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Manivannan HP, Veeraraghavan VP, Francis AP. Prediction of Multi-targeting Pharmacological Activity of Bioactive Compounds from Medicinal Plants Against Hepatocellular Carcinoma Through Advanced Network Pharmacology and Bioinformatics-Based Investigation. Appl Biochem Biotechnol 2025; 197:2979-3007. [PMID: 39820926 DOI: 10.1007/s12010-024-05150-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/24/2024] [Indexed: 01/19/2025]
Abstract
The primary objective of this study was to identify bioactive compounds from four medicinal plants with multi-targeting activity against hepatocellular carcinoma (HCC). A comprehensive analysis led to the identification of a subset of compounds possessing favorable drug-likeness, pharmacokinetics, and absence of toxicity profiles. Target analysis for 42 phytochemicals revealed 210 potential targets associated with HCC. Protein-protein interaction (PPI) analysis of these targets uncovered five critical hub genes, STAT3, SRC, AKT1, MAPK3, and EGFR, in our study. Correlation analysis of these hub genes indicated a strong positive correlation between EGFR, MAPK3, and SRC expression highlighting their interconnected roles in HCC. Survival analysis underscored the significant prognostic role of these hub genes in HCC underscoring their potential as biomarkers. The co-expression analysis unveiled an intricate network of interactions among the hub genes, while the enrichment analysis demonstrated their enrichment in diverse biological and signaling pathways related to HCC. Molecular docking analysis between the seven phytochemicals and five identified targets revealed that bauerenol exhibited good affinity towards all the targets. Subsequent molecular dynamics (MD) simulations demonstrated that bauerenol formed stable complexes with STAT3, AKT1, EGFR, and MAPK3, suggesting its potential as a multi-targeted inhibitor. Our research suggests that bauerenol shows promise as an inhibitor for HCC targets and stands out as a notable lead compound. However, further experimental studies are necessary to confirm its activity and to evaluate its potential as a therapeutic agent for HCC.
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Affiliation(s)
- Hema Priya Manivannan
- Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, India
| | - Vishnu Priya Veeraraghavan
- Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, India
| | - Arul Prakash Francis
- Centre of Molecular Medicine and Diagnostics (COMManD), Saveetha Dental College and Hospitals, Saveetha Institute of Medical and Technical Sciences, Saveetha University, Chennai, 600077, India.
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Han YM, Ahn HR, Lee DY, Song MY, Lee SW, Jang YK, Jeon BY, Kim EH. Therapeutic Potential of Hongjam in A Diethylnitrosamine and Thioacetamide-induced Hepatocellular Carcinoma Mouse Model. J Cancer Prev 2024; 29:165-174. [PMID: 39790225 PMCID: PMC11706731 DOI: 10.15430/jcp.24.029] [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: 12/06/2024] [Revised: 12/23/2024] [Accepted: 12/25/2024] [Indexed: 01/12/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common and lethal type of primary liver cancer, frequently arising from chronic liver injury and inflammation. Despite treatment advancements, HCC prognosis remains poor, emphasizing the need for effective preventive and therapeutic strategies. This study investigates the hepatoprotective and anti-tumor effects of Hongjam, a steamed freeze-dried silkworm powder, in a diethylnitrosamine (DEN) and thioacetamide (TAA)-induced HCC mouse model. Mice were administered DEN intraperitoneally for 8 weeks, followed by TAA in drinking water for 9 weeks, with Hongjam supplementation (0.01, 0.1, and 1 g/kg) provided daily through food. Hongjam markedly reduced the tumor incidence, the size, and the histological lesions compared to the DEN/TAA group. Serum biochemical analysis revealed reduction in liver damage markers, including alkaline phosphatase, alanine aminotransferase, aspartate aminotransferase, and total bilirubin, with a notable decrease in total bilirubin surpassing. Immunohistochemical and Western blot analyses demonstrated that Hongjam downregulated expression of proliferation markers, including Ki67, phosphorylation of protein kinase B, and proliferating cell nuclear antigen, while upregulating the pro-apoptotic protein Bcl-2-associated X protein, indicating its dual role in suppressing proliferation and promoting apoptosis. Furthermore, Hongjam inhibited angiogenesis by suppressing the expression of key markers, including interleukin 6, VEGF, hypoxia-inducible factor-1 subunit alpha, platelet-derived growth factor subunit beta, matrix metalloproteinase-2, and cluster of differentiation 31, thereby disrupting the tumor microenvironment. These findings suggest that Hongjam exerts multifaceted protective effects against HCC by targeting proliferation, apoptosis, and angiogenesis pathways, while also mitigating liver damage. This study highlights the potential of Hongjam as a functional food or a complementary therapeutic agent for HCC prevention and management.
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Affiliation(s)
- Young-Min Han
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
| | - Hye-Rin Ahn
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
| | - Da-Young Lee
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
| | - Moon-Young Song
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
| | - Seung-Won Lee
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
| | | | | | - Eun-Hee Kim
- College of Pharmacy and Institute of Pharmaceutical Sciences, CHA University, Seongnam, Korea
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Danzeng A, Guo L, Yang ZH, He ZW, Zeng CL, Ciren P, Lan RH, Jiang XW, Wang C, Zhang BH. Postoperative lenvatinib + PD-1 blockade reduces early tumor recurrence in hepatocellular carcinoma with microvascular invasion (Barcelona Clinic Liver Cancer stage 0 or A): a propensity score matching analysis. J Gastrointest Surg 2024; 28:1104-1112. [PMID: 38723996 DOI: 10.1016/j.gassur.2024.05.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/22/2024] [Accepted: 05/03/2024] [Indexed: 05/25/2024]
Abstract
BACKGROUND This study aimed to determine the effectiveness of postoperative adjuvant lenvatinib + PD-1 blockade for patients with early-stage hepatocellular carcinoma (HCC) with microvascular invasion (MVI). METHODS A total of 393 patients with HCC (Barcelona Clinic Liver Cancer stage 0 or A) who underwent curative hepatectomy with histopathologically proven MVI were enrolled according to the inclusion and exclusion criteria and assigned to 2 groups: surgery alone (surgery-alone group) and surgery with lenvatinib and PD-1 blockade (surgery + lenvatinib + PD-1 group) to compare recurrence-free survival (RFS), overall survival (OS), recurrence type, and annual recurrence rate after the application of propensity score matching (PSM). The Cox proportional hazards model was used for univariate and multivariate analyses. RESULTS Overall, 99 matched pairs were selected using PSM. Patients in the surgery + lenvatinib + PD-1 group had significantly higher 3-year RFS rates (76.8%, 65.7%, and 53.5%) than patients in the surgery-alone group (60.6%, 45.5%, and 37.4%) (P = .012). The 2 groups showed no significant difference in recurrence types and OS. Surgery alone, MVI-M2, and alpha-fetoprotein of ≥200 ng/mL were independent risk factors for RFS (P < .05), and history of alcohol use disorder was an independent risk factor for OS (P = .022). CONCLUSION Postoperative lenvatinib + PD-1 blockade improved the RFS in patients with HCC with MVI and was particularly beneficial for specific individuals.
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Affiliation(s)
- Awang Danzeng
- Department of Surgery, Institute of Hepato-Pancreato-Biliary Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ling Guo
- Division of Hepato-Pancreato-Biliary Surgery, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Zhen-Hua Yang
- Department of Surgery, Institute of Hepato-Pancreato-Biliary Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Zheng-Wei He
- Department of Surgery, Institute of Hepato-Pancreato-Biliary Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Cheng-Long Zeng
- Department of Surgery, Institute of Hepato-Pancreato-Biliary Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Pingcuo Ciren
- Department of Surgery, Institute of Hepato-Pancreato-Biliary Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Run-Hu Lan
- Division of Hepato-Pancreato-Biliary Surgery, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Xue-Wei Jiang
- Division of Hepato-Pancreato-Biliary Surgery, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan, China
| | - Chao Wang
- Department of Surgery, Institute of Hepato-Pancreato-Biliary Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Bin-Hao Zhang
- Department of Surgery, Institute of Hepato-Pancreato-Biliary Surgery, Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Mei Y, Zhu Y, Yong KSM, Hanafi ZB, Gong H, Liu Y, Teo HY, Hussain M, Song Y, Chen Q, Liu H. IL-37 dampens immunosuppressive functions of MDSCs via metabolic reprogramming in the tumor microenvironment. Cell Rep 2024; 43:113835. [PMID: 38412100 DOI: 10.1016/j.celrep.2024.113835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Revised: 12/18/2023] [Accepted: 02/06/2024] [Indexed: 02/29/2024] Open
Abstract
Interleukin-37 (IL-37) has been shown to inhibit tumor growth in various cancer types. However, the immune regulatory function of IL-37 in the tumor microenvironment is unclear. Here, we established a human leukocyte antigen-I (HLA-I)-matched humanized patient-derived xenograft hepatocellular carcinoma (HCC) model and three murine orthotopic HCC models to study the function of IL-37 in the tumor microenvironment. We found that IL-37 inhibited HCC growth and promoted T cell activation. Further study revealed that IL-37 impaired the immunosuppressive capacity of myeloid-derived suppressor cells (MDSCs). Pretreatment of MDSCs with IL-37 before adoptive transfer attenuated their tumor-promoting function in HCC tumor-bearing mice. Moreover, IL-37 promoted both glycolysis and oxidative phosphorylation in MDSCs, resulting in the upregulation of ATP release, which impaired the immunosuppressive capacity of MDSCs. Collectively, we demonstrated that IL-37 inhibited tumor development through dampening MDSCs' immunosuppressive capacity in the tumor microenvironment via metabolic reprogramming, making it a promising target for future cancer immunotherapy.
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Affiliation(s)
- Yu Mei
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Ying Zhu
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Kylie Su Mei Yong
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (ASTAR), Singapore 138673, Singapore
| | - Zuhairah Binte Hanafi
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Huanle Gong
- Institute of Blood and Marrow Transplantation, Collaborative Innovation Center of Hematology, Jiangsu Institute of Hematology, First Affiliated Hospital of Soochow University, Soochow University, Suzhou 215006, P.R. China
| | - Yonghao Liu
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Huey Yee Teo
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Muslima Hussain
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Yuan Song
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore
| | - Qingfeng Chen
- Institute of Molecular and Cell Biology, Agency for Science, Technology, and Research (ASTAR), Singapore 138673, Singapore.
| | - Haiyan Liu
- Immunology Program, Life Sciences Institute, Immunology Translational Research Program, and Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117456, Singapore.
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Kolay A, Kumar A. A Novel Liver Cancer POC Diagnostic Detection Technique by a Gate-engineered Source-extended TFET Device. Med Eng Phys 2024; 125:104133. [PMID: 38508806 DOI: 10.1016/j.medengphy.2024.104133] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 02/05/2024] [Accepted: 02/25/2024] [Indexed: 03/22/2024]
Abstract
This work reports a novel POC diagnostic technique to identify the cancerous liver cell lines by designing a Source-Extended (SE) Tunnel Field Effect Transistor (TFET) having a Single-Gate (SG) with Single-Metal (SM) and Dual-Metal (DM) structure. The proposed structures have been equipped with nanocavities by trenching the gate oxide layer where the needle biopsy obtained liver sample has been immobilized. The detection is based on the difference in drain current and the ratio of the proposed device's ON and OFF state currents, which has been evaluated by obtaining the sensitivities. The cancerous and non-cancerous liver cell lines possess different dielectric properties in high frequencies ranging from 100 MHz to 5 GHz, affecting the cavity region's effective capacitances. The change in the dielectric constant of the specimen at 900 MHz has been considered which results in the change in device drain current and device performance. Various parameters of the device, like the adhesive layer in the cavity region, the material of the gate, the length of the cavities, and the orientation of the cavities, have been modified to observe the performance. The total work has been done in the simulation environment, which includes the study considering the different proportions of cancerous and non-cancerous cells in a particular specimen. A comparative analysis has been made between the performance of the proposed SM and DM gate structure. The proposed detection method has been compared with the existing methods reported in the literature. The proposed method can be considered a novel technique and can be implemented as a point of care (POC) diagnostic to detect whether the specimen liver cell line is cancerous.
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Affiliation(s)
- Anirban Kolay
- Nextgen Adaptive Systems Group, Department of Electrical Engineering, National Institute of Technology Patna, Bihar, India
| | - Amitesh Kumar
- Nextgen Adaptive Systems Group, Department of Electrical Engineering, National Institute of Technology Patna, Bihar, India.
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Chavda V, Zajac KK, Gunn JL, Balar P, Khadela A, Vaghela D, Soni S, Ashby CR, Tiwari AK. Ethnic differences in hepatocellular carcinoma prevalence and therapeutic outcomes. Cancer Rep (Hoboken) 2023; 6 Suppl 1:e1821. [PMID: 37344125 PMCID: PMC10440848 DOI: 10.1002/cnr2.1821] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 03/17/2023] [Accepted: 04/10/2023] [Indexed: 06/23/2023] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death worldwide. The incidence of HCC is affected by genetic and non-genetic factors. Genetically, mutations in the genes, tumor protein P53 (TP53), catenin beta 1 (CTNNB1), AT-rich interaction domain 1A (ARIC1A), cyclin dependent kinase inhibitor 2A (CDKN2A), mannose 6-phosphate (M6P), smooth muscle action against decapentaplegic (SMAD2), retinoblastoma gene (RB1), cyclin D, antigen presenting cells (APC), AXIN1, and E-cadherin, have been shown to contribute to the occurrence of HCC. Non-genetic factors, including alcohol consumption, exposure to aflatoxin, age, gender, presence of hepatitis B (HBV), hepatitis C (HCV), and non-alcoholic fatty liver disease (NAFLD), increase the risk of HCC. RECENT FINDINGS The severity of the disease and its occurrence vary based on geographical location. Furthermore, men and minorities have been shown to be disproportionately affected by HCC, compared with women and non-minorities. Ethnicity has been reported to significantly affect tumorigenesis and clinical outcomes in patients diagnosed with HCC. Generally, differences in gene expression and/or the presence of comorbid medical diseases affect or influence the progression of HCC. Non-Caucasian HCC patients are significantly more likely to have poorer survival outcomes, compared to their Caucasian counterparts. Finally, there are a number of factors that contribute to the success rate of treatments for HCC. CONCLUSION Assessment and treatment of HCC must be consistent using evidence-based guidelines and standardized outcomes, as well as international clinical practice guidelines for global consensus. Standardizing the assessment approach and method will enable comparison and improvement of liver cancer research through collaboration between researchers, healthcare providers, and advocacy groups. In this review, we will focus on discussing epidemiological factors that result in deviations and changes in treatment approaches for HCC.
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Affiliation(s)
- Vivek Chavda
- Department of Pharmaceutics and Pharmaceutical TechnologyL M College of PharmacyAhmedabadIndia
| | - Kelsee K. Zajac
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoOhioUSA
| | - Jenna Lynn Gunn
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoOhioUSA
| | - Pankti Balar
- Pharmacy SectionL M College of PharmacyAhmedabadIndia
| | - Avinash Khadela
- Department of PharmacologyL M College of PharmacyAhmedabadIndia
| | - Dixa Vaghela
- Pharmacy SectionL M College of PharmacyAhmedabadIndia
| | - Shruti Soni
- PharmD SectionL M College of PharmacyAhmedabadIndia
| | - Charles R. Ashby
- Department of Pharmaceutical Sciences, College of PharmacySt. John's UniversityNew YorkNew YorkUSA
| | - Amit K. Tiwari
- Department of Pharmacology and Experimental Therapeutics, College of Pharmacy and Pharmaceutical SciencesUniversity of ToledoOhioUSA
- Department of Cancer Biology, College of Medicine and Life SciencesUniversity of ToledoToledoOhioUSA
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7
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Torunoglu ST, Zajda A, Tampio J, Markowicz-Piasecka M, Huttunen KM. Metformin derivatives - Researchers' friends or foes? Biochem Pharmacol 2023; 215:115743. [PMID: 37591450 DOI: 10.1016/j.bcp.2023.115743] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2023] [Revised: 08/09/2023] [Accepted: 08/09/2023] [Indexed: 08/19/2023]
Abstract
Metformin has been used for ages to treat diabetes mellitus due to its safety profile and low cost. However, metformin has variable pharmacokinetics in patients, and due to its poor oral absorption, the therapeutic doses are relatively high, causing unpleasant gastrointestinal adverse effects. Therefore, novel derivatives of metformin have been synthesized during the past decades. Particularly, after the mid-2000 s, when organic cation transporters were identified as the main metformin carriers, metformin derivatives have been under intensive investigation. Nevertheless, due to the biguanide structure, derivatives of metformin have been challenging to synthesize. Moreover, the mechanisms of metformin's action are not fully understood to date, and since it has multifunctional properties, the interests have switched to re-purposing for other diseases. Indeed, metformin derivatives have been demonstrated in many cases to be more effective than metformin itself and have the potential to be used in different diseases, including several types of cancers and neurodegenerative diseases. On the other hand, the pleiotropic nature of metformin and its derivatives can also create challenges. Not all properties are fit for all diseases. In this review, the history of the development of metformin-like compounds is summarized, and insights into their potential for future drug discovery are discussed.
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Affiliation(s)
- Sema Tuna Torunoglu
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
| | - Agnieszka Zajda
- Laboratory of Bioanalysis, Department of Pharmaceutical Chemistry, Drug Analysis and Radiopharmacy, Medical University of Lodz, ul. Muszyńskiego 1, 90-151 Lodz, Poland
| | - Janne Tampio
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland
| | | | - Kristiina M Huttunen
- School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, P.O. Box 1627, FI-70211 Kuopio, Finland.
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Boora S, Sharma V, Kaushik S, Bhupatiraju AV, Singh S, Kaushik S. Hepatitis B virus-induced hepatocellular carcinoma: a persistent global problem. Braz J Microbiol 2023; 54:679-689. [PMID: 37059940 PMCID: PMC10235410 DOI: 10.1007/s42770-023-00970-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2022] [Accepted: 04/05/2023] [Indexed: 04/16/2023] Open
Abstract
Hepatitis B virus (HBV) infections are highly prevalent globally, representing a serious public health problem. The diverse modes of transmission and the burden of the chronic carrier population pose challenges to the effective management of HBV. Vaccination is the most effective preventive measure available in the current scenario. Still, HBV is one of the significant health issues in various parts of the globe due to non-response to vaccines, the high number of concealed carriers, and the lack of access and awareness. Universal vaccination programs must be scaled up in neonates, especially in the developing parts of the world, to prevent new HBV infections. Novel treatments like combinational therapy, gene silencing, and new antivirals must be available for effective management. The prolonged infection of HBV, direct and indirect, can promote the growth of hepatocellular carcinoma (HCC). The present review emphasizes the problems and probable solutions for better managing HBV infections, causal risk factors of HCC, and mechanisms of HCC.
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Affiliation(s)
- Sanjit Boora
- Centre for Biotechnology, Maharshi Dayanand University, 124001, Haryana, Rohtak, India
| | - Vikrant Sharma
- Centre for Biotechnology, Maharshi Dayanand University, 124001, Haryana, Rohtak, India
| | | | | | - Sandeep Singh
- Department of Biochemistry, Maharshi Dayanand University, Rohtak, India
| | - Samander Kaushik
- Centre for Biotechnology, Maharshi Dayanand University, 124001, Haryana, Rohtak, India.
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9
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Jaruga P, Tomar R, Kant M, Vartanian V, Sexton B, Rizzo CJ, Turesky RJ, Stone MP, Lloyd RS, Dizdaroglu M. Synthesis and Characterization of 15N 5-Labeled Aflatoxin B 1-Formamidopyrimidines and Aflatoxin B 1-N7-Guanine from a Partial Double-Stranded Oligodeoxynucleotide as Internal Standards for Mass Spectrometric Measurements. ACS OMEGA 2023; 8:14841-14854. [PMID: 37125130 PMCID: PMC10134230 DOI: 10.1021/acsomega.3c01328] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Accepted: 03/20/2023] [Indexed: 05/03/2023]
Abstract
Aflatoxin B1 (AFB1) exposure through contaminated food is a primary contributor to hepatocellular carcinogenesis worldwide. Hepatitis B viral infections in livers dramatically increase the carcinogenic potency of AFB1 exposures. Liver cytochrome P450 oxidizes AFB1 to the epoxide, which in turn reacts with N7-guanine in DNA, producing the cationic trans-8,9-dihydro-8-(N7-guanyl)-9-hydroxyaflatoxin B1 adduct (AFB1-N7-Gua). The opening of the imidazole ring of AFB1-N7-Gua under physiological conditions causes the formation of the cis- and trans-diastereomers of 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B1 (AFB1-FapyGua). These adducts primarily lead to G → T mutations, with AFB1-FapyGua being significantly more mutagenic than AFB1-N7-Gua. The unequivocal identification and accurate quantification of these AFB1-Gua adducts as biomarkers are essential for a fundamental understanding and prevention of AFB1-induced hepatocellular carcinogenesis. Among a variety of analytical techniques used for this purpose, liquid chromatography-tandem mass spectrometry, with the use of the stable isotope-labeled analogues of AFB1-FapyGua and AFB1-N7-Gua as internal standards, provides the greatest accuracy and sensitivity. cis-AFB1-FapyGua-15N5, trans-AFB1-FapyGua-15N5, and AFB1-N7-Gua-15N5 have been synthesized and used successfully as internal standards. However, the availability of these standards from either academic institutions or commercial sources ceased to exist. Thus, quantitative genomic data regarding AFB1-induced DNA damage in animal models and humans remain challenging to obtain. Previously, AFB1-N7-Gua-15N5 was prepared by reacting AFB1-exo-8,9-epoxide with the uniformly 15N5-labeled DNA isolated from algae grown in a pure 15N-environment, followed by alkali treatment, resulting in the conversion of AFB1-N7-Gua-15N5 to AFB1-FapyGua-15N5. In the present work, we used a different and simpler approach to synthesize cis-AFB1-FapyGua-15N5, trans-AFB1-FapyGua-15N5, and AFB1-N7-Gua-15N5 from a partial double-stranded 11-mer Gua-15N5-labeled oligodeoxynucleotide, followed by isolation and purification. We also show the validation of these 15N5-labeled standards for the measurement of cis-AFB1-FapyGua, trans-AFB1-FapyGua, and AFB1-N7-Gua in DNA of livers of AFB1-treated mice.
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Affiliation(s)
- Pawel Jaruga
- Biomolecular
Measurement Division, National Institute
of Standards and Technology, Gaithersburg, Maryland 20899, United States
| | - Rachana Tomar
- Department
of Chemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Melis Kant
- Biomolecular
Measurement Division, National Institute
of Standards and Technology, Gaithersburg, Maryland 20899, United States
| | - Vladimir Vartanian
- Oregon
Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Benjamin Sexton
- Department
of Chemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Carmelo J. Rizzo
- Department
of Chemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - Robert J. Turesky
- Masonic
Cancer Center, University of Minnesota, Minneapolis, Minnesota 55455, United States
| | - Michael P. Stone
- Department
of Chemistry, Vanderbilt Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37235, United States
| | - R. Stephen Lloyd
- Oregon
Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, Oregon 97239, United States
| | - Miral Dizdaroglu
- Biomolecular
Measurement Division, National Institute
of Standards and Technology, Gaithersburg, Maryland 20899, United States
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10
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Guven DC, Erul E, Sahin TK, Dizdar O, Yalcin S, Sahin IH. The benefit of immunotherapy in patients with hepatocellular carcinoma: a systematic review and meta-analysis. Future Oncol 2022; 18:4119-4136. [PMID: 36533987 DOI: 10.2217/fon-2022-0642] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background: A systemic review of the survival benefit of immune checkpoint inhibitors (ICIs) in phase III hepatocellular carcinoma (HCC) trials was conducted. Methods: Meta-analyses were performed with the generic inverse-variance method with a fixed-effects model. Results: In 10 trials encompassing 6123 patients, ICI-based therapy (monotherapy/combination) improved overall survival (OS) compared with the control arm (hazard ratio [HR]: 0.77; 95% CI: 0.70-0.84; p < 0.001). The survival benefit was consistent across variable treatment lines, Eastern Cooperative Oncology Group performance status and AFP levels. While the OS benefit was more pronounced in hepatitis B-related HCC (HR: 0.70; 95% CI: 0.63-0.77; p < 0.001), OS was improved in hepatitis C-related (HR: 0.83; 95% CI: 0.71-0.98) and nonviral HCC (HR: 0.86; 95% CI: 0.77-0.97). Conclusion: ICI-based therapies should be the standard for all patients with advanced HCC.
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Affiliation(s)
- Deniz Can Guven
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, 06100, Turkey
| | - Enes Erul
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, 06100, Turkey
| | - Taha Koray Sahin
- Department of Internal Medicine, Hacettepe University Faculty of Medicine, Ankara, 06100, Turkey
| | - Omer Dizdar
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, 06100, Turkey
| | - Suayib Yalcin
- Department of Medical Oncology, Hacettepe University Cancer Institute, Ankara, 06100, Turkey
| | - Ibrahim Halil Sahin
- Division of Hematology/Oncology, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA
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11
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Chin WS, Pan SC, Huang CC, Chen PJ, Guo YL. Exposure to Air Pollution and Survival in Follow-Up after Hepatocellular Carcinoma. Liver Cancer 2022; 11:474-482. [PMID: 36158593 PMCID: PMC9485987 DOI: 10.1159/000525346] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Accepted: 05/09/2022] [Indexed: 02/04/2023] Open
Abstract
Introduction Air pollutants are classified as carcinogens by the International Agency for Research on Cancer. Long-term exposure to ambient particulate matter with an aerodiameter of 2.5 μm or lower (PM2.5) has been reported to be linked with increased mortality due to hepatocellular carcinoma (HCC). However, the effects of air pollutants other than PM2.5 on HCC-related mortality have not been fully investigated. Accordingly, we conducted this study to assess the effect of long-term exposure to air pollutants (PM2.5 and nitrogen dioxide [NO2]) on HCC-related mortality. Method In 2005, the Taiwan Liver Cancer Network (TLCN) was established by the National Research Program for Genomic Medicine to recruit liver cancer patients from 5 major medical centers in northern, central, and southern Taiwan. The TLCN had successfully recruited 9,344 patients by the end of 2018. In this study, we included 1,000 patients randomly sampled from the TLCN to assess the effect of exposure to air pollutants on HCC mortality after HCC diagnosis. Daily averages of PM2.5 and NO2 concentrations were retrieved from 77 air quality-monitoring stations and interpolated to the townships of patients' residences by using the Kriging method. The effect of air pollutants on HCC survival was assessed using a Cox proportional hazards model. Results A total of 940 patients were included in the analysis. After adjusting for potential confounders and mutually adjusting for co-pollutants, we observed that the hazards ratio (95% confidence interval) for HCC-related mortality for every 1-μg/m3 increase in PM2.5 concentration was 1.11 (1.08-1.14) and that for every 1-ppb increase in NO2 concentration was 1.08 (1.03-1.13). Conclusion Our study suggests that long-term exposure to PM2.5 and NO2 was associated with decreased survival time in patients with HCC in Taiwan.
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Affiliation(s)
- Wei-Shan Chin
- School of Nursing, College of Medicine, National Taiwan University (NTU) and NTU Hospital, Taipei, Taiwan
| | - Shin-Chun Pan
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County, Taiwan
| | - Ching-Chun Huang
- Department of Environmental and Occupational Medicine, National Taiwan University (NTU) College of Medicine and NTU Hospital, Taipei, Taiwan
| | - Pei-Jer Chen
- Graduate Institute of Microbiology, NTU College of Medicine, Taipei, Taiwan
- Department of Gastroenterology, NTU Hospital, Taipei, Taiwan
| | - Yue Leon Guo
- National Institute of Environmental Health Sciences, National Health Research Institutes, Miaoli County, Taiwan
- Department of Environmental and Occupational Medicine, National Taiwan University (NTU) College of Medicine and NTU Hospital, Taipei, Taiwan
- Institute of Environmental and Occupational Health Sciences, National Taiwan University College of Public Health, Taipei, Taiwan
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12
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Rallis KS, Makrakis D, Ziogas IA, Tsoulfas G. Immunotherapy for advanced hepatocellular carcinoma: From clinical trials to real-world data and future advances. World J Clin Oncol 2022; 13:448-472. [PMID: 35949435 PMCID: PMC9244967 DOI: 10.5306/wjco.v13.i6.448] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2022] [Revised: 04/27/2022] [Accepted: 05/28/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of cancer-associated mortality worldwide. HCC is an inflammation-associated immunogenic cancer that frequently arises in chronically inflamed livers. Advanced HCC is managed with systemic therapies; the tyrosine kinase inhibitor (TKI) sorafenib has been used in 1st-line setting since 2007. Immunotherapies have emerged as promising treatments across solid tumors including HCC for which immune checkpoint inhibitors (ICIs) are licensed in 1st- and 2nd-line treatment setting. The treatment field of advanced HCC is continuously evolving. Several clinical trials are investigating novel ICI candidates as well as new ICI regimens in combination with other therapeutic modalities including systemic agents, such as other ICIs, TKIs, and anti-angiogenics. Novel immunotherapies including adoptive cell transfer, vaccine-based approaches, and virotherapy are also being brought to the fore. Yet, despite advances, several challenges persist. Lack of real-world data on the use of immunotherapy for advanced HCC in patients outside of clinical trials constitutes a main limitation hindering the breadth of application and generalizability of data to this larger and more diverse patient cohort. Consequently, issues encountered in real-world practice include patient ineligibly for immunotherapy because of contraindications, comorbidities, or poor performance status; lack of response, efficacy, and safety data; and cost-effectiveness. Further real-world data from high-quality large prospective cohort studies of immunotherapy in patients with advanced HCC is mandated to aid evidence-based clinical decision-making. This review provides a critical and comprehensive overview of clinical trials and real-world data of immunotherapy for HCC, with a focus on ICIs, as well as novel immunotherapy strategies underway.
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Affiliation(s)
- Kathrine S Rallis
- Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AD, United Kingdom
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
| | - Dimitrios Makrakis
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Division of Oncology, University of Washington School of Medicine, Seattle, WA 98195, United States
| | - Ioannis A Ziogas
- Surgery Working Group, Society of Junior Doctors, Athens 15123, Greece
- Department of Surgery, Division of Hepatobiliary Surgery and Liver Transplantation, Vanderbilt University Medical Center, Nashville, Tennessee 37232, United States
| | - Georgios Tsoulfas
- Department of Transplantation Surgery, Aristotle University School of Medicine, Thessaloniki 54622, Greece
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13
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Ezzat R, Eltabbakh M, El Kassas M. Unique situation of hepatocellular carcinoma in Egypt: A review of epidemiology and control measures. World J Gastrointest Oncol 2021; 13:1919-1938. [PMID: 35070033 PMCID: PMC8713321 DOI: 10.4251/wjgo.v13.i12.1919] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2021] [Revised: 04/17/2021] [Accepted: 10/18/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the sixth most common primary malignancy worldwide, and the third most common cause of death among cancers worldwide. HCC occurs in several pre-existing conditions, including hepatitis C, hepatitis B virus, and non-alcoholic cirrhosis. Egypt used to be the country with the heaviest hepatitis C virus (HCV) burden. The relationship between HCV and HCC is an important research area. In Egypt, HCC is a significant public health problem. A possible cause for the increasing rates of detection of HCC in Egypt is the mass screening program that was carried by the government for detecting and treating HCV. A multidisciplinary approach is now widely applied to HCC management in health centers all over Egypt. Different treatment modalities are available in Egypt, with success rates comparable to global rates. The Egyptian health authorities have made the elimination of HCV from Egypt a special priority, and this approach should lead to a decrease in number of HCC cases in the near future. In this article we review the current situation of HCC in Egypt, including epidemiological aspects, relevant risk factors for HCC development, strategies, and efforts established by health authorities for the screening and prevention of both HCV and HCC in Egypt. We highlight the different modalities for HCC treatment.
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Affiliation(s)
- Reem Ezzat
- Internal Medicine Department, Faculty of Medicine, Assiut University, Assiut 71515, Egypt
| | - Mohamed Eltabbakh
- Tropical Medicine Department, Faculty of Medicine, Ain Shams University, Cairo 11566, Egypt
| | - Mohamed El Kassas
- Endemic Medicine Department, Faculty of Medicine, Helwan University, Cairo 11795, Cairo, Egypt
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14
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Makary MS, Ramsell S, Miller E, Beal EW, Dowell JD. Hepatocellular carcinoma locoregional therapies: Outcomes and future horizons. World J Gastroenterol 2021; 27:7462-7479. [PMID: 34887643 PMCID: PMC8613749 DOI: 10.3748/wjg.v27.i43.7462] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/23/2021] [Revised: 07/09/2021] [Accepted: 10/27/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary cancer of the liver and has an overall five-year survival rate of less than twenty percent. For patients with unresectable disease, evolving liver-directed locoregional therapies provide efficacious treatment across the spectrum of disease stages and via a variety of catheter-directed and percutaneous techniques. Goals of locoregional therapies in HCC may include curative intent in early-stage disease, bridging or downstaging to surgical resection or transplantation for early or intermediate-stage disease, and local disease control and palliation in advanced-stage disease. This review explores the outcomes of chemoembolization, bland embolization, radioembolization, and percutaneous ablative therapies. Attention is also given to prognostic factors related to each of the respective techniques, as well as future directions of locoregional therapies for HCC.
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Affiliation(s)
- Mina S Makary
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Stuart Ramsell
- Department of Radiology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Eric Miller
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Eliza W Beal
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH 43210, United States
| | - Joshua D Dowell
- Department of Radiology, Northwest Radiology, St. Vincent Health, Indianapolis, IN 46260, United States
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15
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Involvement of Kynurenine Pathway in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13205180. [PMID: 34680327 PMCID: PMC8533819 DOI: 10.3390/cancers13205180] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 10/08/2021] [Accepted: 10/13/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary The kynurenine pathway (KP) is a biochemical pathway that synthesizes the vital coenzyme, nicotinamide adenine dinucleotide (NAD+). In cancer, the KP is significantly activated, leading to tryptophan depletion and the production of downstream metabolites, which skews the immune response towards tumour tolerance. More specifically, advanced stage cancers that readily metastasize evidence the most dysregulation in KP enzymes, providing a clear link between the KP and cancer morbidity. Consequently, this provides the rationale for an attractive new drug discovery opportunity for adjuvant therapeutics targeting KP-mediated immune tolerance, which would greatly complement current pharmacological interventions. In this review, we summarize recent developments in the roles of the KP and clinical trials examining KP inhibition in liver cancer. Abstract As the second and third leading cancer-related death in men and the world, respectively, primary liver cancer remains a major concern to human health. Despite advances in diagnostic technology, patients with primary liver cancer are often diagnosed at an advanced stage. Treatment options for patients with advanced hepatocarcinoma (HCC) are limited to systemic treatment with multikinase inhibitors and immunotherapy. Furthermore, the 5-year survival rate for these late-stage HCC patients is approximately 12% worldwide. There is an unmet need to identify novel treatment options and/or sensitive blood-based biomarker(s) to detect this cancer at an early stage. Given that the liver harbours the largest proportion of immune cells in the human body, understanding the tumour–immune microenvironment has gained increasing attention as a potential target to treat cancer. The kynurenine pathway (KP) has been proposed to be one of the key mechanisms used by the tumour cells to escape immune surveillance for proliferation and metastasis. In an inflammatory environment such as cancer, the KP is elevated, suppressing local immune cell populations and enhancing tumour growth. In this review, we collectively describe the roles of the KP in cancer and provide information on the latest research into the KP in primary liver cancer.
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16
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Farha M, Jairath NK, Lawrence TS, El Naqa I. Characterization of the Tumor Immune Microenvironment Identifies M0 Macrophage-Enriched Cluster as a Poor Prognostic Factor in Hepatocellular Carcinoma. JCO Clin Cancer Inform 2021; 4:1002-1013. [PMID: 33136432 DOI: 10.1200/cci.20.00077] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
PURPOSE Hepatocellular carcinoma (HCC) is characterized by a poor prognosis and a high recurrence rate. The tumor immune microenvironment in HCC has been characterized as shifted toward immunosuppression. We conducted a genomic data-driven classification of immune microenvironment HCC subtypes. In addition, we demonstrated their prognostic value and suggested a potential therapeutic targeting strategy. METHODS RNA sequencing data from The Cancer Genome Atlas-Liver Hepatocellular Carcinoma was used (n = 366). Abundance of immune cells was imputed using CIBERSORT and visualized using unsupervised hierarchic clustering. Overall survival (OS) was analyzed using Kaplan-Meier estimates and Cox regression. Differential expression and gene set enrichment analyses were conducted on immune clusters with poor OS and high programmed death-1 (PD-1)/programmed death-ligand 1 (PD-L1) coexpression. A scoring metric combining differentially expressed genes and immune cell content was created, and its prognostic value and immune checkpoint blockade response prediction was evaluated. RESULTS Two clusters were characterized by macrophage enrichment, with distinct M0Hi and M2Hi subtypes. M2Hi (P = .038) and M0Hi (P = .018) were independently prognostic for OS on multivariable analysis. Kaplan-Meier estimates demonstrated that patients in M0Hi and M2Hi treated with sorafenib had decreased OS (P = .041), and angiogenesis hallmark genes were enriched in the M0Hi group. CXCL6 and POSTN were overexpressed in both the M0Hi and the PD-1Hi/PD-L1Hi groups. A score consisting of CXCL6 and POSTN expression and absolute M0 macrophage content was discriminatory for OS (intermediate: hazard ratio [HR], 1.59; P ≤ .001; unfavorable: HR, 2.08; P = .04). CONCLUSION Distinct immune cell clusters with macrophage predominance characterize an aggressive HCC phenotype, defined molecularly by angiogenic gene enrichment and clinically by poor prognosis and sorafenib response. This novel immunogenomic signature may aid in stratification of unresectable patients to receive checkpoint inhibitor and antiangiogenic therapy combinations.
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Affiliation(s)
- Mark Farha
- Department of Medical Education, University of Michigan Medical School, Ann Arbor, MI
| | - Neil K Jairath
- Department of Medical Education, University of Michigan Medical School, Ann Arbor, MI
| | | | - Issam El Naqa
- Department of Radiation Oncology, University of Michigan, Ann Arbor, MI
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17
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Garofalo M, Bellato F, Magliocca S, Malfanti A, Kuryk L, Rinner B, Negro S, Salmaso S, Caliceti P, Mastrotto F. Polymer Coated Oncolytic Adenovirus to Selectively Target Hepatocellular Carcinoma Cells. Pharmaceutics 2021; 13:pharmaceutics13070949. [PMID: 34202714 PMCID: PMC8309094 DOI: 10.3390/pharmaceutics13070949] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 06/08/2021] [Accepted: 06/18/2021] [Indexed: 01/15/2023] Open
Abstract
Despite significant advances in chemotherapy, the overall prognosis of hepatocellular carcinoma (HCC) remains extremely poor. HCC targeting strategies were combined with the tumor cell cytotoxicity of oncolytic viruses (OVs) to develop a more efficient and selective therapeutic system. OVs were coated with a polygalactosyl-b-agmatyl diblock copolymer (Gal32-b-Agm29), with high affinity for the asialoglycoprotein receptor (ASGPR) expressed on the liver cell surface, exploiting the electrostatic interaction of the positively charged agmatine block with the negatively charged adenoviral capsid surface. The polymer coating altered the viral particle diameter (from 192 to 287 nm) and zeta-potential (from -24.7 to 23.3 mV) while hiding the peculiar icosahedral symmetrical OV structure, as observed by TEM. Coated OVs showed high potential therapeutic value on the human hepatoma cell line HepG2 (cytotoxicity of 72.4% ± 4.96), expressing a high level of ASGPRs, while a lower effect was attained with ASPGR-negative A549 cell line (cytotoxicity of 54.4% ± 1.59). Conversely, naked OVs showed very similar effects in both tested cell lines. Gal32-b-Agm29 OV coating enhanced the infectivity and immunogenic cell death program in HepG2 cells as compared to the naked OV. This strategy provides a rationale for future studies utilizing oncolytic viruses complexed with polymers toward effective treatment of hepatocellular carcinoma.
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Affiliation(s)
- Mariangela Garofalo
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy; (F.B.); (S.M.); (S.S.); (P.C.)
- Correspondence: (M.G.); (F.M.); Tel.: +39-04-9827-5710 (M.G.); +39-04-9827-5708 (F.M.)
| | - Federica Bellato
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy; (F.B.); (S.M.); (S.S.); (P.C.)
| | - Salvatore Magliocca
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy; (F.B.); (S.M.); (S.S.); (P.C.)
| | - Alessio Malfanti
- Université Catholique de Louvain, Louvain Drug Research Institute, Advanced Drug Delivery and Biomaterials, Avenue Mounier, 73 bte B1 73.12, 1200 Brussels, Belgium;
| | - Lukasz Kuryk
- Department of Virology, National Institute of Public Health—National Institute of Hygiene, Chocimska 24, 00-791 Warsaw, Poland;
- Clinical Science, Targovax Oy, Saukonpaadenranta 2, 00180 Helsinki, Finland
| | - Beate Rinner
- Division of Biomedical Research, Medical University of Graz, Roseggerweg 48, 8036 Graz, Austria;
| | - Samuele Negro
- Department of Biomedical Sciences, University of Padova, Via Ugo Bassi 58/B, 35131 Padova, Italy;
| | - Stefano Salmaso
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy; (F.B.); (S.M.); (S.S.); (P.C.)
| | - Paolo Caliceti
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy; (F.B.); (S.M.); (S.S.); (P.C.)
| | - Francesca Mastrotto
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Via F. Marzolo 5, 35131 Padova, Italy; (F.B.); (S.M.); (S.S.); (P.C.)
- Correspondence: (M.G.); (F.M.); Tel.: +39-04-9827-5710 (M.G.); +39-04-9827-5708 (F.M.)
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18
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Ceylan H. Identification of hub genes associated with obesity-induced hepatocellular carcinoma risk based on integrated bioinformatics analysis. Med Oncol 2021; 38:63. [PMID: 33900477 DOI: 10.1007/s12032-021-01510-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 04/13/2021] [Indexed: 12/16/2022]
Abstract
Obesity, which has become one of the biggest public health problems of the twenty-first century, accompanies many chronic conditions, including cancer. On the other hand, liver cancer, which is known to be associated with obesity, is considered another serious threat to public health. However, the underlying drivers of the development of obesity-associated hepatocellular carcinoma (HCC) remain blurry. The current study attempted to identify the key genes and pathways in the obesity-induced development of HCC using integrated bioinformatics analyses. Obesity and HCC-associated gene expression datasets were downloaded from Gene Expression Omnibus (GEO) and analyzed to identify overlapping differentially expressed genes (DEGs) and hub genes. The prognostic potentials, survival analysis, and expression levels of hub genes were further assessed. Moreover, the correlation between hub genes and the immune cells infiltration was analyzed. The findings of this research revealed that both mRNA and protein expression levels of the four hub genes (IGF1, ACADL, CYP2C9, and G6PD) involved in many important metabolic pathways are remarkably altered in both obese individuals and patients with HCC. The results demonstrated that these dysregulated genes in both obesity and HCC may serve as considerable targets for the prevention and treatment of HCC development in obese individuals.
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Affiliation(s)
- Hamid Ceylan
- Department of Molecular Biology and Genetics, Faculty of Science, Atatürk University, 25400, Erzurum, Turkey.
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19
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Fukushima H, Kono H, Hirayama K, Akazawa Y, Nakata Y, Wakana H, Fujii H. Changes in Function and Dynamics in Hepatic and Splenic Macrophages in Non-Alcoholic Fatty Liver Disease. Clin Exp Gastroenterol 2020; 13:305-314. [PMID: 32922061 PMCID: PMC7457821 DOI: 10.2147/ceg.s248635] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Accepted: 07/27/2020] [Indexed: 12/16/2022] Open
Abstract
Background The aim of this study was to investigate the populations and functions of hepatic and splenic macrophages (Mfs) in non-alcoholic fatty liver disease (NAFLD). Materials and Methods Experiment 1: Wild-type and STAM® mice were given chow or high-fat diets for designated periods. In isolated Mfs, phagocytosis and cytokine production were assessed. Immunohistochemistry for CD68 and F4/80 and expression of CD14 and CD16 were assessed. Experiment 2: Bone marrow cells harvested from enhanced green fluorescent protein (EGFP) mice were transplanted into wild-type mice with or without splenectomy after total body irradiation that was kept on methionine- and choline-deficient diets. Results Experiment 1: The number of CD68-positive cells and the percentage of F4/80-positive/CD68-positive cells increased with the progression of NAFLD. Production of TNF-α and IL-6 by hepatic Mfs was greater than that by splenic Mfs in mice with NASH. The number of CD14+CD16− Mfs increased in the spleen and decreased in the liver in animals that had progressed to NASH. Furthermore, the number of CD14+CD16+ hepatic Mfs was increased in animals that had progressed to NASH with fibrosis. Experiment 2: EGFP-positive cells were observed in the liver after transplantation. In the splenectomy group, EGFP-positive Mfs were also observed; however, the number was significantly less than that in the sham operation group. Conclusion The populations and functions of hepatic and splenic Mfs are altered during the progression of NAFLD. In addition, increased hepatic Mfs during the progression of NAFLD may migrate from bone marrow to the liver via the spleen.
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Affiliation(s)
- Hisataka Fukushima
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hiroshi Kono
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Kazuyoshi Hirayama
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yoshihiro Akazawa
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Yuuki Nakata
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hiroyuki Wakana
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan
| | - Hideki Fujii
- First Department of Surgery, Faculty of Medicine, University of Yamanashi, Yamanashi, Japan.,Department of Surgery, Kofu Municipal Hospital, Yamanashi, Japan
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20
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Benson AB, D'Angelica MI, Abbott DE, Abrams TA, Alberts SR, Anaya DA, Anders R, Are C, Brown D, Chang DT, Cloyd J, Covey AM, Hawkins W, Iyer R, Jacob R, Karachristos A, Kelley RK, Kim R, Palta M, Park JO, Sahai V, Schefter T, Sicklick JK, Singh G, Sohal D, Stein S, Tian GG, Vauthey JN, Venook AP, Hammond LJ, Darlow SD. Guidelines Insights: Hepatobiliary Cancers, Version 2.2019. J Natl Compr Canc Netw 2020; 17:302-310. [PMID: 30959462 DOI: 10.6004/jnccn.2019.0019] [Citation(s) in RCA: 199] [Impact Index Per Article: 39.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and updated recommendations regarding systemic therapy for first-line and subsequent-line treatment of patients with hepatocellular carcinoma.
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Affiliation(s)
- Al B Benson
- 1Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | | | - Robert Anders
- 7The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
| | | | | | | | - Jordan Cloyd
- 11The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | - William Hawkins
- 12Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | - Rojymon Jacob
- 14University of Alabama at Birmingham Comprehensive Cancer Center
| | | | - R Kate Kelley
- 16UCSF Helen Diller Family Comprehensive Cancer Center
| | - Robin Kim
- 17Huntsman Cancer Institute at the University of Utah
| | | | - James O Park
- 19University of Washington/Seattle Cancer Care Alliance
| | | | | | | | | | - Davendra Sohal
- 24Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | - G Gary Tian
- 26St. Jude Children's Research Hospital/The University of Tennessee Health Science Center
| | | | - Alan P Venook
- 16UCSF Helen Diller Family Comprehensive Cancer Center
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Singh V, Yeoh BS, Abokor AA, Golonka RM, Tian Y, Patterson AD, Joe B, Heikenwalder M, Vijay-Kumar M. Vancomycin prevents fermentable fiber-induced liver cancer in mice with dysbiotic gut microbiota. Gut Microbes 2020; 11:1077-1091. [PMID: 32223398 PMCID: PMC7524287 DOI: 10.1080/19490976.2020.1743492] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Owing to their health benefits, dietary fermentable fibers, such as refined inulin, are increasingly fortified in processed foods to enhance their nutritional value. However, we previously demonstrated that when inulin was fed to Toll-like receptor 5 deficient (T5KO) mice susceptible to dysbiosis, a subset of them developed cholestasis and subsequently liver cancer in a gut microbiota-dependent manner. Therefore, we hypothesized that clearance of bacterial taxa, and thereby gut metabolites, involved in the onset and progression to liver cancer could abate the disease in these mice. Such a reshaping of microbiota by vancomycin treatment was sufficient to halt the development of liver cancer in inulin-fed T5KO mice; however, this intervention did not remedy disease penetrance for cholestatic liver injury and its sequelae, including hyperbilirubinemia, hypolipidemia, cholemia and liver fibrosis. Selective depletion of gut bacterial communities was observed in vancomycin-treated mice, including Gram-positive Lachnospiraceae and Ruminococcaceae belonging to the phylum Firmicutes, Bifidobacteria of the phylum Actinobacteria, which ferment fibers, and Clostridium cluster XIVa, which produce secondary bile acids. Lack of liver cancer in vancomycin-treated mice strongly correlated with the substantial loss of secondary bile acids in circulation. Although cholemia was unabated by vancomycin, the composition of serum bile acids shifted toward an abundance of hydrophilic primary bile acids, denoted by the increase in conjugated-to-unconjugated bile acid ratio. Taken together, the present study suggests that microbiotal regulation of bile acid metabolism is one of the critical mediators of fermentable fiber-induced liver cancer in dysbiotic mice.
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Affiliation(s)
- Vishal Singh
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Beng San Yeoh
- Microbiome Consortium, Center for Hypertension and Precision Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA,Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Ahmed A. Abokor
- Microbiome Consortium, Center for Hypertension and Precision Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA,Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Rachel M. Golonka
- Microbiome Consortium, Center for Hypertension and Precision Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA,Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Yuan Tian
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Andrew D. Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bina Joe
- Microbiome Consortium, Center for Hypertension and Precision Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA,Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany
| | - Matam Vijay-Kumar
- Microbiome Consortium, Center for Hypertension and Precision Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA,Department of Physiology & Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OH, USA,CONTACT Matam Vijay-Kumar (Vijay) Department of Physiology and Pharmacology, The University of Toledo College of Medicine & Life Sciences, Toledo43614, USA
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Zeng LY, Yang SY, Zhang ZQ, Wang T, Wang YZ, Wei XC. Effect of Cholecystectomy on the Occurrence of Knee Osteoarthritis. Orthop Surg 2020; 12:756-760. [PMID: 32476289 PMCID: PMC7307220 DOI: 10.1111/os.12671] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2019] [Revised: 02/21/2020] [Accepted: 03/12/2020] [Indexed: 11/29/2022] Open
Abstract
Objective To evaluate the effect of cholecystectomy on the occurrence of knee osteoarthritis (KOA). Methods The present study was a case‐control study with a retrospective, cross‐sectional, and longitudinal study design. The clinical data for knee osteoarthritis in the Second Hospital of Shanxi Medical University from January 2016 to September 2018 was analyzed. Clinical data, including gender, age, height, weight, smoking, alcohol abuse, prior medical history, and previous surgical history, were recorded. A logistic regression model was used for the univariate and multivariate analysis. Results A total of 1659 patients with KOA (KOA group) and 1195 limb fracture patients (control group) were included in this study. Among the 1659 patients with KOA, 388 patients were male and 1271 were female, while among the 1195 patients in the control group, 638 patients were male and 557 patients were female. The period between cholecystectomy and knee osteoarthritis onset ranged from 0.5 years to 17 years; the average interval time was 8.73 ± 2.11 years. The age at disease onset was significantly older when compared to the control group, while the body mass index in the KOA group was significantly higher when compared to the control group (P < 0.05). There were 97 patients undergoing cholecystectomy in the KOA group and there were 15 patients undergoing cholecystectomy in the control group. The proportion of cholecystectomy in the two groups was statistically significant. After the univariate analysis, there was a statistically significant difference in distribution between the two groups (P < 0.05). The multivariate logistic regression analysis revealed that there was a significant difference in the distribution of these two groups (P < 0.05), indicating that cholecystectomy is associated with the occurrence of KOA. Conclusion There is a close relationship between cholecystectomy and KOA. However, the specific mechanism remains unknown and should be further researched.
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Affiliation(s)
- Ling-Yuan Zeng
- Department of Orthopaedic Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Shu-Yan Yang
- Department of Blood Transfusion, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Zhi-Qiang Zhang
- Department of Orthopaedic Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | - Tao Wang
- Department of Orthopaedic Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
| | | | - Xiao-Chun Wei
- Department of Orthopaedic Surgery, The Second Hospital of Shanxi Medical University, Taiyuan, China
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23
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Elsalem L, Jum'ah AA, Alfaqih MA, Aloudat O. The Bacterial Microbiota of Gastrointestinal Cancers: Role in Cancer Pathogenesis and Therapeutic Perspectives. Clin Exp Gastroenterol 2020; 13:151-185. [PMID: 32440192 PMCID: PMC7211962 DOI: 10.2147/ceg.s243337] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/22/2019] [Accepted: 04/13/2020] [Indexed: 12/24/2022] Open
Abstract
The microbiota has an essential role in the pathogenesis of many gastrointestinal diseases including cancer. This effect is mediated through different mechanisms such as damaging DNA, activation of oncogenic pathways, production of carcinogenic metabolites, stimulation of chronic inflammation, and inhibition of antitumor immunity. Recently, the concept of "pharmacomicrobiomics" has emerged as a new field concerned with exploring the interplay between drugs and microbes. Mounting evidence indicates that the microbiota and their metabolites have a major impact on the pharmacodynamics and therapeutic responses toward anticancer drugs including conventional chemotherapy and molecular-targeted therapeutics. In addition, microbiota appears as an attractive target for cancer prevention and treatment. In this review, we discuss the role of bacterial microbiota in the pathogenesis of different cancer types affecting the gastrointestinal tract system. We also scrutinize the evidence regarding the role of microbiota in anticancer drug responses. Further, we discuss the use of probiotics, fecal microbiota transplantation, and antibiotics, either alone or in combination with anticancer drugs for prevention and treatment of gastrointestinal tract cancers.
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Affiliation(s)
- Lina Elsalem
- Department of Pharmacology, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Ahmad A Jum'ah
- Department of Conservative Dentistry, Faculty of Dentistry, Jordan University of Science and Technology, Irbid, Jordan
| | - Mahmoud A Alfaqih
- Department of Physiology and Biochemistry, Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
| | - Osama Aloudat
- Faculty of Medicine, Jordan University of Science and Technology, Irbid, Jordan
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24
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Getaneh F, Atnafu A. Patterns of Hepatocellular Carcinoma on Computed Tomography at Tikur Anbessa specialized hospital, Addis Ababa, Ethiopia. Ethiop J Health Sci 2020; 30:209-214. [PMID: 32165810 PMCID: PMC7060377 DOI: 10.4314/ejhs.v30i2.8] [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] [Indexed: 11/24/2022] Open
Abstract
Background Hepatocellular cancer is the commonest liver cancer which contributes to a high incidence of morbidity and mortality in both developed and developing countries. Despite the anticipated high burden of the disease in the country, there is paucity of data on the associated risk factors and its pattern on imaging. The aim of this study was to assess Computed Tomography patterns and the risk factors of hepatocellular carcinoma. Methods A cross-sectional, prospective study on patients with a diagnosis of HCC on Computed Tomography examination, at Tikur Anbessa Specialized Hospital from July, 2016 to July, 2017. All patients who had characteristic Computed Tomography features and those who were diagnosed by Fine needle aspiration cytology (FNAC)/biopsy and had Computed Tomography examination were included in the study. Risk factors identified were reviewed from patients' medical records. Result A total of 70(n=70) patients were included in the study. The mean age was 50 ± 16 years. Fifty-seven (81.4%) of the participants were males, and 13(18.6%) were females. Forty-five (64.3%) of them came from urban areas and 25(35.7%) of them were from rural areas. The lesions were focal in 52(74.3%) and infiltrative in 18(25.7%) of the cases. Vascular invasion and distant metastases were seen in 49(70%) and 17(24.3%) respectively. Twenty-nine (41%) had negative hepatitis markers, and 13(19%) were not investigated for hepatitis infection. Conclusion The majority of the patients presented with advanced disease such as vascular invasion and metastases. The major risk factors such as hepatitis infection were negative in significant number of patients. The risk factors in our setting should be studied further. Moreover, high-risk group selection and screening is essential to diagnose HCC early.
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Affiliation(s)
- Ferehiwot Getaneh
- Department of Radiology, College of Health Sciences, Addis Ababa University Addis Ababa, Ethiopia
| | - Asfaw Atnafu
- Department of Radiology, College of Health Sciences, Addis Ababa University Addis Ababa, Ethiopia
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25
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Wang T, Kong J, Yang X, Shen S, Zhang M, Wang W. Clinical features of sarcomatoid change in patients with intrahepatic cholangiocarcinoma and prognosis after surgical liver resection: A Propensity Score Matching analysis. J Surg Oncol 2019; 121:524-537. [PMID: 31867746 DOI: 10.1002/jso.25815] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 12/10/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma with sarcomatoid change (iCCA-SC) is a rare histological subtype of iCCA, the clinical features and outcomes after surgical resection on the prognosis is still unknown. METHODS We retrospectively reviewed the clinical data of patients with histologically proven iCCA who underwent curative liver resection at our hospital between January 2008 and December 2018. Propensity score matching analysis was used to match patients with and without sarcomatoid change at a ratio of 1:4. The nomogram integrating all significant independent factors for overall survival (OS) and recurrence-free survival (RFS) was constructed to predict prognosis for iCCA. The predictive accuracy ability of the nomogram was determined by Harrell's index (C-index). RESULTS A total of 40 iCCA-SC and 160 ordinary iCCA patients were included in this study. RFS and OS in the iCCA-SC group were significantly lower than those in the ordinary iCCA group (P<.001 and P = .002, respectively). The calibration curve for the probability of survival showed good agreement between the nomogram prediction and actual observation. CONCLUSION The histological sarcomatoid subtype is an independent predictor of tumor recurrence and shorter OS in iCCA patients. The nomogram we established could provide more accurate prognostic prediction for iCCA patients.
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Affiliation(s)
- Tao Wang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
| | - Junjie Kong
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
| | - Xianwei Yang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
| | - Shu Shen
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
| | - Menglan Zhang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, China
| | - Wentao Wang
- Department of Liver Surgery and Liver Transplantation Center, West China Hospital of Sichuan University, Chengdu, China
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Raza S, Rajak S, Anjum B, Sinha RA. Molecular links between non-alcoholic fatty liver disease and hepatocellular carcinoma. HEPATOMA RESEARCH 2019; 5:42. [PMID: 31867441 PMCID: PMC6924993 DOI: 10.20517/2394-5079.2019.014] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) and its advanced complication, non-alcoholic steatohepatitis (NASH), have become leading causes of hepatocellular carcinoma (HCC) worldwide. In this review, we discuss the role of metabolic, gut microbial, immune and endocrine mediators which promote the progression of NAFLD to HCC. In particular, this progression involves multiple hits resulting from lipotoxicity, oxidative stress, inhibition of hepatic autophagy and inflammation. Furthermore, dysbiosis in the gut associated with obesity also promotes HCC via induction of proinflammatory cytokines and Toll like receptor signalling as well as altered bile metabolism. Additionally, compromised T-cell function and impaired hepatic hormonal action promote the development of NASH-associated HCC. Lastly, we discuss the current challenges involved in the diagnosis and treatment of NAFLD/NASH-associated HCC.
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Affiliation(s)
- Sana Raza
- Department of Bioscience, Integral University, Lucknow 226026, India
| | - Sangam Rajak
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Baby Anjum
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
| | - Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow 226014, India
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27
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Animal Models of Hepatocellular Carcinoma Prevention. Cancers (Basel) 2019; 11:cancers11111792. [PMID: 31739536 PMCID: PMC6895981 DOI: 10.3390/cancers11111792] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Revised: 11/08/2019] [Accepted: 11/10/2019] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a deadly disease and therapeutic efficacy in advanced HCC is limited. Since progression of chronic liver disease to HCC involves a long latency period of a few decades, a significant window of therapeutic opportunities exists for prevention of HCC and improve patient prognosis. Nonetheless, there has been no clinical advancement in instituting HCC chemopreventive strategies. Some of the major challenges are heterogenous genetic aberrations of HCC, significant modulation of tumor microenvironment and incomplete understanding of HCC tumorigenesis. To this end, animal models of HCC are valuable tools to evaluate biology of tumor initiation and progression with specific insight into molecular and genetic mechanisms involved. In this review, we describe various animal models of HCC that facilitate effective ways to study therapeutic prevention strategies that have translational potential to be evaluated in a clinical context.
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Sonohara F, Yamada S, Tanaka N, Tashiro M, Sunagawa Y, Morimoto D, Tanaka H, Takami H, Hayashi M, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Kodera Y. Comparison of non-invasive liver reserve and fibrosis models: Implications for surgery and prognosis for hepatocellular carcinoma. Hepatol Res 2019; 49:1305-1315. [PMID: 31260575 DOI: 10.1111/hepr.13400] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2019] [Revised: 06/05/2019] [Accepted: 06/25/2019] [Indexed: 12/13/2022]
Abstract
AIM This study aimed to assess the clinical utility of preoperative evaluation of liver fibrosis using platelet-albumin-bilirubin (PALBI) grade, Fibrosis-4 index (FIB-4), and aspartate transaminase-to-platelet ratio index (APRI) for hepatocellular carcinoma (HCC) patients and explore the clinical impact of these models with regard to perioperative risks and HCC prognosis. METHODS Between January 2003 and December 2018, 305 consecutive patients who underwent hepatectomy for HCC were enrolled. RESULTS The APRI showed the most robust diagnostic performance through each fibrosis stage among three models (PALBI, FIB-4, and APRI): fibrosis stage 3 (f3), area under the curve [AUC] = 0.55, 0.72, and 0.76; and f4, AUC = 0.51, 0.71, and 0.76, respectively). In addition, survival analysis revealed that all three models were significantly associated with HCC prognosis. PALBI (grade 1 vs. 2, 3): recurrence-free survival (RFS): median survival time (MST), 34 vs. 17 months, 0.007; overall survival (OS): MST, 115 vs. 68, 0.02. FIB-4 (grade 1, 2 vs. 3): RFS: MST, 34 vs. 22, 0.004, OS: MST, 120 vs. 63, 0.0001. APRI (grade 1, 2 vs. 3), RFS: MST, 30 vs. 20, 0.0005; OS: MST, 107 vs. 55, 0.0003. Among three scoring systems, only PALBI grade was significantly associated with both operative time (median, 303 vs. 340 min, 0.01) and intraoperative blood loss (median, 581 vs. 859 mL, 0.03). CONCLUSIONS This study showed robust performances of selected liver reserve and fibrosis models to predict HCC prognosis. Of them, PALBI might be used for assessing perioperative risks for hepatectomy for HCC.
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Affiliation(s)
- Fuminori Sonohara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Nobutake Tanaka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuru Tashiro
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuki Sunagawa
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daishi Morimoto
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Haruyoshi Tanaka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery, Nagoya University Graduate School of Medicine, Nagoya, Japan
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Aiello VD, Tanigawa RY, Chate RC, de Campos FPF, Mansur AJ. Progressive dyspnea and a right atrial mass in an 80-year-old man. Autops Case Rep 2019; 9:e2019135. [PMID: 31807438 PMCID: PMC6880769 DOI: 10.4322/acr.2019.135] [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: 08/16/2019] [Accepted: 10/01/2019] [Indexed: 11/23/2022]
Abstract
Hepatocellular carcinoma (HCC) is among the five most frequent causes of cancer death worldwide, according to the WHO. The disease is related to alcohol abuse, viral infections, and other causes of cirrhosis, and unfortunately, in some developed countries, the incidence shows an increasing trend. Although the diagnosis of the HCC often relies upon the context of a chronic hepatopathy, some cases may present a silent course, and the initial symptoms ensue when the disease is in an advanced stage with no chance for any therapeutic attempt. The clinical picture of the HCC is varied, and unexpected forms may surprise the clinician. One of the unusual presentations of the HCC is shock by the blockage of the venous return to the right atrium by the inferior vena cava infiltration. Herein we present a case of an old patient who sought medical care complaining of dyspnea. The clinical workup disclosed a right thorax pleural effusion and imaging exams depicted a mass in the right hepatic lobe, invasion of the inferior vena cava (IVC) and the right atrium (RA). During the attempts of clinical investigation, the patient passed away. The autopsy disclosed an HCC involving the right hepatic lobe, with the invasion of the IVC and the RA. The authors highlight the importance of recognizing the bizarre presentation of not so rare diseases.
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Affiliation(s)
- Vera Demarchi Aiello
- Universidade de São Paulo (USP), Medical School, Heart Institute, Laboratory of Pathology. São Paulo, SP, Brazil
| | - Ryan Yukimatsu Tanigawa
- Universidade de São Paulo (USP), Medical School, Department of Pathology. São Paulo, SP, Brazil
| | - Rodrigo Caruso Chate
- Universidade de São Paulo (USP), Medical School, Hospital das Clínicas, Division of Radiology. São Paulo, SP, Brazil
| | | | - Alfredo José Mansur
- Universidade de São Paulo (USP), Medical School, Heart Institute, General Outpatient Clinics, Division of Clinical Cardiology. São Paulo, SP, Brazil
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Gentile EA, Castronuovo CC, Cuestas ML, Gómez N, Davio C, Oubiña JR, Mathet VL. F127 poloxamer effect on cytotoxicity induction of tumour cell cultures treated with doxorubicin. ACTA ACUST UNITED AC 2019; 71:1655-1662. [PMID: 31456253 DOI: 10.1111/jphp.13158] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Accepted: 07/28/2019] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Hepatocellular carcinoma is the most common liver malignancy and the third leading cause of cancer death worldwide. One crucial limitation in the pharmacotherapy for this tumour is its chemotherapy-resistant nature produced by the overexpression of several members of the ATP-binding cassette protein family that efflux drugs out of cells, as observed with the breast cancer resistant protein (BCRP). OBJECTIVES This study aimed to assess the ability of Pluronic® F127 to reverse the multidrug resistance phenotype in two human hepatocellular cell lines. METHODS PLC/PRF/5 and SKHep1 cells were exposed to Pluronic® F127 at several concentrations. The effect of F127 on BCRP expression (mRNA and protein), mitochondrial transmembrane potential and cell hypodiploidy was assessed. Finally, the effect of this copolymer on cytotoxicity of doxorubicin in both hepatoma cell lines was investigated, as expressed by its reverse resistance index. KEY FINDINGS It was demonstrated that F127 in both cell lines contributes to chemosensitization, as shown by BCRP down-regulation, an altered mitochondrial transmembrane potential and hypodiploidy and reverse resistance index values. A remarkable dependence of these effects significantly correlated with the copolymer concentration. CONCLUSIONS These findings further uncover the potential usefulness of this copolymer as multidrug resistance reversal agent, increasing the efficacy of cancer therapies.
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Affiliation(s)
- Emiliano Alberto Gentile
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), Ciudad Autónoma de Buenos Aires, Argentina
| | - Cynthia Cecilia Castronuovo
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), Ciudad Autónoma de Buenos Aires, Argentina
| | - María Luján Cuestas
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), Ciudad Autónoma de Buenos Aires, Argentina
| | - Natalia Gómez
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Farmacológicas (ININFA), Ciudad Autónoma de Buenos Aires, Argentina
| | - Carlos Davio
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones Farmacológicas (ININFA), Ciudad Autónoma de Buenos Aires, Argentina
| | - José Raúl Oubiña
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), Ciudad Autónoma de Buenos Aires, Argentina
| | - Verónica Lidia Mathet
- CONICET-Universidad de Buenos Aires, Instituto de Investigaciones en Microbiología y Parasitología Médica (IMPAM), Ciudad Autónoma de Buenos Aires, Argentina
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Inchingolo R, Posa A, Mariappan M, Spiliopoulos S. Locoregional treatments for hepatocellular carcinoma: Current evidence and future directions. World J Gastroenterol 2019; 25:4614-4628. [PMID: 31528090 PMCID: PMC6718039 DOI: 10.3748/wjg.v25.i32.4614] [Citation(s) in RCA: 57] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 07/12/2019] [Accepted: 07/19/2019] [Indexed: 02/06/2023] Open
Abstract
Liver cancers are the second most frequent cause of global cancer-related mortality of which 90% are attributable to hepatocellular carcinoma (HCC). Despite the advent of screening programmes for patients with known risk factors, a substantial number of patients are ineligible for curative surgery at presentation with limited outcomes achievable with systemic chemotherapy/external radiotherapy. This has led to the advent of numerous minimally invasive options including but not limited to trans-arterial chemoembolization, radiofrequency/microwave ablation and more recently selective internal radiation therapy many of which are often the first-line treatment for select stages of HCC or serve as a conduit to liver transplant. The authors aim to provide a comprehensive overview of these various image guided minimally invasive therapies with a brief focus on the technical aspects accompanied by a critical analysis of the literature to assess the most up-to-date evidence from comparative systematic reviews and meta-analyses finishing with an assessment of novel combination regimens and future directions of travel.
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Affiliation(s)
- Riccardo Inchingolo
- Division of Interventional Radiology, Department of Radiology, Madonna delle Grazie Hospital, Matera 75100, Italy
- Department of Radiology, King´s College Hospital, London SE5 9RS, United Kingdom
| | - Alessandro Posa
- Department of Radiology, IRCSS Fatebenefratelli Hospital, Roma 00186, Italy
| | - Martin Mariappan
- Interventional Radiology Department, Aberdeen Royal Infirmary Hospital, Aberdeen AB25 2ZN, United Kingdom
| | - Stavros Spiliopoulos
- 2nd Radiology Department, School of Medicine; National and Kapodistrian University of Athens, Chaidari Athens 12461, Greece
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β-ionone inhibits nonalcoholic fatty liver disease and its association with hepatocarcinogenesis in male Wistar rats. Chem Biol Interact 2019; 308:377-384. [PMID: 31150631 DOI: 10.1016/j.cbi.2019.05.046] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 05/24/2019] [Accepted: 05/27/2019] [Indexed: 02/07/2023]
Abstract
Among the primary neoplasias that affect the liver, hepatocellular carcinoma (HCC) is the most frequent and the third leading cause of death related to cancer. Several risk factors predispose individuals to HCC such as nonalcoholic fatty liver disease (NAFLD), whose incidence has significantly increased worldwide. β-ionone (βI) isoprenoid is a known chemopreventive of hepatocarcinogenesis. However, the effects of this compound on NAFLD isolated or in association with hepatocarcinogenesis have not yet been evaluated. A high-fat emulsion administered for 6 weeks resulted in NAFLD in male rats, and oral treatment with βI during this period significantly attenuated its development. Moreover, the presence of NAFLD potentiated hepatocarcinogenesis induced by the resistant hepatocyte (RH) model in these animals by increasing the number and percentage of the liver section area occupied by placental glutathione S-transferase (GST-P)-positive persistent preneoplastic lesions (pPNLs), that are thought to evolve into HCC. This indicates that this NAFLD/RH protocol is suitable for studies of the influence of NAFLD on the HCC development. Therefore, here we also investigated the chemopreventive effect of βI under these two associated conditions. In this context, βI reduced the number and percentage of the liver section area occupied by pPNLs, as well as cell proliferation and the number of oval cells, which are considered potential targets for the development of HCC. Thus, βI presents not only a promising inhibitory effect on NAFLD isolated but also chemopreventive activity when it is associated with hepatocarcinogenesis.
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Chand V, Pandey A, Kopanja D, Guzman G, Raychaudhuri P. Opposing Roles of the Forkhead Box Factors FoxM1 and FoxA2 in Liver Cancer. Mol Cancer Res 2019; 17:1063-1074. [PMID: 30814128 PMCID: PMC6497570 DOI: 10.1158/1541-7786.mcr-18-0968] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Revised: 12/10/2018] [Accepted: 02/22/2019] [Indexed: 12/11/2022]
Abstract
The forkhead box transcription factor FoxM1 is essential for hepatocellular carcinoma (HCC) development, and its overexpression coincides with poor prognosis. Here, we show that the mechanisms by which FoxM1 drives HCC progression involve overcoming the inhibitory effects of the liver differentiation gene FoxA2. First, the expression patterns of FoxM1 and FoxA2 in human HCC are opposite. We show that FoxM1 represses expression of FoxA2 in G1 phase. Repression of FoxA2 in G1 phase is important, as it is capable of inhibiting expression of the pluripotency genes that are expressed mainly in S-G2 phases. Using a transgenic mouse model for oncogenic Ras-driven HCC, we provide genetic evidence for a repression of FoxA2 by FoxM1. Conversely, FoxA2 inhibits expression of FoxM1 and inhibits FoxM1-induced tumorigenicity. Also, FoxA2 inhibits Ras-induced HCC progression that involves FoxM1. IMPLICATIONS: The observations provide strong genetic evidence for an opposing role of FoxM1 and FoxA2 in HCC progression. Moreover, FoxM1 drives high-grade HCC progression partly by inhibiting the hepatocyte differentiation gene FoxA2.
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Affiliation(s)
- Vaibhav Chand
- Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, Chicago, Illinois
| | - Akshay Pandey
- Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, Chicago, Illinois
| | - Dragana Kopanja
- Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, Chicago, Illinois
| | - Grace Guzman
- Department of Pathology, University of Illinois, College of Medicine, Chicago, Illinois
| | - Pradip Raychaudhuri
- Department of Biochemistry and Molecular Genetics, University of Illinois, College of Medicine, Chicago, Illinois.
- Jesse Brown VA Medical Center, Chicago, Illinois
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Sonohara F, Yamada S, Tanaka N, Suenaga M, Takami H, Hayashi M, Niwa Y, Sugimoto H, Hattori N, Kanda M, Tanaka C, Kobayashi D, Nakayama G, Koike M, Fujiwara M, Kodera Y. Perioperative and prognostic implication of albumin-bilirubin-TNM score in Child-Pugh class A hepatocellular carcinoma. Ann Gastroenterol Surg 2019; 3:65-74. [PMID: 30697612 PMCID: PMC6345730 DOI: 10.1002/ags3.12212] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 06/22/2018] [Accepted: 08/26/2018] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND AND AIM A reliable classification for predicting postoperative prognosis and perioperative risk of hepatocellular carcinoma (HCC) patients is required to make a precise decision for HCC treatment. In the present study, we assessed the perioperative and prognostic importance of indocyanine green (ICG) testing, tumor-node-metastasis (TNM) stage, albumin-bilirubin (ALBI) grade, and ALBI-TNM (ALBI-T) score using consecutive resected HCC cases. METHODS Between 1998 and 2011, 273 consecutive patients who underwent primary and curative hepatectomy for HCC were identified. Among these 273 cases, 235 Child-Pugh class A patients were enrolled in the present study. RESULTS Correlation analysis showed that the value of linear predictor for ALBI grade was significantly correlated with ICG 15-minute retention rates (r = 0.51, P < 0.0001). Survival analysis for both recurrence-free survival (RFS) and overall survival (OS) showed there were significant differences between the two groups stratified by stage or ALBI-T score (stage, RFS: P = 0.01, OS: P = 0.003; ALBI-T, RFS: P < 0.0001, OS: P < 0.0001). In addition, Cox proportional hazard model identified ALBI-T score was a significant predictor for both RFS and OS (RFS, P = 0.001; OS, P = 0.004). Furthermore, ALBI-T score could predict perioperative risk in hepatectomy such as longer operation time and excessive intraoperative blood loss. CONCLUSIONS This study showed a robust association of ALBI-T score with postoperative HCC patient survival and perioperative risk in hepatectomy. ALBI-T score can be used as a simple and powerful tool for assessing HCC patients with further study.
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Affiliation(s)
- Fuminori Sonohara
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Suguru Yamada
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Nobutake Tanaka
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Masaya Suenaga
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Hideki Takami
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Masamichi Hayashi
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Yukiko Niwa
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
- Department of SurgeryKomaki City HospitalKomakiJapan
| | - Norifumi Hattori
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Mitsuro Kanda
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Chie Tanaka
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Daisuke Kobayashi
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Goro Nakayama
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Masahiko Koike
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Michitaka Fujiwara
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
| | - Yasuhiro Kodera
- Department of Gastroenterological SurgeryNagoya University Graduate School of MedicineNagoyaJapan
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Fang D, Xiong Z, Xu J, Yin J, Luo R. Chemopreventive mechanisms of galangin against hepatocellular carcinoma: A review. Biomed Pharmacother 2019; 109:2054-2061. [DOI: 10.1016/j.biopha.2018.09.154] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2018] [Revised: 09/26/2018] [Accepted: 09/26/2018] [Indexed: 02/07/2023] Open
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Coskun E, Jaruga P, Vartanian V, Erdem O, Egner PA, Groopman JD, Lloyd RS, Dizdaroglu M. Aflatoxin-Guanine DNA Adducts and Oxidatively Induced DNA Damage in Aflatoxin-Treated Mice in Vivo as Measured by Liquid Chromatography-Tandem Mass Spectrometry with Isotope Dilution. Chem Res Toxicol 2018; 32:80-89. [PMID: 30525498 DOI: 10.1021/acs.chemrestox.8b00202] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
Dietary exposure to aflatoxin B1 (AFB1) is a significant contributor to the incidence of hepatocellular carcinomas globally. AFB1 exposure leads to the formation of AFB1-N7-guanine (AFB1-N7-Gua) and two diastereomers of the imidazole ring-opened 8,9-dihydro-8-(2,6-diamino-4-oxo-3,4-dihydropyrimid-5-yl-formamido)-9-hydroxyaflatoxin B1 (AFB1-FapyGua) in DNA. These adducts lead to G → T transversion mutations with the ring-opened adduct being more mutagenic than the cationic species. Accurate measurement of these three adducts as biomarkers in DNA and urine will help identify dietary exposure to AFB1 as a risk factor in the development of hepatocellular carcinoma worldwide. Herein, we report an improved methodology for the measurement of AFB1-N7-Gua and the two diastereomers of AFB1-FapyGua using liquid chromatography-tandem mass spectrometry with isotope dilution. We measured the levels of these compounds in liver DNA of six control mice and six AFB1-treated mice. Levels varying from 1.5 to 45 lesions/106 DNA bases in AFB1-treated mice were detected depending on the compound and animal. No background levels of these adducts were detected in control mice. We also tested whether the AFB1 treatment caused oxidatively induced DNA base damage using gas chromatography-tandem mass spectrometry with isotope dilution. Although background levels of several pyrimidine- and purine-derived lesions were detected, no increases in these levels were found upon AFB1 treatment of mice. On the other hand, significantly increased levels of (5' R)- and (5' S)-8,5'-cyclo-2'-deoxyadenosines were observed in liver DNA of AFB1-treated mice. The impact of this work is expected to achieve the accurate measurement of three AFB1-DNA adducts and oxidatively induced DNA lesions as biomarkers of AFB1 exposure as germane to investigations designed for the prevention of aflatoxin-related hepatocellular carcinomas and for determining the effects of genetic deficiencies in human populations.
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Affiliation(s)
- Erdem Coskun
- Biomolecular Measurement Division , National Institute of Standards and Technology , Gaithersburg , Maryland 20899 , United States
| | - Pawel Jaruga
- Biomolecular Measurement Division , National Institute of Standards and Technology , Gaithersburg , Maryland 20899 , United States
| | - Vladimir Vartanian
- Oregon Institute of Occupational Health Sciences , Oregon Health & Science University , Portland , Oregon 97239 , United States
| | - Onur Erdem
- Biomolecular Measurement Division , National Institute of Standards and Technology , Gaithersburg , Maryland 20899 , United States.,Department of Toxicology, Gülhane Faculty of Pharmacy , University of Health Sciences , Ankara 06010 , Turkey
| | - Patricia A Egner
- Department of Environmental Health and Engineering , Johns Hopkins University Bloomberg School of Public Health , Baltimore , Maryland 21205 , United States
| | - John D Groopman
- Department of Environmental Health and Engineering , Johns Hopkins University Bloomberg School of Public Health , Baltimore , Maryland 21205 , United States
| | - R Stephen Lloyd
- Department of Toxicology, Gülhane Faculty of Pharmacy , University of Health Sciences , Ankara 06010 , Turkey
| | - Miral Dizdaroglu
- Biomolecular Measurement Division , National Institute of Standards and Technology , Gaithersburg , Maryland 20899 , United States
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Yao J, Zhang X, Li J, Zhao D, Gao B, Zhou H, Gao S, Zhang L. Silencing TRIP13 inhibits cell growth and metastasis of hepatocellular carcinoma by activating of TGF-β1/smad3. Cancer Cell Int 2018; 18:208. [PMID: 30564064 PMCID: PMC6296061 DOI: 10.1186/s12935-018-0704-y] [Citation(s) in RCA: 38] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2018] [Accepted: 12/11/2018] [Indexed: 02/07/2023] Open
Abstract
Background TRIP13 is highly expressed in several cancers and is closely connected with cancer progression. However, its roles on the growth and metastasis of hepatocellular carcinoma (HCC), and the underlying mechanism are still unclear. Methods Combining bioinformatics with previous studies, the correlation between TRIP13 and HCC was predicted. TRIP13 expressions from 52 HCC patients and several cell lines were determined. The effects of silencing TRIP13 on cell viability, apoptosis, migration and invasion were respectively detected using CCK-8, flow cytometry and Transwell. qRT-PCR and western blot were performed to reveal associated mechanism. A HCC model was established in BALB/c-nu mice by transplanting HepG2 cells. TRIP13 protein expression and apoptosis in mice tissues were accordingly detected by Immunohistochemistry and TUNEL. Results High expression of TRIP13 in HCC affected the survival rate and it was enriched in RNA degradation and fatty acid metabolism according to bioinformatics and prediction from previous literature. Increased expression of TRIP13 in HCC patient tissues was associated with the progression of HCC. Silencing TRIP13 inhibited cell viability, migration and invasion, and induced cell apoptosis. TRIP13 knockdown also suppressed the formation of tumor in vivo. Meanwhile, silencing TRIP13 decreased the expressions of Ki67 and MMP-2 and increased the expressions of TIMP-2, active-caspase-3 and TGF-β1/smad3 signaling- related genes. Conclusions Silencing TRIP13 acts as a tumor suppresser of HCC to repress cell growth and metastasis in vitro and in vivo, and such a phenomenon possibly involved activation of TGF-β1/smad3 signaling.
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Affiliation(s)
- Jianning Yao
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Xuexiu Zhang
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Jiaheng Li
- 2Reproductive Medicine Department, The Third Affiliated Hospital of Zhengzhou University, No.7 Kangfuqian Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Dongyao Zhao
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Bing Gao
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Haining Zhou
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Shilin Gao
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
| | - Lianfeng Zhang
- 1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, No.1 East Jianshe Road, Erqi District, Zhengzhou, 450052 Henan China
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Komatsu G, Nonomura T, Sasaki M, Ishida Y, Arai S, Miyazaki T. AIM-deficient mouse fed a high-trans fat, high-cholesterol diet: a new animal model for nonalcoholic fatty liver disease. Exp Anim 2018; 68:147-158. [PMID: 30487357 PMCID: PMC6511520 DOI: 10.1538/expanim.18-0108] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Owing to changes in lifestyle, nonalcoholic fatty liver disease (NAFLD) is becoming a
common form of chronic liver injury. NAFLD comprises a wide variety of disease stages,
from simple steatosis to nonalcoholic steatohepatitis, which is a risk factor for the
development of hepatocellular carcinoma (HCC). Because animal models for NAFLD are needed
to investigate the precise pathogenesis, we aimed to establish a new mouse model employing
mice deficient for apoptosis inhibitor of macrophage (AIM−/−),
which exhibit accelerated lipid storage in the liver and high susceptibility to developing
HCC in response to a high-fat diet (HFD). AIM−/− mice were fed
the D09100301 diet, which contains 40 kcal% fat (trans fat 30 kcal%), high cholesterol
(2%), and 40 kcal% carbohydrates (20 kcal% fructose), and then features of obesity and
NAFLD including steatosis, inflammation, fibrosis, and HCC development were analyzed.
Although a comparable grade of liver steatosis was promoted in
AIM−/− mice by the D09100301 diet and the standard HFD (60
kcal% largely lard fat), significantly less lipid storage in visceral fat was observed
when the mice were fed the D09100301 diet. Accelerated liver inflammation was promoted by
the D09100301 diet compared with the HFD, but interestingly, HCC development was decreased
in mice fed the D09100301 diet. Our findings suggest that
AIM−/− mice fed the D09100301 diet exhibited a phenotype
that resembled nonobese NAFLD patients and thus could be an appropriate tool to study the
pathophysiology by which obesity increases the risk of HCC.
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Affiliation(s)
- Ginga Komatsu
- Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Toru Nonomura
- Research Division Pharmacology Group, New Drug Research Center Inc., 452-1 Toiso, Eniwa-shi, Hokkaido 061-1405, Japan
| | - Mai Sasaki
- Research Division Pathology Group, New Drug Research Center Inc., 452-1 Toiso, Eniwa-shi, Hokkaido 061-1405, Japan
| | - Yuki Ishida
- Research Division Pharmacology Group, New Drug Research Center Inc., 452-1 Toiso, Eniwa-shi, Hokkaido 061-1405, Japan
| | - Satoko Arai
- Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Toru Miyazaki
- Laboratory of Molecular Biomedicine for Pathogenesis, Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,AMED-CREST, Japan Agency for Medical Research and Development, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.,Max Planck-The University of Tokyo Center for Integrative Inflammology, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
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Minko IG, Christov PP, Li L, Stone MP, McCullough AK, Lloyd RS. Processing of N 5-substituted formamidopyrimidine DNA adducts by DNA glycosylases NEIL1 and NEIL3. DNA Repair (Amst) 2018; 73:49-54. [PMID: 30448017 DOI: 10.1016/j.dnarep.2018.11.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Revised: 11/02/2018] [Accepted: 11/02/2018] [Indexed: 12/29/2022]
Abstract
A variety of agents cause DNA base alkylation damage, including the known hepatocarcinogen aflatoxin B1 (AFB1) and chemotherapeutic drugs derived from nitrogen mustard (NM). The N7 site of guanine is the primary site of alkylation, with some N7-deoxyguanosine adducts undergoing imidazole ring-opening to stable mutagenic N5-alkyl formamidopyrimidine (Fapy-dG) adducts. These adducts exist as a mixture of canonical β- and unnatural α-anomeric forms. The β species are predominant in double-stranded (ds) DNA. Recently, we have demonstrated that the DNA glycosylase NEIL1 can initiate repair of AFB1-Fapy-dG adducts both in vitro and in vivo, with Neil1-/- mice showing an increased susceptibility to AFB1-induced hepatocellular carcinoma. Here, we hypothesized that NEIL1 could excise NM-Fapy-dG and that NEIL3, a closely related DNA glycosylase, could excise both NM-Fapy-dG and AFB1-Fapy-dG. Product formation from the reaction of human NEIL1 with ds oligodeoxynucleotides containing a unique NM-Fapy-dG followed a bi-component exponential function under single turnover conditions. Thus, two adduct conformations were differentially recognized by hNEIL1. The excision rate of the major form (∼13.0 min-1), presumed to be the β-anomer, was significantly higher than that previously reported for 5-hydroxycytosine, 5-hydroxyuracil, thymine glycol (Tg), and AFB1-Fapy-dG. Product generation from the minor form was much slower (∼0.4 min-1), likely reflecting the rate of conversion of the α anomer into the β anomer. Mus musculus NEIL3 (MmuNEIL3Δ324) excised NM-Fapy-dG from single-stranded (ss) DNA (turnover rate of ∼0.4 min-1), but not from ds DNA. Product formation from ss substrate was incomplete, presumably because of a substantial presence of the α anomer. MmuNEIL3Δ324 could not initiate repair of AFB1-Fapy-dG in either ds or ss DNA. Overall, the data suggest that both NEIL1 and NEIL3 may protect cells against cytotoxic and mutagenic effects of NM-Fapy-dG, but NEIL1 may have a unique role in initiation of base excision repair of AFB1-Fapy-dG.
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Affiliation(s)
- Irina G Minko
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States
| | - Plamen P Christov
- Vanderbilt Institute of Chemical Biology, Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN 37235, United States
| | - Liang Li
- Department of Chemistry and Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235, United States
| | - Michael P Stone
- Department of Chemistry and Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37235, United States
| | - Amanda K McCullough
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States
| | - R Stephen Lloyd
- Oregon Institute of Occupational Health Sciences, Oregon Health & Science University, Portland, OR 97239, United States; Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR 97239, United States; Department of Physiology and Pharmacology, Oregon Health & Science University, Portland, OR 97239, United States.
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Tseng CH. Metformin and risk of hepatocellular carcinoma in patients with type 2 diabetes. Liver Int 2018; 38:2018-2027. [PMID: 29956875 DOI: 10.1111/liv.13872] [Citation(s) in RCA: 82] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 04/23/2018] [Indexed: 12/12/2022]
Abstract
BACKGROUND Whether metformin may reduce hepatocellular carcinoma (HCC) risk requires confirmation. METHODS Type 2 diabetes patients newly diagnosed during 1999-2005 and with 2 or more prescriptions of antidiabetic drugs were enrolled from the Taiwan's National Health Insurance database. A total of 173 917 ever-users and 21 900 never-users of metformin were identified (unmatched cohort). A 1:1 matched-pair cohort of 21 900 ever-users and 21 900 never-users based on a propensity score (PS) was created. Hazard ratios were estimated by Cox regression incorporated with the inverse probability of treatment weighting using the PS. In addition, interactions with aspirin and statin were evaluated. RESULTS In the unmatched cohort, 619 never-users and 2642 ever-users developed HCC, with a respective incidence of 668.0 and 330.7 per 100 000 person-years and an overall hazard ratio of 0.49 (95% confidence interval: 0.45-0.54). The hazard ratios for the first (<25.7 months), second (25.7-56.9 months) and third (>56.9 months) tertile of cumulative duration of metformin therapy were 0.89 (0.81-0.98), 0.50 (0.46-0.56) and 0.23 (0.21-0.26) respectively. Analyses of the matched cohort showed an overall hazard ratio of 0.76 (0.67-0.85), and the hazard ratios for the respective tertiles were 1.39 (1.19-1.62), 0.77 (0.65-0.91) and 0.37 (0.30-0.45). Aspirin and statin were observed to have a significant interaction with metformin. CONCLUSIONS Metformin was associated with a reduced risk of HCC in a dose-response pattern. Users of both metformin and aspirin or metformin and statin had the lowest risk.
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Affiliation(s)
- Chin-Hsiao Tseng
- Department of Internal Medicine, National Taiwan University College of Medicine, Taipei, Taiwan
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan
- Division of Environmental Health and Occupational Medicine, National Health Research Institutes, Zhunan, Taiwan
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Li J, Han X, Yu X, Xu Z, Yang G, Liu B, Xiu P. Clinical applications of liquid biopsy as prognostic and predictive biomarkers in hepatocellular carcinoma: circulating tumor cells and circulating tumor DNA. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2018; 37:213. [PMID: 30176913 PMCID: PMC6122633 DOI: 10.1186/s13046-018-0893-1] [Citation(s) in RCA: 84] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/15/2018] [Accepted: 08/25/2018] [Indexed: 12/14/2022]
Abstract
Hepatocellular carcinoma (HCC) is a highly malignant disease with a poor prognosis and high mortality due to a low early diagnosis rate, resistance to systemic treatments and progression to late-stage liver disease. Owing to limitations in the detection of HCC and the lack of awareness of healthcare systems, fewer than 40% of HCC patients are eligible for surgery due to advanced stages of the disease at the time of diagnosis and the occurrence of multiple lesions in the cirrhotic or fibrotic liver. At present, the updated American Association for the Study of Liver Disease (AASLD) guidelines no longer recommend alpha-fetoprotein (AFP) testing as a part of diagnostic evaluation. Thus, it is imperative to establish a novel diagnostic strategy with high sensitivity and reliability to monitor risk factors to detect HCC at an early stage. In recent years, “liquid biopsy,” (including circulating tumor cells (CTCs) and circulating tumor DNA (ctDNA)), has emerged as a technique for the characterization of circulating cells, providing a strong basis for the individualized treatment of patients. As a noninvasive detection method, liquid biopsy is expected to play an important role in the early diagnosis, dynamic monitoring of cancer patients and drug screening. In this review, we will focus on the clinical applications, recent studies and future prospects of liquid biopsy, particularly focusing on HCC.
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Affiliation(s)
- Jie Li
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China
| | - Xu Han
- Department of Hepatobiliary Surgery, Zibo Central Hospital, Zibo, 255000, Shandong, China
| | - Xiaona Yu
- Department of General Medicine, Weifang Rongfu Military Hospital, Weifang, 261000, Shandong, China
| | - Zongzhen Xu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China
| | - Guangsheng Yang
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China
| | - Bingqi Liu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China
| | - Peng Xiu
- Department of General Surgery, Shandong Provincial Qianfoshan Hospital, Shandong University, Jinan, 250014, Shandong, China.
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Karin M. New insights into the pathogenesis and treatment of non-viral hepatocellular carcinoma: a balancing act between immunosuppression and immunosurveillance. PRECISION CLINICAL MEDICINE 2018; 1:21-28. [PMID: 30687560 PMCID: PMC6333043 DOI: 10.1093/pcmedi/pby005] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Revised: 03/21/2018] [Accepted: 05/07/2018] [Indexed: 12/19/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths
worldwide. HCC initiates as a consequence of chronic liver damage and inflammation caused
by hepatitis B and C virus infections, excessive alcohol consumption, or non-alcoholic
fatty liver disease (NAFLD). Until recently, no effective treatments for advanced HCC were
available and the 5-year survival rate had remained below 8% for many years. New insights
into the mechanisms that drive the development of NAFLD-related HCC indicate that loss of
T-cell-mediated immunosurveillance plays a cardinal role in tumor growth and malignant
progression, in addition to previously identified inflammation-driven compensatory
proliferation. Recently completed groundbreaking clinical studies have shown that
treatments that restore antitumor immunity represent a highly effective therapeutic option
for approximately 20% of advanced HCC patients. Understanding the causes of
inflammation-driven immunosuppression and immune system dysfunction in the 80% of patients
who fail to reignite antitumor immunity despite treatment with checkpoint inhibitors
should lead to further and even more dramatic improvements in HCC immunotherapy.
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Affiliation(s)
- Michael Karin
- Laboratory of Gene Regulation and Signal Transduction, UC San Diego School of Medicine, Department of Pharmacology, 9500 Gilman Drive, La Jolla, CA, USA
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Tak KH, Yu GI, Lee MY, Shin DH. Association Between Polymorphisms of Interleukin 1 Family Genes and Hepatocellular Carcinoma. Med Sci Monit 2018; 24:3488-3495. [PMID: 29802240 PMCID: PMC5996846 DOI: 10.12659/msm.907524] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Background Hepatocellular carcinoma (HCC) is one of the most common malignancies occurring worldwide and is most frequent type of liver cancer. The risk for developing HCC increases with the severity of inflammation and fibrosis. The members of the interleukin-1 (IL-1) family are primarily proinflammatory cytokines due to their ability to stimulate the expression of genes associated with inflammation and autoimmune diseases. Several studies have suggested that some proinflammatory cytokines, such as the IL-1 family (IL-1α, IL-1β, and IL-1 receptor antagonist) are involved in the pathogenesis of HCC. Material/Methods This study aimed to determine whether polymorphisms in the IL-1 family of genes are associated with HCC. We analyzed 178 HCC patients and 397 controls to investigate the association between polymorphisms in IL-1α, IL-1β, and IL-1 receptor antagonist (IL-1RA) genes and HCC in the Korean population. All subjects were genotyped for the selected SNPs in IL-1α, IL-1β, and IL-1RA genes by Golden-Gate SNP Genotyping Assay. Results Statistical analysis revealed a significant association at IL-1β between HCC and controls. Three individual polymorphisms (rs1143633, rs3917356, and rs1143627) were found to be associated with HCC. The SNPs of IL-1β gene (rs1143633A>G and rs1143627T>C) protected against HCC in the dominant model (p=0.027, OR=0.59, 95% CI=0.37–0.94; p=0.019, OR=0.56, 95% CI=0.34–0.91). The SNP of IL-1β gene (rs3917356G>A) increased the risk of HCC in the recessive model (p<0.001, OR=2.58, 95% CI=1.53–4.33), whereas other SNPs in IL-1α and IL-1RA showed no significant association between HCC patients and controls. Conclusions These results suggest that IL-1β in the IL-1 family contributes to HCC susceptibility.
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Affiliation(s)
- Ki Hong Tak
- Department of Occupational and Environmental Medicine, Sungseo Hospital, Daegu, South Korea
| | - Gyeong Im Yu
- Department of Preventive Medicine, School of Medicine and Institute for Cancer Research, Keimyung University, Daegu, South Korea
| | - Mi Young Lee
- Department of Preventive Medicine, School of Medicine and Institute for Cancer Research, Keimyung University, Daegu, South Korea
| | - Dong Hoon Shin
- Department of Preventive Medicine, School of Medicine and Institute for Cancer Research, Keimyung University, Daegu, South Korea
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Braillon A. Adding care to cure for patients with liver disease: A cultural shift. Hepatology 2018; 67:1172. [PMID: 29059472 DOI: 10.1002/hep.29608] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2017] [Accepted: 10/16/2017] [Indexed: 12/07/2022]
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45
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Benson AB, D'Angelica MI, Abbott DE, Abrams TA, Alberts SR, Saenz DA, Are C, Brown DB, Chang DT, Covey AM, Hawkins W, Iyer R, Jacob R, Karachristos A, Kelley RK, Kim R, Palta M, Park JO, Sahai V, Schefter T, Schmidt C, Sicklick JK, Singh G, Sohal D, Stein S, Tian GG, Vauthey JN, Venook AP, Zhu AX, Hoffmann KG, Darlow S. NCCN Guidelines Insights: Hepatobiliary Cancers, Version 1.2017. J Natl Compr Canc Netw 2017; 15:563-573. [PMID: 28476736 DOI: 10.6004/jnccn.2017.0059] [Citation(s) in RCA: 245] [Impact Index Per Article: 30.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The NCCN Guidelines for Hepatobiliary Cancers provide treatment recommendations for cancers of the liver, gallbladder, and bile ducts. The NCCN Hepatobiliary Cancers Panel meets at least annually to review comments from reviewers within their institutions, examine relevant new data from publications and abstracts, and reevaluate and update their recommendations. These NCCN Guidelines Insights summarize the panel's discussion and most recent recommendations regarding locoregional therapy for treatment of patients with hepatocellular carcinoma.
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Affiliation(s)
- Al B Benson
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
| | | | | | | | | | | | | | | | | | | | - William Hawkins
- Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine
| | | | - Rojymon Jacob
- University of Alabama at Birmingham Comprehensive Cancer Center
| | | | - R Kate Kelley
- UCSF Helen Diller Family Comprehensive Cancer Center
| | - Robin Kim
- Huntsman Cancer Institute at the University of Utah
| | | | - James O Park
- Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance
| | | | | | - Carl Schmidt
- The Ohio State University Comprehensive Cancer Center - James Cancer Hospital and Solove Research Institute
| | | | | | - Davendra Sohal
- Case Comprehensive Cancer Center/University Hospitals Seidman Cancer Center and Cleveland Clinic Taussig Cancer Institute
| | | | - G Gary Tian
- St. Jude Children’s Research Hospital/The University of Tennessee Health Science Center
| | | | - Alan P Venook
- UCSF Helen Diller Family Comprehensive Cancer Center
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46
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Huang S, Lin X, Deng X, Luo X, Fang W, Luo R. Decreased cytoplasmic expression of Raptor correlates with disease progression and unfavorable prognosis in hepatocellular carcinoma. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2017; 10:11789-11796. [PMID: 31966542 PMCID: PMC6966046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Accepted: 11/08/2017] [Indexed: 06/10/2023]
Abstract
The purpose of the present study is to explore the correlation between regulatory associated protein of mTOR (Raptor) and clinicopathologic features in hepatocellular carcinoma (HCC), including patient survival. Immunohistochemistry was used to examine the expression of Raptor in 90 HCC tissues and peritumoral liver tissues. The relationship between tumor Raptor expression and clinicopathologic characteristics was analyzed. Survival curves were plotted using the Kaplan-Meier method and compared using the log-rank test. The significance of various survival variables was analyzed using multivariate Cox proportional hazards model. We found that Raptor protein was detected in cytoplasmic compartment. Significantly lower Raptor expression was observed in HCC compared to peritumoral liver cells (P=0.048). The tumor expression levels of Raptor significantly inversely correlated with clinical stage (P=0.026). Patients with high Raptor expression had better recurrence-free survival (P=0.010). Further, we observed that Raptor expression was positively associated with recurrence-free survival of HCC patients with tumor capsule (P=0.043) and without portal vein tumor thrombus (P=0.033) classifications. Finally, we found that Raptor was an independent prognostic factor of recurrence-free survival for patients with HCC (P=0.042). To conclude, our results support that decreased cytoplasmic expression of Raptor is a potentially unfavorable factor in the progression and prognosis of HCC.
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Affiliation(s)
- Shisi Huang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical UniversityGuangzhou, China
- Department of Oncology, Haikou Municipal People’s Hospital and Central South University Xiangya Medical College Affiliated HospitalHaikou, China
| | - Xian Lin
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical UniversityGuangzhou, China
| | - Xiaojie Deng
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical UniversityGuangzhou, China
| | - Xiaojun Luo
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical UniversityGuangzhou, China
| | - Weiyi Fang
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical UniversityGuangzhou, China
| | - Rongcheng Luo
- Cancer Center, Integrated Hospital of Traditional Chinese Medicine, Southern Medical UniversityGuangzhou, China
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Ramadori P, Cubero FJ, Liedtke C, Trautwein C, Nevzorova YA. Alcohol and Hepatocellular Carcinoma: Adding Fuel to the Flame. Cancers (Basel) 2017; 9:cancers9100130. [PMID: 28946672 PMCID: PMC5664069 DOI: 10.3390/cancers9100130] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 09/15/2017] [Accepted: 09/19/2017] [Indexed: 02/06/2023] Open
Abstract
Primary tumors of the liver represent the fifth most common type of cancer in the world and the third leading cause of cancer-related death. Case-control studies from different countries report that chronic ethanol consumption is associated with an approximately 2-fold increased odds ratio for hepatocellular carcinoma (HCC). Despite the substantial epidemiologic data in humans demonstrating that chronic alcohol consumption is a major risk factor for HCC development, the pathways causing alcohol-induced liver cancer are poorly understood. In this overview, we summarize the epidemiological evidence for the association between alcohol and liver cancer, review the genetic, oncogenic, and epigenetic factors that drive HCC development synergistically with ethanol intake and discuss the essential molecular and metabolic pathways involved in alcohol-induced liver tumorigenesis.
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Affiliation(s)
- Pierluigi Ramadori
- Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
| | - Francisco Javier Cubero
- Department of Immunology, Complutense University School of Medicine, Madrid 28040, Spain.
- 13 de Octubre Health Research Institute (imas12), Madrid 28041, Spain.
| | - Christian Liedtke
- Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
| | - Christian Trautwein
- Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
| | - Yulia A Nevzorova
- Department of Internal Medicine III, University Hospital RWTH Aachen, Pauwelsstrasse 30, D-52074 Aachen, Germany.
- Department of Animal Physiology II, Faculty of Biology, Complutense University, Madrid 28040, Spain.
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48
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Li T, Liu Y, Sun Y. Long non-coding RNA AB209630 suppresses cell proliferation and metastasis in human hepatocellular carcinoma. Exp Ther Med 2017; 14:3419-3424. [PMID: 29042928 PMCID: PMC5639348 DOI: 10.3892/etm.2017.4927] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2016] [Accepted: 03/24/2017] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most prevalent cancers worldwide and the second most common cause of cancer-related mortalities. With a high potential for metastasis and recurrence, HCC is refractory to cure. The present study aimed to explore the role of a recent-discovered LncRNA, AB209630, in human HCC, in order to provide new insights useful for clinical HCC diagnosis and treatment. Reverse transcription-quantitative polymerase chain reaction was performed to examine the expression of AB209630 in clinical HCC samples and the adjacent non-cancerous tissues. The reduced expression of AB209630 observed in HCC tissues and cultured HCC cells compared with normal hepatic tissues and cells prompted the construction of an AB209630-expressing plasmid with a CBP tag on the plasmid backbone. Cell proliferation and colony formation assays were conducted to detect the effects of AB209630 on HCC cell proliferation. In addition, Transwell assay and wound-healing assays were performed, the results of which further indicated that the overexpression of AB209630 inhibited the migration and invasion of HCC cells. These results revealed the inhibitory effects of AB209630 on HCC progression, and suggest the potential of AB209630 as an inhibitor of HCC for clinical use.
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Affiliation(s)
- Teng Li
- Department of Interventional Radiology, The People's Hospital of Weifang, Weifang, Shandong 261041, P.R. China
| | - Yun Liu
- Department of Hematology, The People's Hospital of Weifang, Weifang, Shandong 261041, P.R. China
| | - Yanming Sun
- Department of Interventional Radiology, The People's Hospital of Weifang, Weifang, Shandong 261041, P.R. China
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Huang MY, Chung CH, Chang WK, Lin CS, Chen KW, Hsieh TY, Chien WC, Lin HH. The role of thiazolidinediones in hepatocellular carcinoma risk reduction: a population-based cohort study in Taiwan. Am J Cancer Res 2017; 7:1606-1616. [PMID: 28744408 PMCID: PMC5523039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2017] [Accepted: 06/01/2017] [Indexed: 06/07/2023] Open
Abstract
OBJECTIVES The aim of this study was to investigate the effect of thiazolidinediones (TZDs) on the risk of hepatocellular carcinoma (HCC) development among diabetes mellitus (DM) patients. METHODS We conducted a population-based case-control study in Taiwan based on data from the Taiwan National Health Insurance Research Database. A total of 76,349 newly diagnosed DM patients were identified from claims between 2000 and 2010. Among diabetics, 3,026 and 12,104 patients respectively, received or did not receive TZDs. Comparison frequency was matched with age, sex, and index date, excluding those with cancer at baseline. The incidence of HCC at the end of 2010 and the risks associated with the presence of hepatitis B and C infections were analyzed. The effect of TZDs use on the reduction of HCC risk was also assessed. RESULTS The incidence of HCC was lower in the TZD cohort compared with the non-TZD cohort (418.3 vs. 484.6 per 100,000 person-years), with an adjusted hazard ratio (HR) of 0.53 (95% confidence interval = 0.38-0.77) using multivariable Cox proportional hazard regression. In the stratified analysis, HCC risk reduction was greater for diabetics without the comorbidities of cirrhosis, hepatitis B, hepatitis C, nonalcoholic fatty liver disease, end-stage renal disease, and hyperlipidemia, in the TZD cohort than in the non-TZD cohort. Male sex, cirrhosis, hepatitis B, and hepatitis C were significant independent factors predicting HCC (HRs of 1.43, 13.96, 2.31, and 2.15, respectively). CONCLUSIONS This study suggests that the use of TZDs may reduce the risk of developing HCC among DM patients. Comorbidity with cirrhosis and/or hepatitis B/C infection appears to be associated with an extremely increased risk of developing HCC in this patient subset. These high-risk patients should be closely monitored.
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Affiliation(s)
- Mao-Yu Huang
- Division of Gastroenterology, Department of Internal Medicine, Taoyuan Armed Forces General HospitalTaoyuan County, Taiwan
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical CenterTaipei, Taiwan
| | - Chi-Hsiang Chung
- School of Public Health, National Defense Medical CenterTaipei, Taiwan
| | - Wei-Kuo Chang
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical CenterTaipei, Taiwan
| | - Chun-Shu Lin
- Department of Radiation Oncology, Tri-Service General Hospital, National Defense Medical CenterTaipei, Taiwan
| | - Kai-Wen Chen
- Division of Gastroenterology, Department of Internal Medicine, Hualien Armed Forces General HospitalHualien County, Taiwan
| | - Tsai-Yuan Hsieh
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical CenterTaipei, Taiwan
| | - Wu-Chien Chien
- School of Public Health, National Defense Medical CenterTaipei, Taiwan
- Department of Medical Research, Tri-Service General Hospital, National Defense Medical CenterTaipei, Taiwan
| | - Hsuan-Hwai Lin
- Division of Gastroenterology, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical CenterTaipei, Taiwan
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50
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Zheng J, Zhao M, Li J, Lou G, Yuan Y, Bu S, Xi Y. Obesity-associated digestive cancers: A review of mechanisms and interventions. Tumour Biol 2017; 39:1010428317695020. [PMID: 28351315 DOI: 10.1177/1010428317695020] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
The prevalence of obesity has steadily increased over the past few decades. Previous studies suggest that obesity is an oncogenic factor and that over 20% of all cancers are obesity-related. Among such cancers, digestive system malignancies (including esophageal adenocarcinomas, colorectal cancers, and cancers of the gastric cardia, liver, and pancreas) are reported most frequently. While the 5-year survival rates of cancers of the breast and prostate are 90%, that rate is only 45% for digestive cancers. In this review, the mechanisms of obesity-associated digestive cancers are discussed, with an emphasis on obesity-related gene mutations, insulin and insulin-like growth factor signaling pathways, chronic inflammation, and altered adipokine levels. Evidence that these factors often function interdependently rather than independently in carcinogenesis is presented. Recommended interventions that may reduce the burden of obesity-associated digestive cancers, such as participation in physical activity, diet modulation, and calorie restriction, are also described.
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Affiliation(s)
- Jiachen Zheng
- Diabetes Center, Zhejiang Provincial Key Laboratory of Pathophysiology, Institute of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
| | - Ming Zhao
- Diabetes Center, Zhejiang Provincial Key Laboratory of Pathophysiology, Institute of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
| | - Jiahui Li
- Diabetes Center, Zhejiang Provincial Key Laboratory of Pathophysiology, Institute of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
| | - Guoying Lou
- Diabetes Center, Zhejiang Provincial Key Laboratory of Pathophysiology, Institute of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
| | - Yanyan Yuan
- Diabetes Center, Zhejiang Provincial Key Laboratory of Pathophysiology, Institute of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
| | - Shizhong Bu
- Diabetes Center, Zhejiang Provincial Key Laboratory of Pathophysiology, Institute of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
| | - Yang Xi
- Diabetes Center, Zhejiang Provincial Key Laboratory of Pathophysiology, Institute of Biochemistry and Molecular Biology, School of Medicine, Ningbo University, Ningbo, China
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