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Zhang Y, Xiang Y, Cao Z, Dai K, Gui S, Liu Y, Liu Z, Shi Y, Cao H, Xiao J. Oxidative stress biomarkers for assessing the synergistic toxicity of emamectin benzoate and cyantraniliprole on liver function. Sci Rep 2025; 15:17051. [PMID: 40379747 PMCID: PMC12084635 DOI: 10.1038/s41598-025-02429-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2025] [Accepted: 05/13/2025] [Indexed: 05/19/2025] Open
Abstract
Multiple pesticide residues in agricultural products and environments, especially those with synergistic toxicity, pose a potential risk to human health. We observed a remarkable increase in serum biochemical parameters related to rat liver function when rat liver was exposed to the binary mixture of emamectin benzoate and cyantraniliprole. The present study aimed to investigate the toxicity interactions and underlying mechanisms of the binary mixture by using an L-02 cell model and metabolomics analysis. Cytotoxicity tests have shown that binary mixtures of emamectin benzoate and cyantraniliprole produced either additive or synergistic toxic effect on the cell viability of the human hepatic epithelial cell line L-02. The interaction within the binary mixtures resulted in the production of excessive reactive oxygen species (ROS) and malondialdehyde, as well as overexpression of antioxidant enzyme activities. The synergism was driven by aggravated production of ROS, leading to an imbalance in mitochondrial oxidation and energy metabolism, suggesting the possible use of ROS as an effective toxicity endpoint. Based on the benchmark dose calculated to determine the combined toxicity threshold, the model-averaged estimates of the benchmark dose lower confidence limits (4.74-9.58 mmol/L) of the binary mixtures at concentration ratios of 3:15, 3:45, 4:15, and 4:45 were 20% more toxic than their individual active ingredients. These findings have important implications for risk assessments of pesticide residue in food and highlight the need to consider concentration ratios and oxidative stress endpoints in such assessments.
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Affiliation(s)
- Yaxuan Zhang
- Joint Research Center for Food Nutrition and Health of IHM, School of Plant Protection, Anhui Agricultural University, Hefei, China
| | - Yuxin Xiang
- Joint Research Center for Food Nutrition and Health of IHM, School of Plant Protection, Anhui Agricultural University, Hefei, China
- Key Laboratory of Agri-Products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, 230036, Anhui, China
| | - Zhiyong Cao
- Joint Research Center for Food Nutrition and Health of IHM, School of Plant Protection, Anhui Agricultural University, Hefei, China
- Key Laboratory of Agri-Products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, 230036, Anhui, China
| | - Kaijie Dai
- Joint Research Center for Food Nutrition and Health of IHM, School of Plant Protection, Anhui Agricultural University, Hefei, China
- Key Laboratory of Agri-Products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, 230036, Anhui, China
| | - Shuyan Gui
- Key Laboratory of Agri-Products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, 230036, Anhui, China
| | - Yuying Liu
- Joint Research Center for Food Nutrition and Health of IHM, School of Plant Protection, Anhui Agricultural University, Hefei, China
- Key Laboratory of Agri-Products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, 230036, Anhui, China
| | - Ziqi Liu
- Joint Research Center for Food Nutrition and Health of IHM, School of Plant Protection, Anhui Agricultural University, Hefei, China
- Key Laboratory of Agri-Products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, 230036, Anhui, China
| | - Yanhong Shi
- College of Resource & Environment, Anhui Agricultural University, Hefei, 230036, Anhui, China
- Key Laboratory of Agri-Products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, 230036, Anhui, China
| | - Haiqun Cao
- Joint Research Center for Food Nutrition and Health of IHM, School of Plant Protection, Anhui Agricultural University, Hefei, China
- Key Laboratory of Agri-Products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, 230036, Anhui, China
| | - Jinjing Xiao
- Joint Research Center for Food Nutrition and Health of IHM, School of Plant Protection, Anhui Agricultural University, Hefei, China.
- Key Laboratory of Agri-Products Quality and Biosafety (Anhui Agricultural University), Ministry of Education, Hefei, 230036, Anhui, China.
- School of Resource & Environment, Anhui Agricultural University, 130 West Changjiang Road, Hefei, 230036, Anhui, People's Republic of China.
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Huang P, Rodriguez-Matos FJ, Qi J, Trehan R, Myojin Y, Zhu XB, Greten TF, Ma C. Hepatic immune environment differences among common mouse strains in models of MASH and liver cancer. JHEP Rep 2025; 7:101380. [PMID: 40342632 PMCID: PMC12060451 DOI: 10.1016/j.jhepr.2025.101380] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 02/20/2025] [Accepted: 02/24/2025] [Indexed: 05/11/2025] Open
Abstract
Background & Aims Inbred mouse strains are critical tools for studying immune regulation of metabolic dysfunction-associated steatohepatitis (MASH) and hepatocellular carcinoma (HCC). Here, we profiled mouse strain-associated hepatic immune differences, and performed mice-human cross-species immune comparisons. Methods Immune landscapes of C57BL/6, BALB/c, and FVB/N mice were compared under healthy, MASH, or HCC state using high-dimensional spectral flow cytometry (n = 4 per condition). MASH was induced by feeding methionine- and choline-deficient or Western diet + carbon tetrachloride. HCC was caused by hydrodynamic plasmid injection of MYC/sg-p53. Public mouse and human scRNA-seq datasets were used for validation and cross-species comparisons. Results In healthy mice, liver CD4+ T (24% vs. 14% vs. 34%, p <0.05) and B cells (36.5% vs. 35% vs.18%, p <0.05) varied the most among three strains. C57BL/6 mice showed TH1 dominance, whereas BALB/c and FVB/N mice had TH2 dominance (log[TH1:TH2] = 0.17, -0.31, -0.17). In MASH mice, expansion of liver myeloid cells and innate lymphocytes were commonly found, but changes of B cells (log(fold-change) = -0.38, -0.28, -0.58, p <0.05) and T subsets (e.g. CD4+ T log(fold-change) = -0.21, -0.07, -0.15, p <0.05) varied greatly among strains. MYC/sg-p53 HCC induced a consistent expansion of liver Tregs and CD8+ T cells (p <0.05), but differential shifts of liver immune landscape were seen among strains. The flow cytometry data was supported by public scRNA-seq datasets matching C57BL/6 background. Further cross-species comparison in MASH condition confirmed shared changes of adaptive lymphocytes between mice and humans. In two MASH models, BALB/c or C57BL/6 mice were more consistent to recapture loss of CD4+ T or B cells, respectively (p <0.05). Conclusions Substantial liver immune differences exist among common mouse strains. Mice can recapitulate certain human liver immune changes with strain variations. Impact and implications Our immune cell profiling study revealed that the liver immune environment can be quite different among common mouse strains both under healthy and pathologic states, such as steatohepatitis or neoplastic processes. Our results serve as a data resource for studies investigating liver immunology and provide valuable insights for the design of studies on various immune cells in the livers of mice.
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Affiliation(s)
- Patrick Huang
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Francisco J. Rodriguez-Matos
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Jonathan Qi
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Rajiv Trehan
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yuta Myojin
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Xiao Bin Zhu
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Tim F. Greten
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- NCI CCR Liver Cancer Program, National Institutes of Health, Bethesda, MD, USA
| | - Chi Ma
- Gastrointestinal Malignancy Section, Thoracic and Gastrointestinal Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
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Fujiwara N, Lopez C, Marsh TL, Raman I, Marquez CA, Paul S, Mishra SK, Kubota N, Katz C, Kanzaki H, Gonzalez M, Quirk L, Deodhar S, Selvakumar P, Raj P, Parikh ND, Roberts LR, Schwartz ME, Nguyen MH, Befeler AS, Page-Lester S, Srivastava S, Feng Z, Reddy KR, Khaderi S, Asrani SK, Kanwal F, El-Serag HB, Marrero JA, Singal AG, Hoshida Y. Phase 3 Validation of PAaM for Hepatocellular Carcinoma Risk Stratification in Cirrhosis. Gastroenterology 2025; 168:556-567.e7. [PMID: 39521255 PMCID: PMC7617545 DOI: 10.1053/j.gastro.2024.10.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 10/08/2024] [Accepted: 10/21/2024] [Indexed: 11/16/2024]
Abstract
BACKGROUND & AIMS Hepatocellular carcinoma (HCC) risk stratification is an urgent unmet need for cost-effective HCC screening and early detection in patients with cirrhosis to improve poor HCC prognosis. METHODS Molecular (prognostic liver secretome signature with α-fetoprotein) and clinical (aMAP [age, male sex, albumin-bilirubin, and platelets] score) variable-based scores were integrated into PAaM (prognostic liver secretome signature with α-fetoprotein plus age, male sex, albumin-bilirubin, and platelets), which was subsequently validated in 2 phase 3 biomarker validation studies: the statewide Texas HCC Consortium and nationwide HCC Early Detection Strategy prospective cohorts, following the prospective specimen collection, retrospective blinded evaluation design. The associations between baseline PAaM and incident HCC were assessed using Fine-Gray regression, with overall death and liver transplantation as competing events. RESULTS Of 2156 patients with cirrhosis in the Texas HCC Consortium, PAaM identified 404 (19%) high-risk, 903 (42%) intermediate-risk, and 849 (39%) low-risk patients with annual HCC incidence rates of 5.3%, 2.7%, and 0.6%, respectively. Compared with low-risk patients, high- and intermediate-risk groups had sub-distribution hazard ratios for incident HCC of 7.51 (95% CI, 4.42-12.8) and 4.20 (95% CI, 2.52-7.01), respectively. Of 1328 patients with cirrhosis in the HCC early detection strategy, PAaM identified 201 high-risk (15%), 540 intermediate-risk (41%), and 587 low-risk (44%) patients, with annual HCC incidence rates of 6.2%, 1.8%, and 0.8%, respectively. High- and intermediate-risk groups were associated with sub-distribution hazard ratios for incident HCC of 6.54 (95% CI, 3.85-11.1) and 1.77 (95% CI, 1.02-3.08), respectively. Subgroup analysis showed robust risk stratification across HCC etiologies, including metabolic dysfunction-associated steatotic liver disease and cured hepatitis C infection. CONCLUSIONS PAaM enables accurate HCC risk stratification in patients with cirrhosis from contemporary etiologies.
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Affiliation(s)
- Naoto Fujiwara
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas; Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Mie, Japan
| | - Camden Lopez
- Biostatistics Program, Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Tracey L Marsh
- Biostatistics Program, Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Indu Raman
- BioCenter, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Cesia A Marquez
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Subhojit Paul
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sumit K Mishra
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Naoto Kubota
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Courtney Katz
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Hiroaki Kanzaki
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Michael Gonzalez
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Lisa Quirk
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Sneha Deodhar
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | | | - Prithvi Raj
- BioCenter, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, Michigan
| | - Lewis R Roberts
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota
| | - Myron E Schwartz
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, New York
| | - Mindie H Nguyen
- Division of Gastroenterology and Hepatology, Stanford University Medical Center, Palo Alto, California
| | - Alex S Befeler
- Division of Gastroenterology and Hepatology, Saint Louis University School of Medicine, St Louis, Missouri
| | - Stephanie Page-Lester
- Biostatistics Program, Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Sudhir Srivastava
- Cancer Biomarker Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Rockville, Maryland
| | - Ziding Feng
- Biostatistics Program, Public Health Science Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - K Rajender Reddy
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Saira Khaderi
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | - Sumeet K Asrani
- Baylor University Medical Center, Baylor Scott and White, Dallas, Texas
| | - Fasiha Kanwal
- Department of Medicine, Baylor College of Medicine, Houston, Texas
| | | | - Jorge A Marrero
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Amit G Singal
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
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Yeo YH, Abdelmalek M, Khan S, Moylan CA, Rodriquez L, Villanueva A, Yang JD. Current and emerging strategies for the prevention of hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2025; 22:173-190. [PMID: 39653784 DOI: 10.1038/s41575-024-01021-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 11/07/2024] [Indexed: 01/05/2025]
Abstract
Liver cancer is the third leading cause of cancer-related deaths globally, with incident cases expected to rise from 905,700 in 2020 to 1.4 million by 2040. Hepatocellular carcinoma (HCC) accounts for about 80% of all primary liver cancers. Viral hepatitis and chronic excessive alcohol consumption are major risk factors for HCC, but metabolic dysfunction-associated steatotic liver disease is also becoming a dominant cause. The increasing numbers of cases of HCC and changes in risk factors highlight the urgent need for updated and targeted prevention strategies. Preventive interventions encompass strategies to decrease the burden of chronic liver diseases and their progression to HCC. These strategies include nutritional interventions and medications that have shown promise in preclinical models. Although prevailing approaches focus on treating chronic liver disease, leveraging a wider range of interventions represents a promising area to safeguard at-risk populations. In this Review, we explore existing evidence for preventive strategies by highlighting established and potential paths to reducing HCC risk effectively and safely, especially in individuals with chronic liver diseases. We categorize the preventive strategies by the mechanism of action, including anti-inflammatory, antihyperglycaemic, lipid-lowering, nutrition and dietary, antiviral, and antifibrotic pathways. For each category, we discuss the efficacy and safety information derived from mechanistic, translational, observational and clinical trial data, pinpointing knowledge gaps and directions for future research.
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Affiliation(s)
- Yee Hui Yeo
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Manal Abdelmalek
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
| | - Seema Khan
- Robert H. Lurie Comprehensive Cancer Center, Northwestern Memorial Hospital, Chicago, IL, USA
| | - Cynthia A Moylan
- Division of Gastroenterology, Duke University Health System, Durham, NC, USA
| | - Luz Rodriquez
- Gastrointestinal & Other Cancers Research Group, NCI, Rockville, MD, USA
| | - Augusto Villanueva
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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5
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Schneider AT, Koppe C, Crouchet E, Papargyriou A, Singer MT, Büttner V, Keysberg L, Szydlowska M, Jühling F, Moehlin J, Chen MC, Leone V, Mueller S, Neuß T, Castoldi M, Lesina M, Bergmann F, Hackert T, Steiger K, Knoefel WT, Zaufel A, Kather JN, Esposito I, Gaida MM, Ghallab A, Hengstler JG, Einwächter H, Unger K, Algül H, Gassler N, Schmid RM, Rad R, Baumert TF, Reichert M, Heikenwalder M, Kondylis V, Vucur M, Luedde T. A decision point between transdifferentiation and programmed cell death priming controls KRAS-dependent pancreatic cancer development. Nat Commun 2025; 16:1765. [PMID: 39971907 PMCID: PMC11839950 DOI: 10.1038/s41467-025-56493-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 01/21/2025] [Indexed: 02/21/2025] Open
Abstract
KRAS-dependent acinar-to-ductal metaplasia (ADM) is a fundamental step in the development of pancreatic ductal adenocarcinoma (PDAC), but the involvement of cell death pathways remains unclear. Here, we show that key regulators of programmed cell death (PCD) become upregulated during KRAS-driven ADM, thereby priming transdifferentiated cells to death. Using transgenic mice and primary cell and organoid cultures, we show that transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase regulating cell survival and inflammatory pathways, prevents the elimination of transdifferentiated cells through receptor-interacting protein kinase 1 (RIPK1)-mediated apoptosis and necroptosis, enabling PDAC development. Accordingly, pharmacological inhibition of TAK1 induces PCD in patient-derived PDAC organoids. Importantly, cell death induction via TAK1 inhibition does not appear to elicit an overt injury-associated inflammatory response. Collectively, these findings suggest that TAK1 supports cellular plasticity by suppressing spontaneous PCD activation during ADM, representing a promising pharmacological target for the prevention and treatment of PDAC.
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Affiliation(s)
- Anne T Schneider
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Christiane Koppe
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Emilie Crouchet
- University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France
| | - Aristeidis Papargyriou
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Institute of Stem Cell Research, Helmholtz Center Munich, German Research Center for Environmental Health, Neuherberg, Germany
| | - Michael T Singer
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Veronika Büttner
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Leonie Keysberg
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Marta Szydlowska
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Frank Jühling
- University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France
| | - Julien Moehlin
- University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France
| | - Min-Chun Chen
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Valentina Leone
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
- Research Unit Radiation Cytogenetics, Helmholtz-Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany
| | - Sebastian Mueller
- Institute of Molecular Oncology and Functional Genomics, School of Medicine, TU Munich, Munich, Germany
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
| | - Thorsten Neuß
- Lehrstuhl für Biophysik E27, Center for Protein Assemblies (CPA), Technical University Munich (TUM), Garching, Germany
| | - Mirco Castoldi
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Marina Lesina
- Comprehensive Cancer Center München, Institute for Tumor Metabolism, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Frank Bergmann
- Institut of Pathology, Heidelberg University Hospital, Heidelberg, Germany
- Clinical Pathology, Klinikum Darmstadt GmbH, Darmstadt, Germany
| | - Thilo Hackert
- Department of General, Visceral, and Transplantation Surgery, University Hospital Heidelberg, Heidelberg, Germany
- Department of General, Visceral and Thoracic Surgery, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Katja Steiger
- Institute of Pathology, School of Medicine, Technical University of Munich, Munich, Germany
| | - Wolfram T Knoefel
- Department of Surgery A, Heinrich-Heine-University Düsseldorf and University Hospital Düsseldorf, Duesseldorf, Germany
| | - Alex Zaufel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Jakob N Kather
- Else Kroener Fresenius Center for Digital Health (EFFZ), Technical University Dresden, Dresden, Germany
- Division of Pathology and Data Analytics, Leeds Institute of Medical Research at St James's, University of Leeds, Leeds, UK
- Medical Oncology, National Center for Tumor Diseases (NCT), University Hospital Heidelberg, Heidelberg, Germany
| | - Irene Esposito
- Institute of Pathology, University Hospital Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany
| | - Matthias M Gaida
- Institute of Pathology, University Medical Center Mainz, JGU-Mainz, Mainz, Germany
- Research Center for Immunotherapy, University Medical Center Mainz, JGU-Mainz, Mainz, Germany
- Joint Unit Immunopathology, Institute of Pathology, University Medical Center, JGU-Mainz, Mainz, Germany
- TRON, Translational Oncology at the University Medical Center, JGU-Mainz, Mainz, Germany
| | - Ahmed Ghallab
- Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the Technical University Dortmund, Dortmund, Germany
- Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt
| | - Jan G Hengstler
- Leibniz Research Centre for Working Environment and Human Factors (IfADo) at the Technical University Dortmund, Dortmund, Germany
| | - Henrik Einwächter
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Kristian Unger
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
- Research Unit Translational Metabolic Oncology, Institute for Diabetes and Cancer, Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Neuherberg, Germany
| | - Hana Algül
- Comprehensive Cancer Center München, Institute for Tumor Metabolism, TUM School of Medicine and Health, Technical University of Munich, Munich, Germany
| | - Nikolaus Gassler
- Section Pathology of the Institute of Forensic Medicine, University Hospital Jena, Jena, Germany
| | - Roland M Schmid
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
| | - Roland Rad
- Center for Translational Cancer Research (TranslaTUM), School of Medicine, Technical University of Munich, Munich, Germany
- Department of Internal Medicine II, Klinikum Rechts der Isar, Technical University of Munich, Munich, Germany
| | - Thomas F Baumert
- University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France
- Pôle des Pathologies Hépatiques et Digestives, Service d'Hepato-Gastroenterologie, Strasbourg University Hospitals, Strasbourg, France
- Institut Hospitalo-Universitaire (IHU) Strasbourg, Strasbourg, France
- Institut Universitaire de France (IUF), Paris, France
| | - Maximilian Reichert
- Translational Pancreatic Cancer Research Center, Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Klinik und Poliklinik für Innere Medizin II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany
- Center for Organoid Systems (COS), Technical University of Munich, Garching, Germany
- Munich Institute of Biomedical Engineering (MIBE), Technical University of Munich, Garching, Germany
- German Center for Translational Cancer Research (DKTK), Munich, Germany
| | - Mathias Heikenwalder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
- The M3 Research Institute, Karls Eberhards Universität Tübingen, Tübingen, Germany
| | - Vangelis Kondylis
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Mihael Vucur
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany
| | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Medical Faculty at Heinrich-Heine-University, Duesseldorf, Germany.
- Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany.
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Suzuki H, Fujiwara N, Singal AG, Baumert TF, Chung RT, Kawaguchi T, Hoshida Y. Prevention of liver cancer in the era of next-generation antivirals and obesity epidemic. Hepatology 2025:01515467-990000000-01139. [PMID: 39808821 PMCID: PMC7617594 DOI: 10.1097/hep.0000000000001227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2024] [Accepted: 10/07/2024] [Indexed: 01/16/2025]
Abstract
Preventive interventions are expected to substantially improve the prognosis of patients with primary liver cancer, predominantly HCC and cholangiocarcinoma. HCC prevention is challenging in the face of the evolving etiological landscape, particularly the sharp increase in obesity-associated metabolic disorders, including metabolic dysfunction-associated steatotic liver disease. Next-generation anti-HCV and HBV drugs have substantially reduced, but not eliminated, the risk of HCC and have given way to new challenges in identifying at-risk patients. The recent development of new therapeutic agents and modalities has opened unprecedented opportunities to refine primary, secondary, and tertiary HCC prevention strategies. For primary prevention (before exposure to risk factors), public health policies, such as universal HBV vaccination, have had a substantial prognostic impact. Secondary prevention (after or during active exposure to risk factors) includes regular HCC screening and chemoprevention. Emerging biomarkers and imaging modalities for HCC risk stratification and detection may enable individual risk-based personalized and cost-effective HCC screening. Clinical studies have suggested the potential utility of lipid-lowering, antidiabetic/obesity, and anti-inflammatory agents for secondary prevention, and some of them are being evaluated in prospective clinical trials. Computational and experimental studies have identified potential chemopreventive strategies directed at diverse molecular, cellular, and systemic targets for etiology-specific and/or agnostic interventions. Tertiary prevention (in conjunction with curative-intent therapies for HCC) is an area of active research with the development of new immune-based neoadjuvant/adjuvant therapies. Cholangiocarcinoma prevention may advance with recent efforts to elucidate risk factors. These advances will collectively lead to substantial improvements in liver cancer mortality rates.
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Affiliation(s)
- Hiroyuki Suzuki
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Naoto Fujiwara
- Department of Gastroenterology and Hepatology, Graduate School of Medicine, Mie University, Tsu, Japan
| | - Amit G. Singal
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Thomas F. Baumert
- Inserm, U1110, Institute for Translational Medicine and Liver Diseases, University of Strasbourg, F-67000, France
- IHU Strasbourg, F-67000 Strasbourg, France
- Gastroenterology and Hepatology Service, Strasbourg University Hospitals, F-67000Strasbourg, France
| | - Raymond T. Chung
- Liver Center, GI Division, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Takumi Kawaguchi
- Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
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Cherradi S, Roux S, Dupuy M, Tabone-Eglinger S, Tuaillon E, Ziol M, Assenat E, Duong HT. Modelling hepatocellular carcinoma microenvironment phenotype to evaluate drug efficacy. Sci Rep 2025; 15:1179. [PMID: 39774014 PMCID: PMC11706984 DOI: 10.1038/s41598-024-84304-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Accepted: 12/23/2024] [Indexed: 01/11/2025] Open
Abstract
Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related death worldwide. Treating HCC is challenging because of the poor drug effectiveness and the lack of tools to predict patient responses. To resolve these issues, we established a patient-centric spheroid model using HepG2, TWNT-1, and THP-1 co-culture, that mimics HCC phenotype. We developed a target-independent cell killing (TICK) exclusion strategy to monitor the therapeutic response. We demonstrated that our model reproduced the Barcelona Clinic Liver Cancer (BCLC) molecular classification, displayed known alterations of epigenetic players, and responded to tyrosine kinase inhibitors (TKIs) such as sorafenib, cabozantinib, and lenvatinib in a patient-dependent manner. Importantly, we reported for the first time that our model correctly predicted 34 clinical outcomes to TKIs out of 37 case studies on 32 HCC patients confirming that patient-centric spheroids, combined with our TICK exclusion strategy, are valuable models for drug discovery and opening a near perspective to personalized care.
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Affiliation(s)
- Sara Cherradi
- PredictCan Biotechnologies SAS, Biopôle Euromédecine, Grabels, France
| | - Salomé Roux
- PredictCan Biotechnologies SAS, Biopôle Euromédecine, Grabels, France
| | - Marie Dupuy
- Service d'Oncologie Médicale, Hôpital Saint Eloi, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
| | - Séverine Tabone-Eglinger
- Plateforme de Gestion des Echantillons Biologiques, Centre Léon Bérard, Cancer Research Center of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Lyon, France
| | - Edouard Tuaillon
- Centre de Ressources Biologiques (CRB), Centre Hospitalier Universitaire de Montpellier, Montpellier, France
| | - Marianne Ziol
- Centre de Ressources Biologiques du Groupe hospitalier Paris Seine Saint-Denis, Paris, France
| | - Eric Assenat
- Service d'Oncologie Médicale, Hôpital Saint Eloi, Centre Hospitalier Universitaire de Montpellier, Montpellier, France
| | - Hong Tuan Duong
- PredictCan Biotechnologies SAS, Biopôle Euromédecine, Grabels, France.
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Roca Suarez AA, Jühling F, Moehlin J, Mailly L, Virzì A, Brignon N, Durand SC, Oudot MA, Schaeffer E, Martin R, Meiss-Heydmann L, Bach C, Boulahtouf Z, Girard L, Osswald E, Jamey C, Brumaru D, Dali-Youcef N, Mukherji A, Saez-Palma M, Testoni B, Zoulim F, Koneru B, Fujiwara N, Hoshida Y, Felli E, Pessaux P, Tremblay ML, Parent R, Schuster C, Baumert TF, Lupberger J. Protein tyrosine phosphatase delta is a STAT3-phosphatase and suppressor of metabolic liver disease. EGASTROENTEROLOGY 2025; 3:e100159. [PMID: 40124988 PMCID: PMC11927410 DOI: 10.1136/egastro-2024-100159] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/08/2025] [Indexed: 03/25/2025]
Abstract
ABSTRACT Objective Impaired hepatic expression of protein tyrosine phosphatase delta (PTPRD) is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection. However, the PTPRD-expressing hepatic cell types, signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown. Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans, and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis (MASH). Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays. The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers. Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice, showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function. Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease. We further validated PTPRD as a STAT3 phosphatase in the liver, acting as a regulator of peroxisomal fatty acid metabolism. During MASH, low PTPRD led to increased liver steatosis in Ptprd+/- mice and a pronounced unfolded protein response, which impacts insulin signalling. Accordingly, silencing of PTPRD blunted insulin-induced AKT phosphorylation. Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors. Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis, which is recapitulated in clinical manifestations of metabolic liver disease.
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Affiliation(s)
- Armando Andres Roca Suarez
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
- Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- The Lyon Hepatology Institute, IHU EVEREST, Lyon, France
| | - Frank Jühling
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Julien Moehlin
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Laurent Mailly
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
- ÆPIC Animal Facility Platform, Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Alessia Virzì
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Nicolas Brignon
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
- ÆPIC Animal Facility Platform, Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Sarah C Durand
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Marine A Oudot
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Eugenie Schaeffer
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Romain Martin
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
- ÆPIC Animal Facility Platform, Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Laura Meiss-Heydmann
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Charlotte Bach
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Zakaria Boulahtouf
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Lea Girard
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Emma Osswald
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Carole Jamey
- Laboratoire de Biochimie et de Biologie Moléculaire, Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Daniel Brumaru
- Laboratoire de Biochimie et de Biologie Moléculaire, Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
| | - Nassim Dali-Youcef
- Laboratoire de Biochimie et de Biologie Moléculaire, Pôle de biologie, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch-Graffenstaden, France
- Centre National de la Recherche Scientifique, UMR 7104, Illkirch-Graffenstaden, France
- Institut National de la Santé et de la Recherche Médicale, U1258, Illkirch-Graffenstaden, France
| | - Atish Mukherji
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Maria Saez-Palma
- Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- The Lyon Hepatology Institute, IHU EVEREST, Lyon, France
| | - Barbara Testoni
- Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- The Lyon Hepatology Institute, IHU EVEREST, Lyon, France
| | - Fabien Zoulim
- Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- The Lyon Hepatology Institute, IHU EVEREST, Lyon, France
- Hospices Civils de Lyon (HCL), Lyon, France
| | - Bhuvaneswari Koneru
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Emanuele Felli
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
- Institut Hospitalo-Universitaire, Service Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
| | - Patrick Pessaux
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
- Institut Hospitalo-Universitaire, Service Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
| | - Michel L Tremblay
- Rosalind and Morris Goodman Cancer Institute, Montreal, Quebec, Canada
- Department of Biochemistry, McGill University, Montreal, Quebec, Canada
- Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Romain Parent
- Inserm U1052, CNRS UMR-5286, Cancer Research Center of Lyon (CRCL), Lyon, France
- University of Lyon, Université Claude-Bernard (UCBL), Lyon, France
- The Lyon Hepatology Institute, IHU EVEREST, Lyon, France
| | - Catherine Schuster
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
| | - Thomas F Baumert
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
- Institut Universitaire de France (IUF), Paris, France
| | - Joachim Lupberger
- Institute for Translational Medicine and Liver Disease (ITM), Inserm UMR_S1110, University of Strasbourg, Strasbourg, France
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Giardoglou P, Gavra I, Amanatidou AI, Kalafati IP, Symianakis P, Kafyra M, Moulos P, Dedoussis GV. Development of a Polygenic Risk Score for Metabolic Dysfunction-Associated Steatotic Liver Disease Prediction in UK Biobank. Genes (Basel) 2024; 16:33. [PMID: 39858580 PMCID: PMC11765347 DOI: 10.3390/genes16010033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2024] [Revised: 12/23/2024] [Accepted: 12/24/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of liver-related morbidity and mortality. Although the invasive liver biopsy remains the golden standard for MASLD diagnosis, Magnetic Resonance Imaging-derived Proton Density Fat Fraction (MRI-PDFF) is an accurate, non-invasive method for the assessment of treatment response. This study aimed at developing a Polygenic Risk Score (PRS) to improve MRI-PDFF prediction using UK Biobank data to assess an individual's genetic liability to MASLD. METHODS We iteratively sequestered 10% of MRI-PDFF samples as a validation set and split the rest of each dataset into base and target partitions, containing GWAS summary statistics and raw genotype data, respectively. PRSice2 was deployed to derive PRS candidates. Based on the frequency of SNP appearances along the PRS candidates, we generated different SNP sets according to variable frequency cutoffs. By applying the PRSs to the validation set, we identified the optimal SNP set, which was then applied to a Greek nonalcoholic fatty liver disease (NAFLD) study. RESULTS Data from 3553 UK Biobank participants yielded 49 different SNP sets. After calculating the PRS on the validation set for every SNP set, an optimal PRS with 75 SNPs was selected (incremental R2 = 0.025, p-value = 0.00145). Interestingly, 43 SNPs were successfully mapped to MASLD-related known genes. The selected PRS could predict traits, like LDL cholesterol and diastolic blood pressure in the UK Biobank, as also disease outcome in the Greek NAFLD study. CONCLUSIONS Our findings provide strong evidence that PRS is a powerful prediction model for MASLD, while it can also be applied on populations of different ethnicity.
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Affiliation(s)
- Panagiota Giardoglou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Ioanna Gavra
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Athina I. Amanatidou
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Ioanna Panagiota Kalafati
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
- Department of Nutrition and Dietetics, School of Physical Education, Sport Science and Dietetics, University of Thessaly, 42132 Trikala, Greece
| | - Panagiotis Symianakis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Maria Kafyra
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
| | - Panagiotis Moulos
- Institute for Fundamental Biomedical Research, Biomedical Sciences Research Center ‘Alexander Fleming’, 16672 Vari, Greece;
| | - George V. Dedoussis
- Department of Nutrition and Dietetics, School of Health Science and Education, Harokopio University, 17671 Athens, Greece; (P.G.); (M.K.)
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10
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Yıldırım Ç, Yay F, İmre A, Soysal O, Yıldırım HÇ. CXCL10, SCGN, and H2BC5 as Potential Key Genes Regulated by HCV Infection. Genes (Basel) 2024; 15:1502. [PMID: 39766770 PMCID: PMC11675613 DOI: 10.3390/genes15121502] [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: 10/11/2024] [Revised: 11/19/2024] [Accepted: 11/20/2024] [Indexed: 01/03/2025] Open
Abstract
Introduction: Hepatitis C infections are the main causes of fatal clinical conditions such as cirrhosis and HCC development, and biomarkers are needed to predict the development of these complications. Therefore, it is important to first determine which genes are deregulated in HCV-cells compared to healthy individuals. In our study, we aimed to identify the genes that are commonly upregulated or downregulated in HCV-infected cells using two different databases. Material and Method: In this study, differentially expressed genes (DEGs) that were commonly upregulated or downregulated were identified using publicly available databases GSE66842 and GSE84587. Afterwards, the interactions of DEG products with each other and other proteins were examined using the STRING database. Enrichment analyses of DEGs were performed using the Enrichr-KG web tool including the Gene Ontology Biological Process, KEGG, Jensen_DISEASES and DisGeNET libraries. miRNAs targeting DEGs were detected using miRDB and TargetScanHuman8.0. Results: In HCV-infected cells, the CXCL10 expression is increased in both databases, while the SCGN and H2BC5 (HIST1H2BD) expression is decreased. No direct interaction was found among CXCL10, SCGN, H2BC5 in the top ten proteins. CXCL10 is a member of Hepatitis C and viral protein interactions with cytokine and cytokine receptor KEGG pathways. H2BC5 is a member of viral carcinogenesis KEGG pathways. Predicted overlapping miRNAs targeted by common DEGs were as follows: 59 were where CXCL10 was the estimated target, 22 where SCGN was the estimated target and 29 where H2BC5 (HIST1H2BD) was the estimated target. Conclusions: Our study identified genes that were upregulated or downregulated in HCV-infected cells in both databases and miRNAs associated with these genes, using two different databases. This study creates groundwork for future studies to investigate whether these genes can predict HCV prognosis and HCV-associated HCC development.
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Affiliation(s)
- Çiğdem Yıldırım
- Department of Infectious Diseases and Clinical Microbiology, Nigde Training and Research Hospital, 51100 Nigde, Turkey; (A.İ.); (O.S.)
| | - Fatih Yay
- Clinical Biochemistry Laboratory, Nigde Training and Research Hospital, 51100 Nigde, Turkey;
| | - Ayfer İmre
- Department of Infectious Diseases and Clinical Microbiology, Nigde Training and Research Hospital, 51100 Nigde, Turkey; (A.İ.); (O.S.)
| | - Orçun Soysal
- Department of Infectious Diseases and Clinical Microbiology, Nigde Training and Research Hospital, 51100 Nigde, Turkey; (A.İ.); (O.S.)
| | - Hasan Çağrı Yıldırım
- Department of Medical Oncology, Nigde Training and Research Hospital, 51100 Nigde, Turkey;
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Schwarz M, Simbrunner B, Jachs M, Hartl L, Balcar L, Bauer DJM, Semmler G, Hofer BS, Scheiner B, Pinter M, Stättermayer AF, Trauner M, Reiberger T, Mandorfer M. High histamine levels are associated with acute-on-chronic liver failure and liver-related death in patients with advanced chronic liver disease. Liver Int 2024; 44:2904-2914. [PMID: 39136222 DOI: 10.1111/liv.16056] [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: 11/03/2023] [Revised: 06/20/2024] [Accepted: 07/22/2024] [Indexed: 10/25/2024]
Abstract
BACKGROUND AND AIMS The role of histamine in advanced chronic liver disease (ACLD) is poorly understood. We investigated plasma histamine levels across ACLD stages and their prognostic value. METHODS We included patients with evidence of ACLD, defined by portal hypertension (hepatic venous pressure gradient [HVPG] ≥6 mmHg) and/or a liver stiffness measurement by transient elastography ≥10 kPa, who underwent HVPG measurement between 2017 and 2020. Acute-on-chronic liver failure (ACLF) and/or liver-related death were defined as composite endpoint. RESULTS Of 251 patients, 82.5% had clinically significant portal hypertension (median HVPG: 17 mmHg [interquartile range (IQR) 12-21]) and 135 patients (53.8%) were decompensated at baseline. Median plasma histamine was 8.5 nmol/L (IQR: 6.4-11.5), 37.1% of patients showed elevated values (>9.9 nmol/L). Histamine levels did not differ significantly across Child-Turcotte-Pugh (CTP) stages nor strata of model for end-stage liver disease (MELD) or HVPG. Histamine levels correlated with markers of circulatory dysfunction (i.e. sodium, renin and aldosterone). During a median follow-up of 29.2 months, 68 patients developed ACLF or liver-related death. In univariate as well as in multivariate analysis (adjusting for age, sex, HVPG as well as either MELD, clinical stage, and serum albumin or CTP and serum sodium), elevated histamine levels remained associated with the composite endpoint. CTP-based multivariate model adjusted sub-distribution hazard ratio (asHR): 1.010 (95% CI: 1.004-1.021), p < .001; MELD-based multivariate model asHR: 1.030 (95% CI: 1.017-1.040), p < .001. CONCLUSION High levels of histamine were linked to circulatory dysfunction in ACLD patients and independently associated with increased risks of ACLF or liver-related death. Further mechanistic studies on the link between histamine signalling and development of hyperdynamic circulation and ACLF are warranted.
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Affiliation(s)
- Michael Schwarz
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt Simbrunner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Mathias Jachs
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Hartl
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lorenz Balcar
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - David J M Bauer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Georg Semmler
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Benedikt S Hofer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Bernhard Scheiner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Matthias Pinter
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Albert F Stättermayer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Trauner
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Christian-Doppler Laboratory for Portal Hypertension and Liver Fibrosis, Medical University of Vienna, Vienna, Austria
| | - Mattias Mandorfer
- Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Medicine III, Medical University of Vienna, Vienna, Austria
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Mukherji A, Jühling F, Simanjuntak Y, Crouchet E, Del Zompo F, Teraoka Y, Haller A, Baltzinger P, Paritala S, Rasha F, Fujiwara N, Gadenne C, Slovic N, Oudot MA, Durand SC, Ponsolles C, Schuster C, Zhuang X, Holmes J, Yeh ML, Abe-Chayama H, Heikenwälder M, Sangiovanni A, Iavarone M, Colombo M, Foung SKH, McKeating JA, Davidson I, Yu ML, Chung RT, Hoshida Y, Chayama K, Lupberger J, Baumert TF. An atlas of the human liver diurnal transcriptome and its perturbation by hepatitis C virus infection. Nat Commun 2024; 15:7486. [PMID: 39209804 PMCID: PMC11362569 DOI: 10.1038/s41467-024-51698-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2023] [Accepted: 08/15/2024] [Indexed: 09/04/2024] Open
Abstract
Chronic liver disease and cancer are global health challenges. The role of the circadian clock as a regulator of liver physiology and disease is well established in rodents, however, the identity and epigenetic regulation of rhythmically expressed genes in human disease is less well studied. Here we unravel the rhythmic transcriptome and epigenome of human hepatocytes using male human liver chimeric mice. We identify a large number of rhythmically expressed protein coding genes in human hepatocytes of male chimeric mice, which includes key transcription factors, chromatin modifiers, and critical enzymes. We show that hepatitis C virus (HCV) infection, a major cause of liver disease and cancer, perturbs the transcriptome by altering the rhythmicity of the expression of more than 1000 genes, and affects the epigenome, leading to an activation of critical pathways mediating metabolic alterations, fibrosis, and cancer. HCV-perturbed rhythmic pathways remain dysregulated in patients with advanced liver disease. Collectively, these data support a role for virus-induced perturbation of the hepatic rhythmic transcriptome and pathways in cancer development and may provide opportunities for cancer prevention and biomarkers to predict HCC risk.
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Affiliation(s)
- Atish Mukherji
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Frank Jühling
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Yogy Simanjuntak
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Emilie Crouchet
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Fabio Del Zompo
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Yuji Teraoka
- Department of Gastroenterology, National Hospital Organization Kure Medical Center, Hiroshima, Japan
| | - Alexandre Haller
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/University of Strasbourg, Illkirch, France
| | - Philippe Baltzinger
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/University of Strasbourg, Illkirch, France
| | - Soumith Paritala
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Fahmida Rasha
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Naoto Fujiwara
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Cloé Gadenne
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Nevena Slovic
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Marine A Oudot
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Sarah C Durand
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Clara Ponsolles
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Catherine Schuster
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France
| | - Xiaodong Zhuang
- Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK
- Institute of Immunity & Transplantation, Division of Infection & Immunity, UCL, Pears Building, Rowland Hill St, London, NW3 2PP, UK
| | - Jacinta Holmes
- University of Melbourne, St Vincent's Hospital, Melbourne, VIC, Australia
| | - Ming-Lun Yeh
- Hepatobiliary Division, Department of Internal Medicine, School of Medicine and Hepatitis Research Center, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
| | - Hiromi Abe-Chayama
- Center for Medical Specialist Graduate Education and Research, Hiroshima University, Hiroshima, Japan
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
- M3 Research Center, Tübingen, Germany and Cluster of Excellence iFIT (EXC 2180) "Image-Guided and Functionally Instructed Tumor Therapies, " Eberhard-Karls University of Tübingen, Tübingen, Germany
| | - Angelo Sangiovanni
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | - Massimo Iavarone
- Division of Gastroenterology and Hepatology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy
| | | | - Steven K H Foung
- Department of Pathology, Stanford University School of Medicine, Stanford, CA, 94305, USA
| | - Jane A McKeating
- Nuffield Department of Medicine, University of Oxford, Oxford, OX3 7FZ, UK
- Chinese Academy of Medical Sciences Oxford Institute, University of Oxford, Oxford, UK
| | - Irwin Davidson
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), CNRS/INSERM/University of Strasbourg, Illkirch, France
| | - Ming-Lung Yu
- Hepatobiliary Division, Department of Internal Medicine, School of Medicine and Hepatitis Research Center, College of Medicine, and Center for Liquid Biopsy and Cohort Research, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, 80708, Taiwan
- School of Medicine and Doctoral Program of Clinical and Experimental Medicine, College of Medicine and Center of Excellence for Metabolic Associated Fatty Liver Disease, National Sun Yat-sen University, Kaohsiung, Taiwan
| | - Raymond T Chung
- Gastrointestinal Division, Hepatology and Liver Center, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Yujin Hoshida
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Kazuaki Chayama
- RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- Hiroshima Institute of Life Sciences, Hiroshima, Japan
| | - Joachim Lupberger
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France.
| | - Thomas F Baumert
- University of Strasbourg, Institute of Translational Medicine and Liver Diseases (ITM), Inserm UMR_S1110, Strasbourg, France.
- Gastroenterology and Hepatology Service, Strasbourg University Hospitals, Strasbourg, France.
- Institut Universitaire de France, Paris, France.
- IHU, Strasbourg, France.
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13
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Lopez-Pascual A. Navigating liver disease complexity: Innovations in in vitro modeling and precision medicine. Hepatology 2024; 80:20-23. [PMID: 38088881 DOI: 10.1097/hep.0000000000000719] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 11/28/2023] [Indexed: 01/30/2024]
Affiliation(s)
- Amaya Lopez-Pascual
- Hepatology Unit, CCUN, Navarra University Clinic, Pamplona, Spain
- Instituto de Investigaciones Sanitarias de Navarra IdiSNA, Pamplona, Spain
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Huang K, Liao J, He J, Lai S, Peng Y, Deng Q, Wang H, Liu Y, Peng L, Bai Z, Yu N, Li Y, Jiang Z, Su J, Li J, Tang Y, Chen M, Lu L, Chen X, Yao J, Zhao S. A real-time augmented reality system integrated with artificial intelligence for skin tumor surgery: experimental study and case series. Int J Surg 2024; 110:3294-3306. [PMID: 38549223 PMCID: PMC11175769 DOI: 10.1097/js9.0000000000001371] [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: 10/11/2023] [Accepted: 03/11/2024] [Indexed: 06/15/2024]
Abstract
BACKGROUND Skin tumors affect many people worldwide, and surgery is the first treatment choice. Achieving precise preoperative planning and navigation of intraoperative sampling remains a problem and is excessively reliant on the experience of surgeons, especially for Mohs surgery for malignant tumors. MATERIALS AND METHODS To achieve precise preoperative planning and navigation of intraoperative sampling, we developed a real-time augmented reality (AR) surgical system integrated with artificial intelligence (AI) to enhance three functions: AI-assisted tumor boundary segmentation, surgical margin design, and navigation in intraoperative tissue sampling. Non-randomized controlled trials were conducted on manikin, tumor-simulated rabbits, and human volunteers in Hunan Engineering Research Center of Skin Health and Disease Laboratory to evaluate the surgical system. RESULTS The results showed that the accuracy of the benign and malignant tumor segmentation was 0.9556 and 0.9548, respectively, and the average AR navigation mapping error was 0.644 mm. The proposed surgical system was applied in 106 skin tumor surgeries, including intraoperative navigation of sampling in 16 Mohs surgery cases. Surgeons who have used this system highly recognize it. CONCLUSIONS The surgical system highlighted the potential to achieve accurate treatment of skin tumors and to fill the gap in global research on skin tumor surgery systems.
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Affiliation(s)
- Kai Huang
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
- Tencent AI Lab, Shenzhen, People’s Republic of China
| | - Jun Liao
- Tencent AI Lab, Shenzhen, People’s Republic of China
| | - Jishuai He
- Tencent AI Lab, Shenzhen, People’s Republic of China
| | - Sicen Lai
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Yihao Peng
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Qian Deng
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Han Wang
- Tencent AI Lab, Shenzhen, People’s Republic of China
| | - Yuancheng Liu
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Lanyuan Peng
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Ziqi Bai
- Tencent AI Lab, Shenzhen, People’s Republic of China
| | - Nianzhou Yu
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Yixin Li
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Zixi Jiang
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Juan Su
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Jinmao Li
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Yan Tang
- Department of Dermatology
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Mingliang Chen
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Lixia Lu
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Xiang Chen
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
| | - Jianhua Yao
- Tencent AI Lab, Shenzhen, People’s Republic of China
| | - Shuang Zhao
- Department of Dermatology
- Hunan Key Laboratory of Skin Cancer and Psoriasis
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital
- Hunan Engineering Research Center of Skin Health and Disease, Central South University
- National Engineering Research Center of Personalized Diagnostic and Therapeutic Technology, Hunan
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15
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Mohamad NA, Galarza TE, Martín GA. H2 antihistamines: May be useful for combination therapies in cancer? Biochem Pharmacol 2024; 223:116164. [PMID: 38531422 DOI: 10.1016/j.bcp.2024.116164] [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: 12/03/2023] [Revised: 03/13/2024] [Accepted: 03/22/2024] [Indexed: 03/28/2024]
Abstract
Cancer morbimortality is still a great concern despite advances in research and therapies. Histamine and its receptors' ligands can modulate different biological responses according to the cell type and the receptor subtype involved. Besides the wide variety of histamine functions in normal tissues, diverse roles in the acquisition of hallmarks of cancer such as sustained proliferative signaling, resistance to cell death, angiogenesis, metastasis, altered immunity and modified microenvironment have been described. This review summarizes the present knowledge of the various roles of histamine H2 receptor (H2R) ligands in neoplasias. A bioinformatic analysis of human tumors showed dissimilar results in the expression of the H2R gene according to tumor type when comparing malignant versus normal tissues. As well, the relationship between patients' survival parameters and H2R gene expression levels also varied, signaling important divergences in the role of H2R in neoplastic progression in different cancer types. Revised experimental evidence showed multiple effects of H2R antihistamines on several of the cited hallmarks of cancer. Interventional and retrospective clinical studies evaluated different H2R antihistamines in cancer patients with two main adjuvant uses: improving antitumor efficacy (which includes regulation of immune response) and preventing toxic adverse effects produced by chemo or radiotherapy. While there is a long path to go, research on H2R antihistamines may provide new opportunities for developing more refined combination therapeutic strategies for certain cancer types to improve patients' survival and health-related quality of life.
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Affiliation(s)
- Nora A Mohamad
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - Tamara E Galarza
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Laboratorio de Radioisótopos, Buenos Aires, Argentina
| | - Gabriela A Martín
- Universidad de Buenos Aires, Facultad de Farmacia y Bioquímica, Laboratorio de Radioisótopos, Buenos Aires, Argentina; Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina.
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16
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Moriwaki T, Tani H, Haga K, Morita-Umei Y, Soma Y, Umei TC, Sekine O, Takatsuna K, Kishino Y, Kanazawa H, Fujita J, Fukuda K, Tohyama S, Ieda M. Scalable production of homogeneous cardiac organoids derived from human pluripotent stem cells. CELL REPORTS METHODS 2023; 3:100666. [PMID: 38113855 PMCID: PMC10753388 DOI: 10.1016/j.crmeth.2023.100666] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/06/2023] [Revised: 08/24/2023] [Accepted: 11/16/2023] [Indexed: 12/21/2023]
Abstract
Three-dimensional (3D) cultures are known to more closely mimic in vivo conditions compared with 2D cultures. Cardiac spheroids (CSs) and organoids (COs) are useful for 3D tissue engineering and are advantageous for their simplicity and mass production for regenerative therapy and drug discovery. Herein, we describe a large-scale method for producing homogeneous human induced pluripotent stem cell (hiPSC)-derived CSs (hiPSC-CSs) and COs without scaffolds using a porous 3D microwell substratum with a suction system. Our method has many advantages, such as increased efficiency and improved functionality, homogeneity, and sphericity of hiPSC-CSs. Moreover, we have developed a substratum on a clinically relevant large scale for regenerative therapy and have succeeded in producing approximately 40,000 hiPSC-CSs with high sphericity at once. Furthermore, we efficiently produced a fused CO model consisting of hiPSC-derived atrial and ventricular cardiomyocytes localized on opposite sides of one organoid. This method will facilitate progress toward hiPSC-based clinical applications.
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Affiliation(s)
- Taijun Moriwaki
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Hidenori Tani
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Joint Research Laboratory for Medical Innovation in Heart Disease, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Kotaro Haga
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Yuika Morita-Umei
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Kanagawa Institute of Industrial Science and Technology (KISTEC), Kawasaki, Kanagawa, Japan
| | - Yusuke Soma
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Tomohiko C Umei
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Otoya Sekine
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Kaworu Takatsuna
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Yoshikazu Kishino
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Hideaki Kanazawa
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Jun Fujita
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan; Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX, USA
| | - Keiichi Fukuda
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
| | - Shugo Tohyama
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan.
| | - Masaki Ieda
- Department of Cardiology, Keio University School of Medicine, Shinjuku, Tokyo, Japan
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17
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Antropova EA, Khlebodarova TM, Demenkov PS, Volianskaia AR, Venzel AS, Ivanisenko NV, Gavrilenko AD, Ivanisenko TV, Adamovskaya AV, Revva PM, Kolchanov NA, Lavrik IN, Ivanisenko VA. Reconstruction of the regulatory hypermethylation network controlling hepatocellular carcinoma development during hepatitis C viral infection. J Integr Bioinform 2023; 20:jib-2023-0013. [PMID: 37978846 PMCID: PMC10757076 DOI: 10.1515/jib-2023-0013] [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: 04/30/2023] [Accepted: 07/31/2023] [Indexed: 11/19/2023] Open
Abstract
Hepatocellular carcinoma (HCC) has been associated with hepatitis C viral (HCV) infection as a potential risk factor. Nonetheless, the precise genetic regulatory mechanisms triggered by the virus, leading to virus-induced hepatocarcinogenesis, remain unclear. We hypothesized that HCV proteins might modulate the activity of aberrantly methylated HCC genes through regulatory pathways. Virus-host regulatory pathways, interactions between proteins, gene expression, transport, and stability regulation, were reconstructed using the ANDSystem. Gene expression regulation was statistically significant. Gene network analysis identified four out of 70 HCC marker genes whose expression regulation by viral proteins may be associated with HCC: DNA-binding protein inhibitor ID - 1 (ID1), flap endonuclease 1 (FEN1), cyclin-dependent kinase inhibitor 2A (CDKN2A), and telomerase reverse transcriptase (TERT). It suggested the following viral protein effects in HCV/human protein heterocomplexes: HCV NS3(p70) protein activates human STAT3 and NOTC1; NS2-3(p23), NS5B(p68), NS1(E2), and core(p21) activate SETD2; NS5A inhibits SMYD3; and NS3 inhibits CCN2. Interestingly, NS3 and E1(gp32) activate c-Jun when it positively regulates CDKN2A and inhibit it when it represses TERT. The discovered regulatory mechanisms might be key areas of focus for creating medications and preventative therapies to decrease the likelihood of HCC development during HCV infection.
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Affiliation(s)
| | - Tamara M. Khlebodarova
- Institute of Cytology and Genetics, Siberian Branch of RAS, Novosibirsk, Russia
- Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Pavel S. Demenkov
- Institute of Cytology and Genetics, Siberian Branch of RAS, Novosibirsk, Russia
- Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
| | | | - Artur S. Venzel
- Institute of Cytology and Genetics, Siberian Branch of RAS, Novosibirsk, Russia
- Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Nikita V. Ivanisenko
- Institute of Cytology and Genetics, Siberian Branch of RAS, Novosibirsk, Russia
- Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Alexandr D. Gavrilenko
- Institute of Cytology and Genetics, Siberian Branch of RAS, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
| | - Timofey V. Ivanisenko
- Institute of Cytology and Genetics, Siberian Branch of RAS, Novosibirsk, Russia
- Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
| | - Anna V. Adamovskaya
- Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
| | - Polina M. Revva
- Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
| | - Nikolay A. Kolchanov
- Institute of Cytology and Genetics, Siberian Branch of RAS, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
| | - Inna N. Lavrik
- Translational Inflammation Research, Medical Faculty, Otto von Guericke University Magdeburg, 39106Magdeburg, Germany
| | - Vladimir A. Ivanisenko
- Institute of Cytology and Genetics, Siberian Branch of RAS, Novosibirsk, Russia
- Kurchatov Genomic Center of the Institute of Cytology and Genetics of Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia
- Novosibirsk State University, Novosibirsk, Russia
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18
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Lee YT, Fujiwara N, Yang JD, Hoshida Y. Risk stratification and early detection biomarkers for precision HCC screening. Hepatology 2023; 78:319-362. [PMID: 36082510 PMCID: PMC9995677 DOI: 10.1002/hep.32779] [Citation(s) in RCA: 61] [Impact Index Per Article: 30.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/25/2022] [Accepted: 08/28/2022] [Indexed: 12/08/2022]
Abstract
Hepatocellular carcinoma (HCC) mortality remains high primarily due to late diagnosis as a consequence of failed early detection. Professional societies recommend semi-annual HCC screening in at-risk patients with chronic liver disease to increase the likelihood of curative treatment receipt and improve survival. However, recent dynamic shift of HCC etiologies from viral to metabolic liver diseases has significantly increased the potential target population for the screening, whereas annual incidence rate has become substantially lower. Thus, with the contemporary HCC etiologies, the traditional screening approach might not be practical and cost-effective. HCC screening consists of (i) definition of rational at-risk population, and subsequent (ii) repeated application of early detection tests to the population at regular intervals. The suboptimal performance of the currently available HCC screening tests highlights an urgent need for new modalities and strategies to improve early HCC detection. In this review, we overview recent developments of clinical, molecular, and imaging-based tools to address the current challenge, and discuss conceptual framework and approaches of their clinical translation and implementation. These encouraging progresses are expected to transform the current "one-size-fits-all" HCC screening into individualized precision approaches to early HCC detection and ultimately improve the poor HCC prognosis in the foreseeable future.
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Affiliation(s)
- Yi-Te Lee
- California NanoSystems Institute, Crump Institute for Molecular Imaging, Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, California
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Ju Dong Yang
- Karsh Division of Gastroenterology and Hepatology, Cedars-Sinai Medical Center, Los Angeles, California; Comprehensive Transplant Center, Cedars-Sinai Medical Center, Los Angeles, Los Angeles, California; Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas
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19
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Xia D, Jin R, Pan R, Chen HY, Jiang D. In Situ Spatial Analysis of Metabolic Heterogeneity in Single Living Tumor Spheroids Using Nanocapillary-Based Electrospray Ionization Mass Spectroscopy. Anal Chem 2023. [PMID: 37358923 DOI: 10.1021/acs.analchem.3c00479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/28/2023]
Abstract
Spatial metabolomic analysis of individual tumor spheroids can help investigate metabolic rearrangements in different cellular regions of a spheroid. In this work, a nanocapillary-based electrospray ionization mass spectroscopy (ESI-MS) method is established that could realize the spatial sampling of cellular components in different regions of a single living tumor spheroid and the subsequent MS analysis for a metabolic study. During the penetration of the nanocapillary into the spheroid for sampling, this "wound surface" at the outer layer of the spheroid takes only 0.1% of the whole area that maximally maintains the cellular activity inside the spheroid for the metabolic analysis. Using the ESI-MS analysis, different metabolic activities in the inner and outer (upper and lower) layers of a single spheroid are revealed, giving a full investigation of the metabolic heterogeneity inside one living tumor spheroid for the first time. In addition, the metabolic activities between the outer layer of the spheroid and two-dimensional (2D)-cultured cells show obvious differences, which suggests more frequent cell-cell and cell-extracellular environment interactions during the culture of the spheroid. This observation not only establishes a powerful tool for the in situ spatial analysis of the metabolic heterogeneity in single living tumor spheroids but also provides molecular information to elucidate the metabolic heterogeneity in this three-dimensional (3D)-cultured cell model.
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Affiliation(s)
- Dandan Xia
- The State Key Lab of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, P. R. China
| | - Rong Jin
- The State Key Lab of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, P. R. China
| | - Rongrong Pan
- The State Key Lab of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, P. R. China
| | - Hong-Yuan Chen
- The State Key Lab of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, P. R. China
| | - Dechen Jiang
- The State Key Lab of Analytical Chemistry for Life Science, Chemistry and Biomedicine Innovation Center (ChemBIC), School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, Jiangsu 210093, P. R. China
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20
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Villarruel-Melquiades F, Mendoza-Garrido ME, García-Cuellar CM, Sánchez-Pérez Y, Pérez-Carreón JI, Camacho J. Current and novel approaches in the pharmacological treatment of hepatocellular carcinoma. World J Gastroenterol 2023; 29:2571-2599. [PMID: 37213397 PMCID: PMC10198058 DOI: 10.3748/wjg.v29.i17.2571] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/19/2023] [Accepted: 04/11/2023] [Indexed: 05/07/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most lethal malignant tumours worldwide. The mortality-to-incidence ratio is up to 91.6% in many countries, representing the third leading cause of cancer-related deaths. Systemic drugs, including the multikinase inhibitors sorafenib and lenvatinib, are first-line drugs used in HCC treatment. Unfortunately, these therapies are ineffective in most cases due to late diagnosis and the development of tumour resistance. Thus, novel pharmacological alternatives are urgently needed. For instance, immune checkpoint inhibitors have provided new approaches targeting cells of the immune system. Furthermore, monoclonal antibodies against programmed cell death-1 have shown benefits in HCC patients. In addition, drug combinations, including first-line treatment and immunotherapy, as well as drug repurposing, are promising novel therapeutic alternatives. Here, we review the current and novel pharmacological approaches to fight HCC. Preclinical studies, as well as approved and ongoing clinical trials for liver cancer treatment, are discussed. The pharmacological opportunities analysed here should lead to significant improvement in HCC therapy.
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Affiliation(s)
- Fernanda Villarruel-Melquiades
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - María Eugenia Mendoza-Garrido
- Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
| | - Claudia M García-Cuellar
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Yesennia Sánchez-Pérez
- Subdirección de Investigación Básica, Instituto Nacional de Cancerología (INCan), Mexico City 14080, Mexico
| | - Julio Isael Pérez-Carreón
- Instituto Nacional de Medicina Genómica, Instituto Nacional de Medicina Genómica (INMEGEN), Mexico City 14610, Mexico
| | - Javier Camacho
- Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional (CINVESTAV-IPN), Mexico City 07360, Mexico
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21
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Ahmed T. Functional biomaterials for biomimetic 3D in vitro tumor microenvironment modeling. IN VITRO MODELS 2023; 2:1-23. [PMID: 39872875 PMCID: PMC11756483 DOI: 10.1007/s44164-023-00043-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/07/2022] [Revised: 01/11/2023] [Accepted: 01/16/2023] [Indexed: 01/30/2025]
Abstract
The translational potential of promising anticancer medications and treatments may be enhanced by the creation of 3D in vitro models that can accurately reproduce native tumor microenvironments. Tumor microenvironments for cancer treatment and research can be built in vitro using biomaterials. Three-dimensional in vitro cancer models have provided new insights into the biology of cancer. Cancer researchers are creating artificial three-dimensional tumor models based on functional biomaterials that mimic the microenvironment of the real tumor. Our understanding of tumor stroma activity over the course of cancer has improved because of the use of scaffold and matrix-based three-dimensional systems intended for regenerative medicine. Scientists have created synthetic tumor models thanks to recent developments in materials engineering. These models enable researchers to investigate the biology of cancer and assess the therapeutic effectiveness of available medications. The emergence of biomaterial engineering technologies with the potential to hasten treatment outcomes is highlighted in this review, which also discusses the influence of creating in vitro biomimetic 3D tumor microenvironments utilizing functional biomaterials. Future cancer treatments will rely much more heavily on biomaterials engineering.
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Affiliation(s)
- Tanvir Ahmed
- Department of Pharmaceutical Sciences, North South University, Bashundhara R/A, Dhaka-1229 Dhaka, Bangladesh
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22
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林 杰, 区 活, 王 卫, 马 靖, 张 伟, 刘 清. [Overexpression of CLEC5A inhibits cell proliferation and metastasis and reverses epithelial-mesenchymal transition in hepatocellular carcinoma]. NAN FANG YI KE DA XUE XUE BAO = JOURNAL OF SOUTHERN MEDICAL UNIVERSITY 2023; 43:85-91. [PMID: 36856214 PMCID: PMC9978715 DOI: 10.12122/j.issn.1673-4254.2023.01.11] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Indexed: 03/02/2023]
Abstract
OBJECTIVE To evaluate the effects of CLEC5A expression level on cell proliferation, migration and invasion and epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma (HCC) and explore the role of CLEC5A in the tumorigenesis and progression of HCC. METHODS The expression level of CLEC5A was detected in 50 pairs of HCC and adjacent tissues using immunohistochemical staining, and its association with clinicopathological parameters of HCC patients was analyzed. Cultured HCC cell line SK-HEP-1 was transfected with a lentiviral vector overexpressing CLEC5A, and the transfection efficiency was verified using real-time fluorescence quantitative PCR and Western blotting. The changes in proliferation, migration and invasion abilities of the transfected cells were analyzed using CCK-8, 5-ethynyl-29-deoxyuridine (EdU) and Transwell assays, and EMT of the cells was determined using Western blotting. RESULTS The protein expression level of CLEC5A was significantly lower in HCC tissues than in the adjacent tissues (P < 0.001). The expression level of CLEC5A was significantly correlated with tumor size (P=0.008), tumor number (P=0.010), histological differentiation (P=0.016), microvascular invasion (P=0.024) and BCLC stage (P=0.040). In SK-HEP-1 cells, overexpression of CLEC5A obviously inhibited the cell proliferation, migration and invasion and reversed EMT phenotype of the cells. CONCLUSION CLEC5A is a potential HCC suppressor gene and may serve as a promising therapeutic target for HCC.
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Affiliation(s)
- 杰 林
- />南方医科大学顺德医院（佛山市顺德区第一人民医院）肝胆胰脾外科，广东 佛山 528300Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (Shunde First People's Hospital), Foshan 528308, China
| | - 活辉 区
- />南方医科大学顺德医院（佛山市顺德区第一人民医院）肝胆胰脾外科，广东 佛山 528300Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (Shunde First People's Hospital), Foshan 528308, China
| | - 卫东 王
- />南方医科大学顺德医院（佛山市顺德区第一人民医院）肝胆胰脾外科，广东 佛山 528300Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (Shunde First People's Hospital), Foshan 528308, China
| | - 靖 马
- />南方医科大学顺德医院（佛山市顺德区第一人民医院）肝胆胰脾外科，广东 佛山 528300Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (Shunde First People's Hospital), Foshan 528308, China
| | - 伟杰 张
- />南方医科大学顺德医院（佛山市顺德区第一人民医院）肝胆胰脾外科，广东 佛山 528300Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (Shunde First People's Hospital), Foshan 528308, China
| | - 清波 刘
- />南方医科大学顺德医院（佛山市顺德区第一人民医院）肝胆胰脾外科，广东 佛山 528300Department of Hepatobiliary Surgery, Shunde Hospital, Southern Medical University (Shunde First People's Hospital), Foshan 528308, China
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23
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Roehlen N, Saviano A, El Saghire H, Crouchet E, Nehme Z, Del Zompo F, Jühling F, Oudot MA, Durand SC, Duong FHT, Cherradi S, Gonzalez Motos V, Almeida N, Ponsolles C, Heydmann L, Ostyn T, Lallement A, Pessaux P, Felli E, Cavalli A, Sgrignani J, Thumann C, Koutsopoulos O, Fuchs BC, Hoshida Y, Hofmann M, Vyberg M, Viuff BM, Galsgaard ED, Elson G, Toso A, Meyer M, Iacone R, Schweighoffer T, Teixeira G, Moll S, De Vito C, Roskams T, Davidson I, Heide D, Heikenwälder M, Zeisel MB, Lupberger J, Mailly L, Schuster C, Baumert TF. A monoclonal antibody targeting nonjunctional claudin-1 inhibits fibrosis in patient-derived models by modulating cell plasticity. Sci Transl Med 2022; 14:eabj4221. [PMID: 36542691 DOI: 10.1126/scitranslmed.abj4221] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Tissue fibrosis is a key driver of end-stage organ failure and cancer, overall accounting for up to 45% of deaths in developed countries. There is a large unmet medical need for antifibrotic therapies. Claudin-1 (CLDN1) is a member of the tight junction protein family. Although the role of CLDN1 incorporated in tight junctions is well established, the function of nonjunctional CLDN1 (njCLDN1) is largely unknown. Using highly specific monoclonal antibodies targeting a conformation-dependent epitope of exposed njCLDN1, we show in patient-derived liver three-dimensional fibrosis and human liver chimeric mouse models that CLDN1 is a mediator and target for liver fibrosis. Targeting CLDN1 reverted inflammation-induced hepatocyte profibrogenic signaling and cell fate and suppressed the myofibroblast differentiation of hepatic stellate cells. Safety studies of a fully humanized antibody in nonhuman primates did not reveal any serious adverse events even at high steady-state concentrations. Our results provide preclinical proof of concept for CLDN1-specific monoclonal antibodies for the treatment of advanced liver fibrosis and cancer prevention. Antifibrotic effects in lung and kidney fibrosis models further indicate a role of CLDN1 as a therapeutic target for tissue fibrosis across organs. In conclusion, our data pave the way for further therapeutic exploration of CLDN1-targeting therapies for fibrotic diseases in patients.
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Affiliation(s)
- Natascha Roehlen
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Antonio Saviano
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France.,Institut Hospitalo-Universitaire (IHU), Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Houssein El Saghire
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Emilie Crouchet
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Zeina Nehme
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Fabio Del Zompo
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Frank Jühling
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Marine A Oudot
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Sarah C Durand
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - François H T Duong
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Sara Cherradi
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Victor Gonzalez Motos
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Nuno Almeida
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Clara Ponsolles
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Laura Heydmann
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Tessa Ostyn
- Department of Imaging and Pathology, University of Leuven, 3000 Leuven, Belgium
| | - Antonin Lallement
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France.,Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UNISTRA, 67400 Illkirch, France
| | - Patrick Pessaux
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France.,Institut Hospitalo-Universitaire (IHU), Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Emanuele Felli
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France.,Institut Hospitalo-Universitaire (IHU), Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
| | - Andrea Cavalli
- Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland
| | - Jacopo Sgrignani
- Institute for Research in Biomedicine, Università della Svizzera Italiana, 6500 Bellinzona, Switzerland
| | - Christine Thumann
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Olga Koutsopoulos
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Bryan C Fuchs
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, MA 02215, USA
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA
| | - Maike Hofmann
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, 79106 Freiburg, Germany
| | - Mogens Vyberg
- Center of RNA Medicine, Department of Clinical Medicine, Aalborg University Copenhagen, 2450 København, Denmark.,Department of Pathology, Copenhagen University Hospital Hvidovre, 2650 Hvidovre, Denmark
| | | | | | - Greg Elson
- Alentis Therapeutics, 4123 Allschwil, Switzerland
| | - Alberto Toso
- Alentis Therapeutics, 4123 Allschwil, Switzerland
| | - Markus Meyer
- Alentis Therapeutics, 4123 Allschwil, Switzerland
| | | | | | | | - Solange Moll
- Department of Pathology, University Hospital of Geneva, 1205 Geneva, Switzerland
| | - Claudio De Vito
- Department of Pathology, University Hospital of Geneva, 1205 Geneva, Switzerland
| | - Tania Roskams
- Department of Imaging and Pathology, University of Leuven, 3000 Leuven, Belgium
| | - Irwin Davidson
- Department of Functional Genomics and Cancer, Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/UNISTRA, 67400 Illkirch, France
| | - Danijela Heide
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center, 69120 Heidelberg, Germany
| | - Mirjam B Zeisel
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Joachim Lupberger
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Laurent Mailly
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Catherine Schuster
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France
| | - Thomas F Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, 67000 Strasbourg, France.,Institut Hospitalo-Universitaire (IHU), Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.,Institut Universitaire de France, 75006 Paris, France
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24
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Abstract
Liver cancer, mainly hepatocellular carcinoma (HCC), remains a major cause of cancer-related death worldwide. With the global epidemic of obesity, the major HCC etiologies have been dynamically shifting from viral to metabolic liver diseases. This change has made HCC prevention difficult with increasingly elusive at-risk populations as rational target for preventive interventions. Besides ongoing efforts to reduce obesity and metabolic disorders, chemoprevention in patients who already have metabolic liver diseases may have a significant impact on the poor HCC prognosis. Hepatitis B- and hepatitis C-related HCC incidences have been substantially reduced by the new antivirals, but HCC risk can persist over a decade even after successful viral treatment, highlighting the need for HCC-preventive measures also in these patients. Experimental and retrospective studies have suggested potential utility of generic agents such as lipophilic statins and aspirin for HCC chemoprevention given their well-characterized safety profile, although anticipated efficacy may be modest. In this review, we overview recent clinical and translational studies of generic agents in the context of HCC chemoprevention under the contemporary HCC etiologies. We also discuss newly emerging approaches to overcome the challenges in clinical testing of the agents to facilitate their clinical translation.
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Affiliation(s)
- Fahmida Rasha
- Liver Tumor Translational Research Program; Simmons Comprehensive Cancer Center; Division of Digestive and Liver Diseases; Department of Internal Medicine; University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Subhojit Paul
- Liver Tumor Translational Research Program; Simmons Comprehensive Cancer Center; Division of Digestive and Liver Diseases; Department of Internal Medicine; University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Tracey G Simon
- Liver Center, Division of Gastroenterology, Clinical and Translational Epidemiology Unit, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Yujin Hoshida
- Liver Tumor Translational Research Program; Simmons Comprehensive Cancer Center; Division of Digestive and Liver Diseases; Department of Internal Medicine; University of Texas Southwestern Medical Center, Dallas, TX, USA
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25
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Kim M, Kim M, Salloum S, Qian T, Wong LP, Xu M, Lee Y, Shroff SG, Sadreyev RI, Corey KE, Baumert TF, Hoshida Y, Chung RT. Atorvastatin favorably modulates a clinical hepatocellular carcinoma risk gene signature. Hepatol Commun 2022; 6:2581-2593. [PMID: 35712812 PMCID: PMC9426409 DOI: 10.1002/hep4.1991] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 04/11/2022] [Accepted: 04/15/2022] [Indexed: 11/22/2022] Open
Abstract
Lipophilic but not hydrophilic statins have been shown to be associated with reduced risk for hepatocellular carcinoma (HCC) in patients with chronic viral hepatitis. We investigated differential actions of lipophilic and hydrophilic statins and their ability to modulate a clinical prognostic liver signature (PLS) predicting HCC risk in patients with liver disease. Hepatitis C virus (HCV)-infected Huh7.5.1 cells, recently developed as a model to screen HCC chemopreventive agents, were treated with lipophilic statins (atorvastatin and simvastatin) and hydrophilic statins (rosuvastatin and pravastatin), and then analyzed by RNA sequencing and PLS. Lipophilic statins, particularly atorvastatin, more significantly suppressed the HCV-induced high-risk pattern of PLS and genes in YAP and AKT pathway implicated in fibrogenesis and carcinogenesis, compared with the hydrophilic statins. While atorvastatin inhibited YAP activation through the mevalonate pathway, the distinctive AKT inhibition of atorvastatin was mediated by stabilizing truncated retinoid X receptor alpha, which has been known to enhance AKT activation, representing a target for HCC chemoprevention. In addition, atorvastatin modulated the high-risk PLS in an in vitro model of nonalcoholic fatty liver disease (NAFLD). Conclusion: Atorvastatin distinctively inhibits YAP and AKT activation, which are biologically implicated in HCC development, and attenuates a high-risk PLS in an in vitro model of HCV infection and NAFLD. These findings suggest that atorvastatin is the most potent statin to reduce HCC risk in patients with viral and metabolic liver diseases.
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Affiliation(s)
- Myung‐Ho Kim
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Mi‐Young Kim
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
- Department of GastroenterologyCHA Bundang Medical CenterCHA University School of MedicineSeongnamSouth Korea
- Department of Gastroenterology, Chaum Life CenterCHA University School of MedicineSeoulSouth Korea
| | - Shadi Salloum
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Tongqi Qian
- Liver Tumor Translational Research ProgramSimmons Comprehensive Cancer CenterDivision of Digestive and Liver DiseasesDepartment of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Lai Ping Wong
- Department of Molecular BiologyMassachusetts General HospitalBostonMassachusettsUSA
- Department of GeneticsHarvard Medical SchoolBostonMassachusettsUSA
| | - Min Xu
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Yoojin Lee
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Stuti G. Shroff
- Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Ruslan I. Sadreyev
- Department of Molecular BiologyMassachusetts General HospitalBostonMassachusettsUSA
- Department of PathologyMassachusetts General Hospital and Harvard Medical SchoolBostonMassachusettsUSA
| | - Kathleen E. Corey
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
| | - Thomas F. Baumert
- Institut National de la Santé et de la Recherche MédicaleU1110Institut de Recherche sur les Maladies Virales et HépatiquesStrasbourgFrance
- Pole Hepato‐digestif, IHUStrasbourg University HospitalsStrasbourgFrance
| | - Yujin Hoshida
- Liver Tumor Translational Research ProgramSimmons Comprehensive Cancer CenterDivision of Digestive and Liver DiseasesDepartment of Internal MedicineUniversity of Texas Southwestern Medical CenterDallasTexasUSA
| | - Raymond T. Chung
- Liver CenterGastrointestinal DivisionMassachusetts General HospitalBostonMassachusettsUSA
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26
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Xie L, Wu S, He R, Li S, Lai X, Wang Z. Identification of epigenetic dysregulation gene markers and immune landscape in kidney renal clear cell carcinoma by comprehensive genomic analysis. Front Immunol 2022; 13:901662. [PMID: 36059531 PMCID: PMC9433776 DOI: 10.3389/fimmu.2022.901662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Accepted: 07/28/2022] [Indexed: 12/24/2022] Open
Abstract
Kidney cancer is one the most lethal cancers of the urinary system, but current treatments are limited and its prognosis is poor. This study focused on kidney renal clear cell carcinoma (KIRC) and analyzed the relationship between epigenetic alterations and KIRC prognosis, and explored the prognostic significance of these findings in KIRC patients. Based on multi-omics data, differentially expressed histone-modified genes were identified using the R package limma package. Gene enhancers were detected from data in the FANTOM5 database. Gene promoters were screened using the R package ChIPseeker, and the Bumphunter in the R package CHAMP was applied to screen differentially methylated regions (DMR). Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) functional enrichment analysis of genes was performed using the R package clusterProfiler. We identified 51 dysregulated epigenetic protein coding genes (epi-PCGs) from 872 epi-PCGs, and categorized three molecular subtypes (C1, C2, and C3) of KIRC samples with significantly different prognosis. Notably, among the three molecular subtypes, we found a markedly differential immune features in immune checkpoints, cytokines, immune signatures, and immune cell distribution. C2 subtype had significantly lower enrichment score of IFNγ, cytotoxic score (CYT), and angiogenesis. In addition, an 8-gene signature containing 8 epi-PCGs (ETV4, SH2B3, FATE1, GRK5, MALL, HRH2, SEMA3G, and SLC10A6) was developed for predicting KIRC prognosis. Prognosis of patients with a high 8-gene signature score was significantly worse than those with a low 8-gene signature score, which was also validated by the independent validation data. The 8-gene signature had a better performance compared with previous signatures of KIRC. Overall, this study highlighted the important role of epigenetic regulation in KIRC development, and explored prognostic epi-PCGs, which may provide a guidance for exploiting further pathological mechanisms of KIRC and for developing novel drug targets.
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Affiliation(s)
- Linli Xie
- Department of Pharmacy, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Shuang Wu
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Rong He
- Department of Pharmacy, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Sisi Li
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Xiaodan Lai
- Department of Pharmacy, No. 958 Hospital of Chinese People's Liberation Army (PLA), Chongqing, China
- *Correspondence: Xiaodan Lai, ; Zhe Wang,
| | - Zhe Wang
- Department of Oncology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
- *Correspondence: Xiaodan Lai, ; Zhe Wang,
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27
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Crouchet E, Li S, Sojoodi M, Bandiera S, Fujiwara N, El Saghire H, Zhu S, Qian T, Rasha FA, Del Zompo F, Barrett SC, Schaeffer E, Oudot MA, Ponsolles C, Durand SC, Ghoshal S, Arora G, Giannone F, Chung RT, Slovic N, Van Renne N, Felli E, Pessaux P, Lupberger J, Pochet N, Schuster C, Tanabe KK, Hoshida Y, Fuchs BC, Baumert TF. Hepatocellular carcinoma chemoprevention by targeting the angiotensin-converting enzyme and EGFR transactivation. JCI Insight 2022; 7:159254. [PMID: 35801591 PMCID: PMC9310532 DOI: 10.1172/jci.insight.159254] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 06/01/2022] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is a leading cause of death among cirrhotic patients, for which chemopreventive strategies are lacking. Recently, we developed a simple human cell-based system modeling a clinical prognostic liver signature (PLS) predicting liver disease progression and HCC risk. In a previous study, we applied our cell-based system for drug discovery and identified captopril, an approved angiotensin converting enzyme (ACE) inhibitor, as a candidate compound for HCC chemoprevention. Here, we explored ACE as a therapeutic target for HCC chemoprevention. Captopril reduced liver fibrosis and effectively prevented liver disease progression toward HCC development in a diethylnitrosamine (DEN) rat cirrhosis model and a diet-based rat model for nonalcoholic steatohepatitis–induced (NASH-induced) hepatocarcinogenesis. RNA-Seq analysis of cirrhotic rat liver tissues uncovered that captopril suppressed the expression of pathways mediating fibrogenesis, inflammation, and carcinogenesis, including epidermal growth factor receptor (EGFR) signaling. Mechanistic data in liver disease models uncovered a cross-activation of the EGFR pathway by angiotensin. Corroborating the clinical translatability of the approach, captopril significantly reversed the HCC high-risk status of the PLS in liver tissues of patients with advanced fibrosis. Captopril effectively prevents fibrotic liver disease progression toward HCC development in preclinical models and is a generic and safe candidate drug for HCC chemoprevention.
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Affiliation(s)
- Emilie Crouchet
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Shen Li
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Mozhdeh Sojoodi
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Simonetta Bandiera
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Hussein El Saghire
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Shijia Zhu
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Tongqi Qian
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Fahmida Akter Rasha
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Fabio Del Zompo
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Stephen C Barrett
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Eugénie Schaeffer
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Marine A Oudot
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Clara Ponsolles
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Sarah C Durand
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Sarani Ghoshal
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Gunisha Arora
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Fabio Giannone
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France.,Service de chirurgie viscérale et digestive, Pôle hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.,Institut hospitalo-universitaire (IHU), Institute for Minimally Invasive Hybrid Image-Guided Surgery, Université de Strasbourg, Strasbourg, France
| | - Raymond T Chung
- Liver Center and Gastrointestinal Division, Massachusetts General Hospital
| | - Nevena Slovic
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Nicolaas Van Renne
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Emanuele Felli
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France.,Service de chirurgie viscérale et digestive, Pôle hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.,Institut hospitalo-universitaire (IHU), Institute for Minimally Invasive Hybrid Image-Guided Surgery, Université de Strasbourg, Strasbourg, France
| | - Patrick Pessaux
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France.,Service de chirurgie viscérale et digestive, Pôle hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.,Institut hospitalo-universitaire (IHU), Institute for Minimally Invasive Hybrid Image-Guided Surgery, Université de Strasbourg, Strasbourg, France
| | - Joachim Lupberger
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Nathalie Pochet
- Program in Translational NeuroPsychiatric Genomics, Brigham and Women's Hospital, and Harvard Medical School, Boston, Massachusetts, USA.,Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.,Department of Neurology, Harvard Medical School, Boston, Massachusetts, USA
| | - Catherine Schuster
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France
| | - Kenneth K Tanabe
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | - Bryan C Fuchs
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Thomas F Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR-S1110, Strasbourg, France.,Service de chirurgie viscérale et digestive, Pôle hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France
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28
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Fujiwara N, Kubota N, Crouchet E, Koneru B, Marquez CA, Jajoriya AK, Panda G, Qian T, Zhu S, Goossens N, Wang X, Liang S, Zhong Z, Lewis S, Taouli B, Schwartz ME, Fiel MI, Singal AG, Marrero JA, Fobar AJ, Parikh ND, Raman I, Li QZ, Taguri M, Ono A, Aikata H, Nakahara T, Nakagawa H, Matsushita Y, Tateishi R, Koike K, Kobayashi M, Higashi T, Nakagawa S, Yamashita YI, Beppu T, Baba H, Kumada H, Chayama K, Baumert TF, Hoshida Y. Molecular signatures of long-term hepatocellular carcinoma risk in nonalcoholic fatty liver disease. Sci Transl Med 2022; 14:eabo4474. [PMID: 35731891 PMCID: PMC9236162 DOI: 10.1126/scitranslmed.abo4474] [Citation(s) in RCA: 68] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Prediction of hepatocellular carcinoma (HCC) risk is an urgent unmet need in patients with nonalcoholic fatty liver disease (NAFLD). In cohorts of 409 patients with NAFLD from multiple global regions, we defined and validated hepatic transcriptome and serum secretome signatures predictive of long-term HCC risk in patients with NAFLD. A 133-gene signature, prognostic liver signature (PLS)-NAFLD, predicted incident HCC over up to 15 years of longitudinal observation. High-risk PLS-NAFLD was associated with IDO1+ dendritic cells and dysfunctional CD8+ T cells in fibrotic portal tracts along with impaired metabolic regulators. PLS-NAFLD was validated in independent cohorts of patients with NAFLD who were HCC naïve (HCC incidence rates at 15 years were 22.7 and 0% in high- and low-risk patients, respectively) or HCC experienced (de novo HCC recurrence rates at 5 years were 71.8 and 42.9% in high- and low-risk patients, respectively). PLS-NAFLD was bioinformatically translated into a four-protein secretome signature, PLSec-NAFLD, which was validated in an independent cohort of HCC-naïve patients with NAFLD and cirrhosis (HCC incidence rates at 15 years were 37.6 and 0% in high- and low-risk patients, respectively). Combination of PLSec-NAFLD with our previously defined etiology-agnostic PLSec-AFP yielded improved HCC risk stratification. PLS-NAFLD was modified by bariatric surgery, lipophilic statin, and IDO1 inhibitor, suggesting that the signature can be used for drug discovery and as a surrogate end point in HCC chemoprevention clinical trials. Collectively, PLS/PLSec-NAFLD may enable NAFLD-specific HCC risk prediction and facilitate clinical translation of NAFLD-directed HCC chemoprevention.
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Affiliation(s)
- Naoto Fujiwara
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo; Tokyo, 113-8655, Japan
| | - Naoto Kubota
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Emilie Crouchet
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, University of Strasbourg and IHU, Pole Hépato-digestif, Strasbourg University Hospitals; Strasbourg, 67000, France
| | - Bhuvaneswari Koneru
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Cesia A Marquez
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Arun K Jajoriya
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Gayatri Panda
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Tongqi Qian
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Shijia Zhu
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital; Geneva, 44041, Switzerland
| | - Xiaochen Wang
- Department of Immunology, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Shuang Liang
- Department of Immunology, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Zhenyu Zhong
- Department of Immunology, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Sara Lewis
- Department of Radiology, Icahn School of Medicine at Mount Sinai; New York, 10029, U.S
| | - Bachir Taouli
- Department of Radiology, Icahn School of Medicine at Mount Sinai; New York, 10029, U.S
| | - Myron E Schwartz
- Department of Surgery, Icahn School of Medicine at Mount Sinai; New York, 10029, U.S
| | - Maria Isabel Fiel
- Department of Pathology, Icahn School of Medicine at Mount Sinai; New York, 10029, U.S
| | - Amit G Singal
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Jorge A Marrero
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
- Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania; Philadelphia, 19104, U.S
| | - Austin J Fobar
- Division of Gastroenterology and Hepatology, University of Michigan; Ann Arbor, 48109, U.S
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan; Ann Arbor, 48109, U.S
| | - Indu Raman
- BioCenter Microarray Core Facility, Department of Immunology, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Quan-Zhen Li
- BioCenter Microarray Core Facility, Department of Immunology, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
| | - Masataka Taguri
- Department of Data Science, School of Data Science, Yokohama City University; Yokohama, 236-0027, Japan
| | - Atsushi Ono
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University; Hiroshima, 734-8551, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University; Hiroshima, 734-8551, Japan
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University; Hiroshima, 734-8551, Japan
| | - Hayato Nakagawa
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo; Tokyo, 113-8655, Japan
| | - Yuki Matsushita
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo; Tokyo, 113-8655, Japan
| | - Ryosuke Tateishi
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo; Tokyo, 113-8655, Japan
| | - Kazuhiko Koike
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo; Tokyo, 113-8655, Japan
| | | | - Takaaki Higashi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University; Kumamoto, 860-8555, Japan
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University; Kumamoto, 860-8555, Japan
| | - Yo-ichi Yamashita
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University; Kumamoto, 860-8555, Japan
| | - Toru Beppu
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University; Kumamoto, 860-8555, Japan
| | - Hideo Baba
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University; Kumamoto, 860-8555, Japan
| | - Hiromitsu Kumada
- Department of Hepatology, Toranomon Hospital; Tokyo, 105-0001, Japan
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Research Center for Hepatology and Gastroenterology, Hiroshima University; Hiroshima, 734-8551, Japan
- RIKEN Center for Integrative Medical Sciences; Yokohama, 230-0045, Japan
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, University of Strasbourg and IHU, Pole Hépato-digestif, Strasbourg University Hospitals; Strasbourg, 67000, France
| | - Yujin Hoshida
- Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center; Dallas, 75390, U.S
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29
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Mehta H, Lett MJ, Klenerman P, Filipowicz Sinnreich M. MAIT cells in liver inflammation and fibrosis. Semin Immunopathol 2022; 44:429-444. [PMID: 35641678 PMCID: PMC9256577 DOI: 10.1007/s00281-022-00949-1] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Accepted: 05/06/2022] [Indexed: 02/07/2023]
Abstract
Mucosal-associated invariant T cells or MAIT cells are an abundant cell type in humans and especially so in the liver. MAIT cells are a subset of T lymphocytes that sit at a bridge between innate and adaptive immunity, so-called innate-like or "unconventional" T cells. The specificity of their antigen receptor (T cell receptor or TCR) is for the conserved major histocompatibility complex (MHC)-related molecule MR1, which presents a modified bacterial metabolite from the vitamin B2 biosynthesis pathway - this allows them to respond in the presence of many bacteria or yeast. MAIT cells also possess an array of cytokine receptors, which allows triggering independently of the TCR. The combination of such signals drives their functionality - this means they can respond to a range of stimuli and likely play a role not only in infection or inflammation, but also under homeostatic conditions.In this review, we will look at the question of what MAIT cells are doing in the normal liver and how they behave in the setting of disease. These questions are of relevance because MAIT cells are such a distinctive cell type enriched in the liver under normal conditions, and their modulation could be of therapeutic benefit. The recent discovery that they appear to be involved in liver fibrosis is particularly of interest in this context.
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Affiliation(s)
- Hema Mehta
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, South Parks Rd, Oxford, OX1 3SY, UK
| | - Martin Joseph Lett
- Liver Immunology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
| | - Paul Klenerman
- Peter Medawar Building for Pathogen Research, Nuffield Department of Medicine, University of Oxford, South Parks Rd, Oxford, OX1 3SY, UK.
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
| | - Magdalena Filipowicz Sinnreich
- Liver Immunology, Department of Biomedicine, University Hospital Basel and University of Basel, Basel, Switzerland
- Department of Gastroenterology and Hepatology, Basel University Medical Clinic, Cantonal Hospital Baselland, Liestal, Switzerland
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30
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Qian T, Fujiwara N, Koneru B, Ono A, Kubota N, Jajoriya AK, Tung MG, Crouchet E, Song WM, Marquez CA, Panda G, Hoshida A, Raman I, Li QZ, Lewis C, Yopp A, Rich NE, Singal AG, Nakagawa S, Goossens N, Higashi T, Koh AP, Bian CB, Hoshida H, Tabrizian P, Gunasekaran G, Florman S, Schwarz ME, Hiotis SP, Nakahara T, Aikata H, Murakami E, Beppu T, Baba H, Warren A, Bhatia S, Kobayashi M, Kumada H, Fobar AJ, Parikh ND, Marrero JA, Rwema SH, Nair V, Patel M, Kim-Schulze S, Corey K, O’Leary JG, Klintmalm GB, Thomas DL, Dibas M, Rodriguez G, Zhang B, Friedman SL, Baumert TF, Fuchs BC, Chayama K, Zhu S, Chung RT, Hoshida Y. Molecular Signature Predictive of Long-Term Liver Fibrosis Progression to Inform Antifibrotic Drug Development. Gastroenterology 2022; 162:1210-1225. [PMID: 34951993 PMCID: PMC8934284 DOI: 10.1053/j.gastro.2021.12.250] [Citation(s) in RCA: 26] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 01/02/2023]
Abstract
BACKGROUND & AIMS There is a major unmet need to assess the prognostic impact of antifibrotics in clinical trials because of the slow rate of liver fibrosis progression. We aimed to develop a surrogate biomarker to predict future fibrosis progression. METHODS A fibrosis progression signature (FPS) was defined to predict fibrosis progression within 5 years in patients with hepatitis C virus and nonalcoholic fatty liver disease (NAFLD) with no to minimal fibrosis at baseline (n = 421) and was validated in an independent NAFLD cohort (n = 78). The FPS was used to assess response to 13 candidate antifibrotics in organotypic ex vivo cultures of clinical fibrotic liver tissues (n = 78) and cenicriviroc in patients with nonalcoholic steatohepatitis enrolled in a clinical trial (n = 19, NCT02217475). A serum protein-based surrogate FPS was developed and tested in a cohort of compensated cirrhosis patients (n = 122). RESULTS A 20-gene FPS was defined and validated in an independent NAFLD cohort (adjusted odds ratio, 10.93; area under the receiver operating characteristic curve, 0.86). Among computationally inferred fibrosis-driving FPS genes, BCL2 was confirmed as a potential pharmacologic target using clinical liver tissues. Systematic ex vivo evaluation of 13 candidate antifibrotics identified rational combination therapies based on epigallocatechin gallate, which were validated for enhanced antifibrotic effect in ex vivo culture of clinical liver tissues. In patients with nonalcoholic steatohepatitis treated with cenicriviroc, FPS modulation was associated with 1-year fibrosis improvement accompanied by suppression of the E2F pathway. Induction of the PPARα pathway was absent in patients without fibrosis improvement, suggesting a benefit of combining PPARα agonism to improve the antifibrotic efficacy of cenicriviroc. A 7-protein serum protein-based surrogate FPS was associated with the development of decompensation in cirrhosis patients. CONCLUSION The FPS predicts long-term fibrosis progression in an etiology-agnostic manner, which can inform antifibrotic drug development.
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Affiliation(s)
- Tongqi Qian
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Naoto Fujiwara
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S.,Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Bhuvaneswari Koneru
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Atsushi Ono
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S.,Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Naoto Kubota
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Arun K Jajoriya
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Matthew G Tung
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, U.S
| | - Emilie Crouchet
- Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, University of Strasbourg, Strasbourg, France
| | - Won-Min Song
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Cesia Ammi Marquez
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Gayatri Panda
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Ayaka Hoshida
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Indu Raman
- Microarray Core Facility, Department of Immunology, BioCenter, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Quan-Zhen Li
- Microarray Core Facility, Department of Immunology, BioCenter, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Cheryl Lewis
- Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Adam Yopp
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Nicole E Rich
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Amit G Singal
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Shigeki Nakagawa
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Nicolas Goossens
- Division of Gastroenterology and Hepatology, Geneva University Hospital, Switzerland
| | - Takaaki Higashi
- Department of Gastroenterological Surgery, Graduate School of Medical Sciences, Kumamoto University, Kumamoto, Japan
| | - Anna P Koh
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - C Billie Bian
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Hiroki Hoshida
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Parissa Tabrizian
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Ganesh Gunasekaran
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Sander Florman
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Myron E Schwarz
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Spiros P Hiotis
- Department of Surgery, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Takashi Nakahara
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Hiroshi Aikata
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Eisuke Murakami
- Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Toru Beppu
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, U.S
| | - Hideo Baba
- Department of Surgery, University of Texas Southwestern Medical Center, Dallas, U.S
| | | | | | | | | | - Austin J Fobar
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, U.S
| | - Neehar D Parikh
- Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, U.S
| | - Jorge A Marrero
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, U.S.,Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, U.S
| | | | - Venugopalan Nair
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Manishkumar Patel
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, U.S
| | | | - Kathleen Corey
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, U.S
| | | | | | - David L Thomas
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, U.S
| | | | | | - Bin Zhang
- Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Scott L Friedman
- Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, U.S
| | - Thomas F Baumert
- Institut de Recherche sur les Maladies Virales et Hépatiques, Inserm U1110, University of Strasbourg, Strasbourg, France.,IHU, Pole hépato-digestif, Strasbourg University Hospitals, Strasbourg, France
| | - Bryan C Fuchs
- Department of Surgery, Massachusetts General Hospital, Boston, U.S., Ferring Pharmaceuticals, San Diego, U.S
| | - Kazuaki Chayama
- Collaborative Research Laboratory of Medical Innovation, Research Center for Hepatology and Gastroenterology, Hiroshima University, Hiroshima, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Shijia Zhu
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
| | - Raymond T Chung
- Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
| | - Yujin Hoshida
- Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas.
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31
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Kubota N, Fujiwara N, Hoshida Y. Liver cancer risk-predictive molecular biomarkers specific to clinico-epidemiological contexts. Adv Cancer Res 2022; 156:1-37. [PMID: 35961696 PMCID: PMC7616039 DOI: 10.1016/bs.acr.2022.01.005] [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] [Indexed: 11/24/2022]
Abstract
Hepatocellular carcinoma (HCC) risk prediction is increasingly important because of the low annual HCC incidence in patients with the rapidly emerging non-alcoholic fatty liver disease or cured HCV infection. To date, numerous clinical HCC risk biomarkers and scores have been reported in literature. However, heterogeneity in clinico-epidemiological context, e.g., liver disease etiology, patient race/ethnicity, regional environmental exposure, and lifestyle-related factors, obscure their real clinical utility and applicability. Proper characterization of these factors will help refine HCC risk prediction according to certain clinical context/scenarios and contribute to improved early HCC detection. Molecular factors underlying the clinical heterogeneity encompass various features in host genetics, hepatic and systemic molecular dysregulations, and cross-organ interactions, which may serve as clinical-context-specific biomarkers and/or therapeutic targets. Toward the goal to enable individual-risk-based HCC screening by incorporating the HCC risk biomarkers/scores, their assessment in patient with well-defined clinical context/scenario is critical to gauge their real value and to maximize benefit of the tailored patient management for substantial improvement of the poor HCC prognosis.
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Affiliation(s)
- Naoto Kubota
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Naoto Fujiwara
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States; Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Yujin Hoshida
- Liver Tumor Translational Research Program, Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, United States.
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32
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Klöhn M, Schrader JA, Brüggemann Y, Todt D, Steinmann E. Beyond the Usual Suspects: Hepatitis E Virus and Its Implications in Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:5867. [PMID: 34831021 PMCID: PMC8616277 DOI: 10.3390/cancers13225867] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2021] [Revised: 11/16/2021] [Accepted: 11/19/2021] [Indexed: 02/06/2023] Open
Abstract
Hepatitis E virus infections are the leading cause of viral hepatitis in humans, contributing to an estimated 3.3 million symptomatic cases and almost 44,000 deaths annually. Recently, HEV infections have been found to result in chronic liver infection and cirrhosis in severely immunocompromised patients, suggesting the possibility of HEV-induced hepatocarcinogenesis. While HEV-associated formation of HCC has rarely been reported, the expansion of HEV's clinical spectrum and the increasing evidence of chronic HEV infections raise questions about the connection between HEV and HCC. The present review summarizes current clinical evidence of the relationship between HEV and HCC and discusses mechanisms of virus-induced HCC development with regard to HEV pathogenesis. We further elucidate why the development of HEV-induced hepatocellular carcinoma has so rarely been observed and provide an outlook on possible experimental set-ups to study the relationship between HEV and HCC formation.
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Affiliation(s)
- Mara Klöhn
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
| | - Jil Alexandra Schrader
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
| | - Yannick Brüggemann
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
| | - Daniel Todt
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
- European Virus Bioinformatics Center (EVBC), 07743 Jena, Germany
| | - Eike Steinmann
- Department of Molecular and Medical Virology, Ruhr-Universität Bochum, 44801 Bochum, Germany; (M.K.); (J.A.S.); (Y.B.); (D.T.)
- German Centre for Infection Research (DZIF), External Partner Site, 44801 Bochum, Germany
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33
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Crouchet E, Schuster C, Baumert TF. Liver cell circuits and therapeutic discovery for advanced liver disease and cancer. C R Biol 2021; 344:233-248. [PMID: 35786628 PMCID: PMC7613418 DOI: 10.5802/crbiol.64] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 10/11/2021] [Indexed: 11/24/2022]
Abstract
Hepatocellular carcinoma (HCC) is a major global health challenge with rising incidence. Despite the previous approval of several novel therapeutic approaches, HCC remains the second common cause of cancer-related death worldwide. The vast majority of HCCs arises in the context of chronic fibrotic liver diseases caused by viral or metabolic etiologies. In patients with advanced liver disease the risk of HCC persists even after viral cure or control of infection. Moreover, given the change in the lifestyle and increase of obesity and metabolic disorders, HCC incidence is predicted to drastically augment in the next decade. Early detection, improvement of the screening method in patient at-risk and development of chemopreventive strategies are therefore urgently needed to reduce HCC risk. This review summarizes the major challenges in the identification of patient at risk for HCC and the emergent strategies for HCC prevention to improve patients’ outcome.
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