1,2)-linkage of fucose to glycans. Aberrant fucosylation occurs frequently during the development and progression of hepatocellular carcinoma (HCC). However, the association of FUT2 polymorphisms with HCC development has not been studied. Therefore, we aimed to investigate the association of FUT2 polymorphisms with demographic, etiological, and clinical characteristics and with susceptibility to HCC. In this study, a total of 339 patients and 720 controls were recruited. The genotypes of FUT2 at four single-nucleotide polymorphisms (SNPs; rs281377, rs1047781, rs601338, and rs602662) were detected by real-time polymerase chain reaction from these samples. Compared with the wild-type genotype at SNP rs1047781, which is homozygous for nucleotides AA, at least one polymorphic T allele (AT or TT) displayed significant association with clinical stage (p = 0.048) and tumor size (p = 0.022). Our study strongly implicates the polymorphic locus rs1047781 of FUT2 as being associated with HCC development.
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Affiliation(s)
- Chih Tien Chen
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Surgery, Taichung Veterans General Hospital, Taichung, Taiwan
| | - Wen Ying Liao
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Chia Chun Hsu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
- Institute of Biotechnology, National Tsing-Hua University, Hsinchu, Taiwan
| | - Kuan Chun Hsueh
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Division of General Surgery, Department of Surgery, Tungs' Taichung MetroHarbour Hospital, Taichung, Taiwan
| | - Shun Fa Yang
- Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Ying Hock Teng
- Department of Emergency Medicine, School of Medicine, Chung Shan Medical University, Taichung, Taiwan
- Department of Emergency Medicine, Chung Shan Medical University Hospital, Taichung, Taiwan
| | - Yung Luen Yu
- Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan
- Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan
- Department of Biotechnology, Asia University, Taichung, Taiwan
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21
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Goyal H, Hu ZD. Prognostic value of red blood cell distribution width in hepatocellular carcinoma. ANNALS OF TRANSLATIONAL MEDICINE 2017; 5:271. [PMID: 28758097 DOI: 10.21037/atm.2017.06.30] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Red blood cell distribution width (RDW) is a simple, inexpensive, routinely measured and automatically reported blood test parameter, which reflects the degree of anisocytosis of red blood cells in peripheral blood. RDW was found to be associated with and retain clinical significance for assessing disease severity and outcomes in a number of hematological and solid malignancies. Motley of interacting clinical and biochemical factors have an impact on the red cell population biology. Malignancies per se can act as a causative factor, or anisocytosis may develop as a result of chronic inflammation. RDW has also been shown to be affected by nutritional status, which is typically deranged in malignancies. RDW is shown to be a clinically useful marker of disease severity and level of fibrosis in liver cirrhosis of various causes such as hepatitis B, hepatitis C and non-alcoholic fatty liver disease. Whether liver cirrhosis patients with higher RDW are at increased risk of hepatocellular cancer is yet to be determined, but several lines of evidence confirm that RDW has clinical significance in hepatocellular carcinoma (HCC). In this review, we specifically discuss the current literature about the association between RDW and HCC. The available evidences were summarized and the potential underlying mechanisms were analyzed.
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Affiliation(s)
- Hemant Goyal
- Mercer University School of Medicine, Macon, Georgia, USA
| | - Zhi-De Hu
- Department of Laboratory Medicine, General Hospital of Jinan Military Region of PLA, Jinan 250031, China
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22
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Yu Y, Li H, Yang Y, Ding Y, Wang Z, Li G. Evaluating Tumor-Associated Activity of Extracellular Sulfatase by Analyzing Naturally Occurring Substrate in Tumor Microenvironment of Hepatocellular Carcinoma. Anal Chem 2016; 88:12287-12293. [PMID: 28193024 DOI: 10.1021/acs.analchem.6b03469] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Yue Yu
- Nanjing
Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Hao Li
- State
Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation
Center of Chemistry for Life Sciences, Department of Biochemistry, Nanjing University, Nanjing 210093, China
| | - Yucai Yang
- Department
of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - Yitao Ding
- Nanjing
Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing 210008, China
| | - Zhaoxia Wang
- Department
of Oncology, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210011, China
| | - Genxi Li
- State
Key Laboratory of Pharmaceutical Biotechnology and Collaborative Innovation
Center of Chemistry for Life Sciences, Department of Biochemistry, Nanjing University, Nanjing 210093, China
- Center
for
Molecular Recognition and Biosensing, School of Life Sciences, Shanghai University, Shanghai 200444, China
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23
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Down-regulation of β-arrestin2 promotes tumour invasion and indicates poor prognosis of hepatocellular carcinoma. Sci Rep 2016; 6:35609. [PMID: 27759077 PMCID: PMC5069669 DOI: 10.1038/srep35609] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2016] [Accepted: 10/04/2016] [Indexed: 12/24/2022] Open
Abstract
β-arrestins, including β-arrestin1 and β-arrestin2, are multifunctional adaptor proteins. β-arrestins have recently been found to play new roles in regulating intracellular signalling networks associated with malignant cell functions. Altered β-arrestin expression has been reported in many cancers, but its role in hepatocellular carcinoma (HCC) is not clear. We therefore examined the roles of β-arrestins in HCC using an animal model of progressive HCC, HCC patient samples and HCC cell lines with stepwise metastatic potential. We demonstrated that β-arrestin2 level, but not β-arrestin1 level, decreased in conjunction with liver tumourigenesis in a mouse diethylnitrosamine-induced liver tumour model. Furthermore, β-arrestin2 expression was reduced in HCC tissues compared with noncancerous tissues in HCC patients. β-arrestin2 down-regulation in HCC was significantly associated with poor patient prognoses and aggressive pathologic features. In addition, our in vitro study showed that β-arrestin2 overexpression significantly reduced cell migration and invasion in cultured HCC cells. Furthermore, β-arrestin2 overexpression up-regulated E-cadherin expression and inhibited vimentin expression and Akt activation. These results suggest that β-arrestin2 down-regulation increases HCC cell migration and invasion ability. Low β-arrestin2 expression may be indicative of a poor prognosis or early cancer recurrence in patients who have undergone surgery for HCC.
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24
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Role of Antioxidants and Natural Products in Inflammation. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2016; 2016:5276130. [PMID: 27803762 PMCID: PMC5075620 DOI: 10.1155/2016/5276130] [Citation(s) in RCA: 567] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/23/2016] [Accepted: 09/07/2016] [Indexed: 12/15/2022]
Abstract
Inflammation is a comprehensive array of physiological response to a foreign organism, including human pathogens, dust particles, and viruses. Inflammations are mainly divided into acute and chronic inflammation depending on various inflammatory processes and cellular mechanisms. Recent investigations have clarified that inflammation is a major factor for the progression of various chronic diseases/disorders, including diabetes, cancer, cardiovascular diseases, eye disorders, arthritis, obesity, autoimmune diseases, and inflammatory bowel disease. Free radical productions from different biological and environmental sources are due to an imbalance of natural antioxidants which further leads to various inflammatory associated diseases. In this review article, we have outlined the inflammatory process and its cellular mechanisms involved in the progression of various chronic modern human diseases. In addition, we have discussed the role of free radicals-induced tissue damage, antioxidant defence, and molecular mechanisms in chronic inflammatory diseases/disorders. The systematic knowledge regarding the role of inflammation and its associated adverse effects can provide a clear understanding in the development of innovative therapeutic targets from natural sources that are intended for suppression of various chronic inflammations associated diseases.
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25
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Yamaguchi T, Yoshida K, Murata M, Matsuzaki K. Smad3 phospho-isoform signaling in hepatitis C virus-related chronic liver diseases. World J Gastroenterol 2014; 20:12381-12390. [PMID: 25253939 PMCID: PMC4168072 DOI: 10.3748/wjg.v20.i35.12381] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/27/2013] [Revised: 02/22/2014] [Accepted: 05/29/2014] [Indexed: 02/06/2023] Open
Abstract
The risk of hepatocellular carcinoma (HCC) development increases as hepatitis virus C (HCV)-related liver diseases progress, especially in patients with active inflammation. Insight into hepatic carcinogenesis have emerged from recent detailed analyses of transforming growth factor-β and c-Jun-N-terminal kinase signaling processes directed by multiple phosphorylated (phospho)-isoforms of a Smad3 mediator. In the course of HCV-related chronic liver diseases, chronic inflammation and host genetic/epigenetic alterations additively shift the hepatocytic Smad3 phospho-isoform signaling from tumor suppression to carcinogenesis, increasing the risk of HCC. Chronic inflammation represents an early carcinogenic step that provides a nonmutagenic tumor-promoting stimulus. After undergoing successful antiviral therapy, patients with chronic hepatitis C could experience a lower risk of HCC as Smad3 phospho-isoform signaling reverses from potential carcinogenesis to tumor suppression. Even after HCV clearance, however, patients with cirrhosis could still develop HCC because of sustained, intense carcinogenic Smad3 phospho-isoform signaling that is possibly caused by genetic or epigenetic alterations. Smad3 phospho-isoforms should assist with evaluating the effectiveness of interventions aimed at reducing human HCC.
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MESH Headings
- Animals
- Antiviral Agents/therapeutic use
- Carcinoma, Hepatocellular/genetics
- Carcinoma, Hepatocellular/metabolism
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/prevention & control
- Carcinoma, Hepatocellular/virology
- Cell Transformation, Viral
- Hepacivirus/drug effects
- Hepacivirus/genetics
- Hepacivirus/metabolism
- Hepacivirus/pathogenicity
- Hepatitis C, Chronic/complications
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/drug therapy
- Hepatitis C, Chronic/metabolism
- Host-Pathogen Interactions
- Humans
- JNK Mitogen-Activated Protein Kinases/metabolism
- Liver/metabolism
- Liver/pathology
- Liver/virology
- Liver Cirrhosis/drug therapy
- Liver Cirrhosis/genetics
- Liver Cirrhosis/metabolism
- Liver Cirrhosis/pathology
- Liver Cirrhosis/virology
- Liver Neoplasms/genetics
- Liver Neoplasms/metabolism
- Liver Neoplasms/pathology
- Liver Neoplasms/prevention & control
- Liver Neoplasms/virology
- Phosphorylation
- Protein Serine-Threonine Kinases/metabolism
- Receptor, Transforming Growth Factor-beta Type I
- Receptors, Transforming Growth Factor beta/metabolism
- Signal Transduction
- Smad3 Protein/genetics
- Smad3 Protein/metabolism
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26
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Shlomai A, de Jong YP, Rice CM. Virus associated malignancies: the role of viral hepatitis in hepatocellular carcinoma. Semin Cancer Biol 2014; 26:78-88. [PMID: 24457013 DOI: 10.1016/j.semcancer.2014.01.004] [Citation(s) in RCA: 130] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2013] [Revised: 12/29/2013] [Accepted: 01/09/2014] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is the third leading fatal cancer worldwide and its incidence continues to increase. Chronic viral hepatitis involving either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is the leading etiology for HCC, making HCC prevention a major goal of antiviral therapy. While recent clinical observations and translational research have enhanced our understanding of the molecular mechanisms driving the initiation and progression of HCC, much remains unknown. Current data indicates that HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. This complex biology is responsible, at least in part, for the absence of highly efficient target-directed therapies for this deadly cancer. Additionally, the direct or indirect effect of HBV and HCV infection on the development of HCC is still a contentious issue. Thus, the question remains whether viral hepatitis-associated HCC stems from virus-specific factors, and/or from a general mechanism involving inflammation and tissue regeneration. In this review we summarize general mechanisms implicated in HCC, emphasizing data generated by new technologies available today. We also highlight specific pathways by which HBV and HCV could be involved in HCC pathogenesis. However, improvements to current in vitro and in vivo systems for both viruses will be needed to rigorously define the temporal sequence and specific pathway dysregulations that drive the strong clinical link between chronic hepatitis virus infection and HCC.
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Affiliation(s)
- Amir Shlomai
- Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY, USA.
| | - Ype P de Jong
- Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY, USA; Division of Gastroenterology and Hepatology, Center for the Study of Hepatitis C, Weill Cornell Medical College, New York, NY, USA
| | - Charles M Rice
- Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY, USA.
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27
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Cubero FJ, Singh A, Borkham-Kamphorst E, Nevzorova YA, Al Masaoudi M, Haas U, Boekschoten MV, Gassler N, Weiskirchen R, Muller M, Liedtke C, Trautwein C. TNFR1 determines progression of chronic liver injury in the IKKγ/Nemo genetic model. Cell Death Differ 2013; 20:1580-1592. [PMID: 23933814 PMCID: PMC3792433 DOI: 10.1038/cdd.2013.112] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2013] [Revised: 06/18/2013] [Accepted: 07/12/2013] [Indexed: 12/26/2022] Open
Abstract
Death receptor-mediated hepatocyte apoptosis is implicated in a wide range of liver diseases including viral and alcoholic hepatitis, ischemia/reperfusion injury, fulminant hepatic failure, cholestatic liver injury, as well as cancer. Deletion of NF-κB essential modulator in hepatocytes (IKKγ/Nemo) causes spontaneous progression of TNF-mediated chronic hepatitis to hepatocellular carcinoma (HCC). Thus, we analyzed the role of death receptors including TNFR1 and TRAIL in the regulation of cell death and the progression of liver injury in IKKγ/Nemo-deleted livers. We crossed hepatocyte-specific IKKγ/Nemo knockout mice (Nemo(Δhepa)) with constitutive TNFR1(-/-) and TRAIL(-/-) mice. Deletion of TNFR1, but not TRAIL, decreased apoptotic cell death, compensatory proliferation, liver fibrogenesis, infiltration of immune cells as well as pro-inflammatory cytokines, and indicators of tumor growth during the progression of chronic liver injury. These events were associated with diminished JNK activation. In contrast, deletion of TNFR1 in bone-marrow-derived cells promoted chronic liver injury. Our data demonstrate that TNF- and not TRAIL signaling determines the progression of IKKγ/Nemo-dependent chronic hepatitis. Additionally, we show that TNFR1 in hepatocytes and immune cells have different roles in chronic liver injury-a finding that has direct implications for treating chronic liver disease.
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Affiliation(s)
- F J Cubero
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - A Singh
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - E Borkham-Kamphorst
- Institute of Clinical Chemistry and Pathobiochemistry, University Hospital, RWTH Aachen, Aachen, Germany
| | - Y A Nevzorova
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - M Al Masaoudi
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - U Haas
- Institute of Clinical Chemistry and Pathobiochemistry, University Hospital, RWTH Aachen, Aachen, Germany
| | - M V Boekschoten
- Division of Human Nutrition, Metabolism and Genomics, Wageningen University, Wageningen, The Netherlands
| | - N Gassler
- Institute of Pathology, University Hospital, RWTH Aachen, Germany
| | - R Weiskirchen
- Institute of Clinical Chemistry and Pathobiochemistry, University Hospital, RWTH Aachen, Aachen, Germany
| | - M Muller
- Division of Human Nutrition, Metabolism and Genomics, Wageningen University, Wageningen, The Netherlands
| | - C Liedtke
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
| | - C Trautwein
- Department of Internal Medicine III, University Hospital, RWTH Aachen, Aachen, Germany
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28
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Behrens G, Matthews CE, Moore SC, Freedman ND, McGlynn KA, Everhart JE, Hollenbeck AR, Leitzmann MF. The association between frequency of vigorous physical activity and hepatobiliary cancers in the NIH-AARP Diet and Health Study. Eur J Epidemiol 2013; 28:55-66. [PMID: 23354983 DOI: 10.1007/s10654-013-9767-1] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2012] [Accepted: 01/16/2013] [Indexed: 12/19/2022]
Abstract
Despite a potential preventive effect of physical activity on hepatobiliary cancer, little information is available on the relation between the two. We studied the association between frequency of vigorous physical activity and hepatobiliary cancer among 507,897 participants of the NIH-AARP Diet and Health Study, aged 50-71 years at baseline in 1995/1996. During 10 years of follow-up, 628 incident cases of liver cancer and 317 cases of extrahepatic biliary tract cancer were registered. Physical activity levels were assigned according to the frequency of engagement in 20 min or more of vigorous physical activity per week: never/rarely (lowest level), less than once per week, 1-2 times per week, 3-4 times per week, 5 or more times per week (highest level). Using Cox regression, multivariate-adjusted relative risks (RR) comparing the highest with the lowest level of physical activity revealed a statistically significant decreased risk for liver cancer (RR = 0.64, 95% confidence interval (CI) = 0.49-0.84, p-trend <0.001), particularly hepatocellular carcinoma (RR = 0.56, 95% CI = 0.41-0.78, p-trend <0.001), independent of body mass index. By comparison, multivariate analyses indicated that physical activity was not statistically significantly associated with extrahepatic bile duct cancer (RR = 0.86, 95% CI = 0.45-1.65), ampulla of Vater cancer (RR = 0.66, 95% CI = 0.29-1.48), or gallbladder cancer (RR = 0.63, 95% CI = 0.33-1.21). These results suggest a potential preventive effect of physical activity on liver cancer but not extrahepatic biliary tract cancer, independent of body mass index.
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Affiliation(s)
- Gundula Behrens
- Department of Epidemiology and Preventive Medicine, Regensburg University Medical Center, Franz-Josef-Strauss-Allee 11, 93053 Regensburg, Germany.
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29
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Sahasrabuddhe VV, Gunja MZ, Graubard BI, Trabert B, Schwartz LM, Park Y, Hollenbeck AR, Freedman ND, McGlynn KA. Nonsteroidal anti-inflammatory drug use, chronic liver disease, and hepatocellular carcinoma. J Natl Cancer Inst 2012. [PMID: 23197492 DOI: 10.1093/jnci/djs452] [Citation(s) in RCA: 178] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Nonsteroidal anti-inflammatory drugs (NSAIDs) have been shown to reduce chronic inflammation and risk of many cancers, but their effect on risk of hepatocellular carcinoma (HCC) and death due to chronic liver disease (CLD) has not been investigated. METHODS We analyzed prospective data on 300504 men and women aged 50 to 71 years in the National Institutes of Health-AARP Diet and Health Study cohort and linked self-reported aspirin and nonaspirin NSAID use with registry-confirmed diagnoses of HCC (n=250) and death due to CLD (n=428, excluding HCC). We calculated hazard rate ratios (RRs) and their two-sided 95% confidence intervals (CIs) using Cox proportional hazard regression models with adjustment for age, sex, race/ethnicity, cigarette smoking, alcohol consumption, diabetes, and body mass index. All tests of statistical significance were two-sided. RESULTS Aspirin users had statistically significant reduced risks of incidence of HCC (RR = 0.59; 95% CI = 0.45 to 0.77) and mortality due to CLD (RR = 0.55; 95% CI = 0.45 to 0.67) compared to those who did not use aspirin. In contrast, users of nonaspirin NSAIDs had a reduced risk of mortality due to CLD (RR = 0.74; 95% CI= 0.61 to 0.90) but did not have lower risk of incidence of HCC (RR = 1.08; 95% CI = 0.84 to 1.39) compared to those who did not use nonaspirin NSAIDs. The risk estimates did not vary in statistical significance by frequency (monthly, weekly, daily) of aspirin use, but the reduced risk of mortality due to CLD was statistically significant only among monthly users of nonaspirin NSAIDs compared to non-users. CONCLUSIONS Aspirin use was associated with reduced risk of developing HCC and of death due to CLD whereas nonaspirin NSAID use was only associated with reduced risk of death due to CLD.
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Affiliation(s)
- Vikrant V Sahasrabuddhe
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Blvd, EPS 5032, Rockville, MD 20852, USA.
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30
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Xiao C, Wang RH, Lahusen TJ, Park O, Bertola A, Maruyama T, Reynolds D, Chen Q, Xu X, Young HA, Chen WJ, Gao B, Deng CX. Progression of chronic liver inflammation and fibrosis driven by activation of c-JUN signaling in Sirt6 mutant mice. J Biol Chem 2012; 287:41903-13. [PMID: 23076146 DOI: 10.1074/jbc.m112.415182] [Citation(s) in RCA: 134] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The human body has a remarkable ability to regulate inflammation, a biophysical response triggered by virus infection and tissue damage. Sirt6 is critical for metabolism and lifespan; however, its role in inflammation is unknown. Here we show that Sirt6-null (Sirt6(-/-)) mice developed chronic liver inflammation starting at ∼2 months of age, and all animals were affected by 7-8 months of age. Deletion of Sirt6 in T cells or myeloid-derived cells was sufficient to induce liver inflammation and fibrosis, albeit to a lesser degree than that in the global Sirt6(-/-) mice, suggesting that Sirt6 deficiency in the immune cells is the cause. Consistently, macrophages derived from the bone marrow of Sirt6(-/-) mice showed increased MCP-1, IL-6, and TNFα expression levels and were hypersensitive to LPS stimulation. Mechanistically, SIRT6 interacts with c-JUN and deacetylates histone H3 lysine 9 (H3K9) at the promoter of proinflammatory genes whose expression involves the c-JUN signaling pathway. Sirt6-deficient macrophages displayed hyperacetylation of H3K9 and increased occupancy of c-JUN in the promoter of these genes, leading to their elevated expression. These data suggest that Sirt6 plays an anti-inflammatory role in mice by inhibiting c-JUN-dependent expression of proinflammatory genes.
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Affiliation(s)
- Cuiying Xiao
- Genetics of Development and Diseases Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA.
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Abstract
Transforming growth factor-β (TGF-β) is a central regulator in chronic liver disease contributing to all stages of disease progression from initial liver injury through inflammation and fibrosis to cirrhosis and hepatocellular carcinoma. Liver-damage-induced levels of active TGF-β enhance hepatocyte destruction and mediate hepatic stellate cell and fibroblast activation resulting in a wound-healing response, including myofibroblast generation and extracellular matrix deposition. Being recognised as a major profibrogenic cytokine, the targeting of the TGF-β signalling pathway has been explored with respect to the inhibition of liver disease progression. Whereas interference with TGF-β signalling in various short-term animal models has provided promising results, liver disease progression in humans is a process of decades with different phases in which TGF-β or its targeting might have both beneficial and adverse outcomes. Based on recent literature, we summarise the cell-type-directed double-edged role of TGF-β in various liver disease stages. We emphasise that, in order to achieve therapeutic effects, we need to target TGF-β signalling in the right cell type at the right time.
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