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Rigual MDM, Angulo-Aguado M, Zagorac S, Álvarez-Díaz R, Benítez-Mondéjar M, Yi F, Martínez-Garay C, Santos-de-Frutos K, Kim E, Campos-Olivas R, Djouder N. Macrophages harness hepatocyte glutamate to boost liver regeneration. Nature 2025:10.1038/s41586-025-08778-6. [PMID: 40140584 DOI: 10.1038/s41586-025-08778-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2023] [Accepted: 02/12/2025] [Indexed: 03/28/2025]
Abstract
Liver regeneration after hepatectomy follows accurate coordination with the body's specific requirements1-3. However, the molecular mechanisms, factors and particular hepatocyte population influencing its efficiency remain unclear. Here we report on a unique regeneration mechanism involving unconventional RPB5 prefoldin interactor 1 (URI1), which exclusively colocalizes with, binds to and activates glutamine synthase (GS) in pericentral hepatocytes. Genetic GS or URI1 depletion in mouse pericentral hepatocytes increases circulating glutamate levels, accelerating liver regeneration after two-third hepatectomy. Conversely, mouse hepatocytic URI1 overexpression hinders liver restoration, which can be reversed by elevating glutamate through supplementation or genetic GS depletion. Glutamate metabolically reprograms bone-marrow-derived macrophages, stabilizing HIF1α, which transcriptionally activates WNT3 to promote YAP1-dependent hepatocyte proliferation, boosting liver regeneration. GS regulation by URI1 is a mechanism that maintains optimal glutamate levels, probably to spatiotemporally fine-tune liver growth in accordance with the body's homeostasis and nutrient supply. Accordingly, in acute and chronic injury models, including in cirrhotic mice with low glutamate levels and in early mortality after liver resection, as well as in mice undergoing 90% hepatectomy, glutamate addition enhances hepatocyte proliferation and survival. Furthermore, URI1 and GS expression co-localize in human hepatocytes and correlate with WNT3 in immune cells across liver disease stages. Glutamate supplementation may therefore support liver regeneration, benefiting patients awaiting transplants or recovering from hepatectomy.
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Affiliation(s)
- María Del Mar Rigual
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Mariana Angulo-Aguado
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Sladjana Zagorac
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Ruth Álvarez-Díaz
- Bioinformatic Unit, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Marta Benítez-Mondéjar
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Fengming Yi
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Carlos Martínez-Garay
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Karla Santos-de-Frutos
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Eunjeong Kim
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
- KNU G-LAMP Research Center, KNU Institute of Basic Sciences, BK21 FOUR KNU Creative BioResearch Group, Department of Biology, College of Natural Sciences, Kyungpook National University, Daegu, South Korea
| | - Ramón Campos-Olivas
- Spectroscopy and Nuclear Magnetic Resonance Unit, Structural Biology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Nabil Djouder
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, Spain.
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2
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Lee SW, Kim J. Locking the Fate: How PROX1 Represses Plasticity and Liver Cancer. Cell Reprogram 2025. [PMID: 40135273 DOI: 10.1089/cell.2025.0013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025] Open
Abstract
A Transcriptional Ridge in the Waddington Landscape. The Waddington landscape model, proposed in 1957, provides a powerful framework for understanding cell fate determination (Waddington, 1957). As development progresses, cells become restricted to distinct fates, separated by high "ridges" that prevent identity switching. A recent study in Nature Genetics uncovers such a ridge in hepatocyte lineage specification (Lim et al., 2025). Lim et al. report that prospero homeobox protein 1 (PROX1) acts as a hepatocyte-specific safeguard repressor, ensuring lineage stability by actively suppressing alternative cell fates and preventing cholangiocarcinoma development.
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Affiliation(s)
- Seung-Won Lee
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University (OHSU), School of Medicine, Portland, Oregon, USA
| | - Jungsun Kim
- Cancer Early Detection Advanced Research Center, Knight Cancer Institute, Oregon Health & Science University (OHSU), School of Medicine, Portland, Oregon, USA
- Department of Molecular and Medical Genetics, OHSU School of Medicine, Portland, Oregon USA
- Cancer Biology Program, Knight Cancer Institute, OHSU School of Medicine, Portland, Oregon, USA
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3
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Lam WLM, Gabernet G, Poth T, Sator-Schmitt M, Oquendo MB, Kast B, Lohr S, de Ponti A, Weiß L, Schneider M, Helm D, Müller-Decker K, Schirmacher P, Heikenwälder M, Klingmüller U, Schneller D, Geisler F, Nahnsen S, Angel P. RAGE is a key regulator of ductular reaction-mediated fibrosis during cholestasis. EMBO Rep 2025; 26:880-907. [PMID: 39747668 PMCID: PMC11811172 DOI: 10.1038/s44319-024-00356-7] [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: 02/28/2024] [Revised: 12/09/2024] [Accepted: 12/13/2024] [Indexed: 01/04/2025] Open
Abstract
Ductular reaction (DR) is the hallmark of cholestatic diseases manifested in the proliferation of bile ductules lined by biliary epithelial cells (BECs). It is commonly associated with an increased risk of fibrosis and liver failure. The receptor for advanced glycation end products (RAGE) was identified as a critical mediator of DR during chronic injury. Yet, the direct link between RAGE-mediated DR and fibrosis as well as the mode of interaction between BECs and hepatic stellate cells (HSCs) to drive fibrosis remain elusive. Here, we delineate the specific function of RAGE on BECs during DR and its potential association with fibrosis in the context of cholestasis. Employing a biliary lineage tracing cholestatic liver injury mouse model, combined with whole transcriptome sequencing and in vitro analyses, we reveal a role for BEC-specific Rage activity in fostering a pro-fibrotic milieu. RAGE is predominantly expressed in BECs and contributes to DR. Notch ligand Jagged1 is secreted from activated BECs in a Rage-dependent manner and signals HSCs in trans, eventually enhancing fibrosis during cholestasis.
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Affiliation(s)
- Wai-Ling Macrina Lam
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
- Faculty of Biosciences, Ruprecht Karl University of Heidelberg, Heidelberg, Germany
| | - Gisela Gabernet
- Quantitative Biology Center (QBiC), Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Tanja Poth
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Melanie Sator-Schmitt
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Morgana Barroso Oquendo
- Quantitative Biology Center (QBiC), Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Bettina Kast
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Sabrina Lohr
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Aurora de Ponti
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Lena Weiß
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Martin Schneider
- Protein Analysis Unit, Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Dominic Helm
- Protein Analysis Unit, Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Karin Müller-Decker
- Tumor Models Unit, Center for Preclinical Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Peter Schirmacher
- Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Mathias Heikenwälder
- Division of Chronic Inflammation and Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ursula Klingmüller
- Division of Systems Biology of Signal Transduction, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Doris Schneller
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany
| | - Fabian Geisler
- TUM School of Medicine and Health, Department of Clinical Medicine - Clinical Department for Internal Medicine II, University Medical Center, Technical University of Munich, München, Germany
| | - Sven Nahnsen
- Quantitative Biology Center (QBiC), Eberhard Karls University of Tübingen, Tübingen, Germany
| | - Peter Angel
- Division of Signal Transduction and Growth Control, German Cancer Research Center (DKFZ), DKFZ-ZMBH Alliance, Heidelberg, Germany.
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Gong D, Mo J, Zhai M, Zhou F, Wang G, Ma S, Dai X, Deng X. Advances, challenges and future applications of liver organoids in experimental regenerative medicine. Front Med (Lausanne) 2025; 11:1521851. [PMID: 39927267 PMCID: PMC11804114 DOI: 10.3389/fmed.2024.1521851] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2024] [Accepted: 12/20/2024] [Indexed: 02/11/2025] Open
Abstract
The liver is a vital organ responsible for numerous metabolic processes in the human body, including the metabolism of drugs and nutrients. After liver damage, the organ can rapidly return to its original size if the causative factor is promptly eliminated. However, when the harmful stimulus persists, the liver's regenerative capacity becomes compromised. Substantial theoretical feasibility has been demonstrated at the levels of gene expression, molecular interactions, and intercellular dynamics, complemented by numerous successful animal studies. However, a robust model and carrier that closely resemble human physiology are still lacking for translating these theories into practice. The potential for liver regeneration has been a central focus of ongoing research. Over the past decade, the advent of organoid technology has provided improved models and materials for advancing research efforts. Liver organoid technology represents a novel in vitro culture system. After several years of refinement, human liver organoids can now accurately replicate the liver's morphological structure, nutrient and drug metabolism, gene expression, and secretory functions, providing a robust model for liver disease research. Regenerative medicine aims to replicate human organ or tissue functions to repair or replace damaged tissues, restore their structure or function, or stimulate the regeneration of tissues or organs within the body. Liver organoids possess the same structure and function as liver tissue, offering the potential to serve as a viable replacement for the liver, aligning with the goals of regenerative medicine. This review examines the role of liver organoids in regenerative medicine.
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Affiliation(s)
- Da Gong
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Jiaye Mo
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People’s Hospital, Shenzhen, China
- Guangxi University of Chinese Medicine, Nanning, China
| | - Mei Zhai
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People’s Hospital, Shenzhen, China
| | - Fulin Zhou
- Department of Clinical Medicine, Guizhou Medical University, Guiyang, China
| | - Guocai Wang
- Department of Physiology, School of Medicine and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
| | - Shaohua Ma
- Institute of Biopharmaceutical and Health Engineering, Shenzhen Key Laboratory of Gene and Antibody Therapy, State Key Laboratory of Chemical Oncogenomics, Tsinghua University Shenzhen International Graduate School, Guangdong, China
| | - Xiaoyong Dai
- Department of Physiology, School of Medicine and State Key Laboratory of Bioactive Molecules and Druggability Assessment, Jinan University, Guangzhou, China
- Institute of Biopharmaceutical and Health Engineering, Shenzhen Key Laboratory of Gene and Antibody Therapy, State Key Laboratory of Chemical Oncogenomics, Tsinghua University Shenzhen International Graduate School, Guangdong, China
| | - Xuesong Deng
- Department of Hepatobiliary Surgery, the First Affiliated Hospital of Shenzhen University, Health Science Center, Shenzhen Second People’s Hospital, Shenzhen, China
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5
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Safrastyan A, Wollny D. Detection of reproducible liver cancer specific ligand-receptor signaling in blood. FRONTIERS IN BIOINFORMATICS 2025; 4:1332782. [PMID: 39850635 PMCID: PMC11754192 DOI: 10.3389/fbinf.2024.1332782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2023] [Accepted: 12/24/2024] [Indexed: 01/25/2025] Open
Abstract
Cell-cell communication mediated by ligand-receptor interactions (LRI) is critical to coordinating diverse biological processes in homeostasis and disease. Lately, our understanding of these processes has greatly expanded through the inference of cellular communication, utilizing RNA extracted from bulk tissue or individual cells. Considering the challenge of obtaining tissue biopsies for these approaches, we considered the potential of studying cell-free RNA obtained from blood. To test the feasibility of this approach, we used the BulkSignalR algorithm across 295 cell-free RNA samples and compared the LRI profiles across multiple cancer types and healthy donors. Interestingly, we detected specific and reproducible LRIs particularly in the blood of liver cancer patients compared to healthy donors. We found an increase in the magnitude of hepatocyte interactions, notably hepatocyte autocrine interactions in liver cancer patients. Additionally, a robust panel of 30 liver cancer-specific LRIs presents a bridge linking liver cancer pathogenesis to discernible blood markers. In summary, our approach shows the plausibility of detecting liver LRIs in blood and builds upon the biological understanding of cell-free transcriptomes.
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Affiliation(s)
- Aram Safrastyan
- RNA Bioinformatics and High Throughput Analysis, Friedrich Schiller University Jena, Jena, Germany
- Genetics and Epigenetics of Aging, Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany
| | - Damian Wollny
- RNA Bioinformatics and High Throughput Analysis, Friedrich Schiller University Jena, Jena, Germany
- Genetics and Epigenetics of Aging, Leibniz Institute on Aging-Fritz Lipmann Institute (FLI), Jena, Germany
- Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany
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6
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Rattanasinchai C, Navasumrit P, Chornkrathok C, Ruchirawat M. Kinase library screening identifies IGF-1R as an oncogenic vulnerability in intrahepatic cholangiocarcinoma stem-like cells. Biochim Biophys Acta Mol Basis Dis 2025; 1871:167521. [PMID: 39369614 DOI: 10.1016/j.bbadis.2024.167521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Revised: 09/05/2024] [Accepted: 09/16/2024] [Indexed: 10/08/2024]
Abstract
BACKGROUND Intrahepatic cholangiocarcinoma (iCCA) is a highly aggressive cancer of the peripheral bile ducts and is recognized by the abundance of cancer stem-like cells (CSCs) within the tumor mass. While CSC markers in iCCA are well-defined, the molecular vulnerabilities of this subpopulation remain elusive. METHODS The 96-well, three dimensional (3D) tumorsphere culture was adapted from a well-established CSC model, validated for CSC markers through gene expression analysis. Kinase library screening was then conducted to reveal potential oncogenic vulnerable pathways. RNA interference was utilized to stably silence the candidate gene in three iCCA cell lines and its impact on iCCA cell proliferation and tumorsphere formation efficiency (TFE) was evaluated. RESULTS Kinase inhibitor library screening identified the top 50 kinase inhibitors crucial for tumorsphere viability, with 11 inhibitors targeting the IGF-1R/PI3K/AKT axis. Further dose-dependent analysis of the top 'hit' inhibitors confirmed IGF-1R as the candidate molecule. Upon stably silencing of IGF-1R, all three iCCA cell lines exhibited decreased AKT activation, impeded proliferation and reduced TFE, indicating a decline in CSC subpopulations. CONCLUSIONS IGF-1R plays a critical role in maintaining iCCA-stem like cell populations. GENERAL SIGNIFICANCE Our data highlight the potential utility of IGF-1R as a prognostic marker of iCCA and a therapeutic target for eliminating its CSC subpopulation.
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Affiliation(s)
- Chotirat Rattanasinchai
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10300, Thailand
| | - Panida Navasumrit
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10300, Thailand
| | - Chidchanok Chornkrathok
- Laboratory of Chemical Carcinogenesis, Chulabhorn Research Institute, Bangkok, 10210, Thailand
| | - Mathuros Ruchirawat
- Laboratory of Environmental Toxicology, Chulabhorn Research Institute, Bangkok 10210, Thailand; Center of Excellence on Environmental Health and Toxicology, CHE, Ministry of Education, Bangkok 10300, Thailand.
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7
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Grazioso TP, del Mar Rigual M, Perna C, Caleiras EJ, Djouder N. Cold exposure reinstates NAD + levels and attenuates hepatocellular carcinoma. Cell Stress 2024; 8:125-139. [PMID: 39781363 PMCID: PMC11708783 DOI: 10.15698/cst2024.12.302] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 12/03/2024] [Accepted: 12/05/2024] [Indexed: 01/12/2025] Open
Abstract
Cold exposure has been historically used for medicinal purposes, but its benefits and associated mechanisms in mammalian organisms still remain unclear. Here, we explore the chemoprotective properties of cold temperature using a mouse model of hepatocellular carcinoma (HCC) that recapitulates several human features. Chronic cold exposure is shown to prolong lifespan in diseased mice, enhance liver health, and suppress the development of aggressive HCC, preventing hepatocellular hypertrophy, high-grade oval cell hyperplasia, liver steatosis, and aberrant hepatocyte hyperproliferation. Mechanistically, exposure to cold temperatures reinstates NAD+ levels in the HCC mouse models that originally exhibited low NAD+ levels, a contributing process to the development of liver tumors. These findings uncover the role of cold therapy to attenuate HCC development and potentially other existing malignancies involving NAD+ modulation.
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Affiliation(s)
- Tatiana P Grazioso
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO)Madrid, ES28029Spain
- Instituto de Investigación Sanitaria HM Hospitales (IISHM)MadridSpain
- Laboratory of Innovation in Oncology, Gynecological, Genitourinary and Skin Cancer Unit, HM CIOCC, Centro Integral Oncológico Clara Campal, Hospital Universitario HM Sanchinarro, HM HospitalesMadrid, ES-28050Spain
| | - Maria del Mar Rigual
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO)Madrid, ES28029Spain
| | - Cristian Perna
- Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCISMadrid, ES28034Spain
- Universidad de AlcaláMadrid, ES28801Spain
| | | | - Nabil Djouder
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas (CNIO)Madrid, ES28029Spain
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8
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Draškovič T, Ranković B, Zidar N, Hauptman N. Upregulation of ABLIM1 Differentiates Intrahepatic Cholangiocarcinoma from Hepatocellular Carcinoma and Both Colorectal and Pancreatic Adenocarcinoma Liver Metastases. Genes (Basel) 2024; 15:1545. [PMID: 39766812 PMCID: PMC11675665 DOI: 10.3390/genes15121545] [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: 10/19/2024] [Revised: 11/22/2024] [Accepted: 11/26/2024] [Indexed: 01/11/2025] Open
Abstract
BACKGROUND Altered gene expression in cancers holds great potential to improve the diagnostics and differentiation of primary and metastatic liver cancers. In this study, the expression of the protein-coding genes ring finger protein 135 (RNF135), ephrin-B2 (EFNB2), ring finger protein 125 (RNF125), homeobox-C 4 (HOXC4), actin-binding LIM protein 1 (ABLIM1) and oncostatin M receptor (OSMR) and the long non-coding RNAs (lncRNA) prospero homeobox 1 antisense RNA 1 (PROX1-AS1) and leukemia inhibitory factor receptor antisense RNA 1 (LIFR-AS1) was investigated in hepatocellular carcinoma, cholangiocarcinoma, colorectal liver metastases and pancreatic ductal adenocarcinoma liver metastases. METHODS This study included 149 formalin-fixed, paraffin-embedded samples from 80 patients. After RNA isolation, quantification, reverse transcription and preamplification, real-time qPCR was performed. The gene expression between different groups was calculated relative to the expression of the reference genes using the ∆∆Cq method and statistically analyzed. The expression of the genes was additionally analyzed using the AmiCA and UCSC Xena platforms. RESULTS In primary cancers, our results showed differential expression between primary tumors and healthy tissues for all the genes and lncRNA examined. Moreover, we found downregulation of RNF135 in hepatocellular carcinoma, downregulation of OSMR in colorectal liver metastases and upregulation of HOXC4 in cholangiocarcinoma compared to primary liver cancers and metastatic cancers. The major finding is the upregulation of ABLIM1 in cholangiocarcinoma compared to hepatocellular carcinoma, colorectal liver metastases, pancreatic ductal adenocarcinoma liver metastases and healthy liver tissue. We propose ABLIM1 as a potential biomarker that differentiates cholangiocarcinoma from other cancers and healthy liver tissue. CONCLUSIONS This study emphasizes the importance of understanding the differences in gene expression between healthy tissues and primary and metastatic cancers and highlights the potential use of altered gene expression as a diagnostic biomarker in these malignancies.
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Affiliation(s)
| | | | | | - Nina Hauptman
- Institute of Pathology, Faculty of Medicine, University of Ljubljana, 1000 Ljubljana, Slovenia; (T.D.); (B.R.); (N.Z.)
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Xiao Z, Yang F, Liu Z, Chen X, Ma S, Li H. An overview of risk assessment and monitoring of malignant transformation in cirrhotic nodules. Therap Adv Gastroenterol 2024; 17:17562848241293019. [PMID: 39493259 PMCID: PMC11528798 DOI: 10.1177/17562848241293019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/13/2024] [Accepted: 10/04/2024] [Indexed: 11/05/2024] Open
Abstract
Cirrhotic liver nodules can progress to hepatocellular carcinoma (HCC) through a multi-step carcinogenesis model, with dysplastic nodules being particularly high risk. Currently, monitoring the progression of non-HCC cirrhotic nodules is primarily through dynamic observation, but there is a lack of sensitive, efficient, and convenient methods. Dynamic monitoring and risk evaluation of malignant transformation are essential for timely treatment and improved patient survival rates. Routine liver biopsies are impractical for monitoring, and imaging techniques like ultrasound, computed tomography, and magnetic resonance imaging are not suitable for all patients or for accurately assessing subcentimeter nodules. Identifying serum biomarkers with high sensitivity, specificity, and stability, and developing a multi-index evaluation model, may provide a more convenient and efficient approach to monitoring pathological changes in cirrhotic nodules.
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Affiliation(s)
- Zhun Xiao
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Fangming Yang
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Zheng Liu
- Department of Combination of Traditional Chinese Medicine and Western Medicine, Medical College, Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Xinju Chen
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou, Henan, China
| | - Suping Ma
- Department of Digestive Diseases, The First Affiliated Hospital of Henan University of Chinese Medicine, No. 19 Renmin Road, Zhengzhou 450000, China
| | - Heng Li
- Yong Loo Lin School of Medicine, National University of Singapore, 28 Medical Drive, Singapore 117456, Singapore
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10
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Zhu Y, Liu W, Luo Z, Xiao F, Sun B. New insights into the roles of lactylation in cancer. Front Pharmacol 2024; 15:1412672. [PMID: 39502530 PMCID: PMC11534861 DOI: 10.3389/fphar.2024.1412672] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2024] [Accepted: 10/10/2024] [Indexed: 11/08/2024] Open
Abstract
Lactylation, a novel discovered posttranslational modification, is a vital component of lactate function and is prevalent in a wide range of cells, interacting with both histone and non-histone proteins. Recent studies have confirmed that lactylation as a new contributor to epigenetic landscape is involved in multiple pathological processes. Accumulating evidence reveals that lactylation exists in different pathophysiological states and leads to inflammation and cancer; however, few mechanisms of lactylation have been elaborated. This review summarizes the biological processes and pathophysiological roles of lactylation in cancer, as well as discusses the relevant mechanisms and potential therapeutic targets, aiming to provide new insights for targeted cancer therapy.
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Affiliation(s)
- Yajun Zhu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Wenhui Liu
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Zhiying Luo
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
| | - Feiyan Xiao
- Center for Clinical Trial and Research, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Bao Sun
- Department of Pharmacy, The Second Xiangya Hospital, Central South University, Changsha, China
- Institute of Clinical Pharmacy, Central South University, Changsha, China
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11
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Chen M, Chen W, Sun S, Lu Y, Wu G, Xu H, Yang H, Li C, He W, Xu M, Li X, Jiang D, Cai Y, Liu C, Zhang W, He Z. CDK4/6 inhibitor PD-0332991 suppresses hepatocarcinogenesis by inducing senescence of hepatic tumor-initiating cells. J Adv Res 2024:S2090-1232(24)00374-6. [PMID: 39218249 DOI: 10.1016/j.jare.2024.08.034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2024] [Revised: 08/08/2024] [Accepted: 08/26/2024] [Indexed: 09/04/2024] Open
Abstract
INTRODUCTION Owing to the limited treatment options for hepatocellular carcinoma (HCC), interventions targeting pre-HCC stages have attracted increasing attention. In the pre-HCC stage, hepatic tumor-initiating cells (hTICs) proliferate abnormally and contribute to hepatocarcinogenesis. Numerous studies have investigated targeted senescence induction as an HCC intervention. However, it remains to be clarified whether senescence induction of hTICs could serve as a pre-HCC intervention. OBJECTIVES This study was designed to investigate whether senescence induction of hTICs in the precancerous stage inhibit HCC initiation. METHODS AND RESULTS HCC models developed from chronic liver injury (CLI) were established by using Fah-/- mice and N-Ras + AKT mice. PD-0332991, a selective CDK4/6 inhibitor that blocks the G1/S transition in proliferating cells, was used to induce senescence during the pre-HCC stage. Upon administration of PD-0332991, we observed a significant reduction in HCC incidence following selective senescence induction in hTICs, and an alleviation liver injury in the CLI-HCC models. PD-0332991 also induced senescence in vitro in cultured hTICs isolated from CLI-HCC models. Moreover, RNA sequencing (RNA-seq) analysis delineated that the "Cyclin D-CDK4/6-INK4-Rb" pathway was activated in both mouse and human liver samples during the pre-HCC stage, while PD-0332991 exhibited substantial inhibition of this pathway, thereby inducing cellular senescence in hTICs. Regarding the immune microenvironment, we demonstrated that senescent hTICs secrete key senescence-associated secretory phenotypic (SASP) factors, CXCL10 and CCL2, to activate and recruit macrophages, and contribute to immune surveillance. CONCLUSION We found that hTICs can be targeted and induced into a senescent state during the pre-HCC stage. The SASP factors released by senescent hTICs further activate the immune response, facilitating the clearance of hTICs, and consequently suppressing HCC occurrence. We highlight the importance of pre-HCC interventions and propose that senescence-inducing drugs hold promise for preventing HCC initiation under CLI.
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Affiliation(s)
- Miaomiao Chen
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Wenjian Chen
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Shiwen Sun
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Yanli Lu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Guoxiu Wu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Hongyu Xu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Huiru Yang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Chong Li
- Zhoupu Community Health Service Center of Pudong New Area, Shanghai, China
| | - Weizhi He
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Mingyang Xu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Xiuhua Li
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Dong Jiang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Yongchao Cai
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Changcheng Liu
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Wencheng Zhang
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China
| | - Zhiying He
- Institute for Regenerative Medicine, Medical Innovation Center and State Key Laboratory of Cardiology, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200123, P. R. China; Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai 200335, P. R. China; Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai 200120, P. R. China.
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Reddy VKK, Shiddapur G, Jagdale N, Kondapalli MP, Adapa S. Investigating Interleukin-6 Levels in Type 2 Diabetes Mellitus Patients With and Without Diabetic Nephropathy. Cureus 2024; 16:e67014. [PMID: 39280507 PMCID: PMC11402502 DOI: 10.7759/cureus.67014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2024] [Accepted: 08/16/2024] [Indexed: 09/18/2024] Open
Abstract
BACKGROUND AND OBJECTIVE Diabetic nephropathy (DN), a severe complication affecting 40% of diabetic individuals, is a leading cause of chronic kidney disease (CKD). It involves a progressive increase in urinary albumin and a decline in the glomerular filtration rate. Early detection and intervention are crucial to preventing CKD progression. The current marker, albuminuria, measured as the urine albumin-to-creatinine ratio (UACR), has limitations, highlighting the need for alternative biomarkers. Researchers have linked the proinflammatory cytokine interleukin-6 (IL-6) to the progression of DN, observing elevated levels in DN patients compared to those without DN. IL-6 also regulates glucose metabolism, promoting insulin effectiveness and secretion. Inflammation and glucose control are two things that IL-6 does. This makes it a promising biomarker and therapeutic target for DN and type 2 diabetes mellitus (T2DM). This study focuses on IL-6 levels in T2DM patients with and without DN. METHODS AND MATERIALS From September 2022 to June 2024, the Department of General Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed to be University), Pune, conducted an observational cross-sectional comparative study on 80 T2DM patients, with 40 in group A (cases = T2DM patients with DN) and 40 in group B (controls = T2DM patients without DN). The study included patients with T2DM between the ages of 40 and 80. The study excludes conditions such as diabetic ketoacidosis, patients with end-stage renal disease, and conditions that increase IL-6, such as COVID-19. The study excluded autoimmune conditions with elevated IL-6, such as rheumatoid arthritis, systemic lupus erythematous, ankylosing spondylitis, psoriasis, and Crohn's disease. We obtained ethical approval and written consent from participants. RESULTS In the current study, 61 patients (76.2%) were 60 years old or younger, while 19 patients (23.8%) were older than 60 years. Among the participants, 38 were females (47.5%) and 42 were males (52.5%). The case group, which consisted of 40 T2DM patients with DN, had a mean glycated hemoglobin (HbA1c) of 7.1700 ± 0.71044. In contrast, the control group, comprising 40 T2DM patients without DN, had a mean HbA1c of 6.8650 ± 0.57179. This difference was statistically significant, with a p value of 0.038. Additionally, the mean UACR in the case group was 134.34 ± 95.56, significantly higher than the control group's mean UACR of 22.32 ± 9.90. This difference was highly significant, with a p value of 0.001. Furthermore, the case group exhibited elevated mean IL-6 levels of 15.48 ± 4.27 compared to the control group's 7.02 ± 2.46, which is also highly significant, reflected by a p value of 0.001. CONCLUSION As the concentration of IL-6 rises in diabetic patients with nephropathy, this study suggests that IL-6 may have an effect on the development of DN. This cytokine is necessary for both the initiation and progression of the condition. Using IL-6 as a supportive diagnostic test could help rule out other potential causes of DN in T2DM. Moreover, this marker does not require invasive procedures, and early measurement may help reduce mortality and morbidity.
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Affiliation(s)
- Vutukuru Kalyan Kumar Reddy
- Department of General Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed to be University), Pune, IND
| | - Govind Shiddapur
- Department of General Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed to be University), Pune, IND
| | - Nilesh Jagdale
- Department of General Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed to be University), Pune, IND
| | - Mohith Prakash Kondapalli
- Department of General Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed to be University), Pune, IND
| | - Saimounika Adapa
- Department of General Medicine, Dr. D. Y. Patil Medical College, Hospital and Research Centre, Dr. D. Y. Patil Vidyapeeth (Deemed to be University), Pune, IND
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Singh D, Khan MA, Mishra D, Goel A, Ansari MA, Akhtar K, Siddique HR. Apigenin enhances sorafenib anti-tumour efficacy in hepatocellular carcinoma. Transl Oncol 2024; 43:101920. [PMID: 38394865 PMCID: PMC10899070 DOI: 10.1016/j.tranon.2024.101920] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 02/10/2024] [Accepted: 02/19/2024] [Indexed: 02/25/2024] Open
Abstract
BACKGROUND The "one drug-one target" paradigm has various limitations affecting drug efficacy, such as resistance profiles and adverse effects. Combinational therapies help reduce unexpected off-target effects and accelerate therapeutic efficacy. Sorafenib- an FDA-approved drug for liver cancer, has multiple limitations. Therefore, it is recommended to identify an agent that increases its effectiveness and reduces toxicity. In this regard, Apigenin, a plant flavone, would be an excellent option to explore. METHODS We used in silico, in vitro, and animal models to explore our hypothesis. For the in vitro study, HepG2 and Huh7 cells were exposed to Apigenin (12-96 μM) and Sorafenib (1-10 μM). For the in vivo study, Diethylnitrosamine (DEN) (25 mg/kg) induced tumor-bearing animals were given Apigenin (50 mg/kg) or Sorafenib (10 mg/kg) alone and combined. Apigenin's bioavailability was checked by UPLC. Tumor nodules were studied macroscopically and by Scanning Electron Microscopy (SEM). Biochemical analysis, histopathology, immunohistochemistry, and qRT-PCR were done. RESULTS The results revealed Apigenin's good bioavailability. In silico study showed binding affinity of both chemicals with p53, NANOG, ß-Catenin, c-MYC, and TLR4. We consistently observed a better therapeutic efficacy in combination than alone treatment. Combination treatment showed i) better cytotoxicity, apoptosis induction, and cell cycle arrest of tumor cells, ii) tumor growth reduction, iii) increased expression of p53 and decreased Cd10, Nanog, ß-Catenin, c-Myc, Afp, and Tlr4. CONCLUSIONS In conclusion, Apigenin could enhance the therapeutic efficacy of Sorafenib against liver cancer and may be a promising therapeutic approach for treating HCC. However, further research is imperative to gain more in-depth mechanistic insights.
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Affiliation(s)
- Deepti Singh
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Mohammad Afsar Khan
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India
| | - Dhruv Mishra
- Department of Zoology, DAV College (PG), Maa Shakumbhari University, Muzaffarnagar-251001, India
| | - Aditya Goel
- Department of Biotechnology, SCLS, Jamia Hamdard University, New Delhi 110062, India
| | - Mairaj Ahmed Ansari
- Department of Biotechnology, SCLS, Jamia Hamdard University, New Delhi 110062, India
| | - Kafil Akhtar
- Department of Pathology, JN Medical College, Aligarh Muslim University, Aligarh 202002, India
| | - Hifzur R Siddique
- Molecular Cancer Genetics & Translational Research Lab, Section of Genetics, Department of Zoology, Aligarh Muslim University, Aligarh 202002, India.
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Fan G, Xie T, Li L, Tang L, Han X, Shi Y. Single-cell and spatial analyses revealed the co-location of cancer stem cells and SPP1+ macrophage in hypoxic region that determines the poor prognosis in hepatocellular carcinoma. NPJ Precis Oncol 2024; 8:75. [PMID: 38521868 PMCID: PMC10960828 DOI: 10.1038/s41698-024-00564-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 03/07/2024] [Indexed: 03/25/2024] Open
Abstract
In hepatocellular carcinoma (HCC), classical cancer stem cells (CSC) markers were shared by normal stem cells, targeting which may hinder hepatic regeneration and cause liver failure. Additionally, the spatial structure of CSC still remained elusive. To address these limitations, we undertook a comprehensive study combining single-cell data (56,022 cells from 20 samples) and spatial data (38,191 spots from eight samples) to obtain CSC signature and uncover its spatial structure. Utilizing the CytoTRACE algorithm, we discretely identified CSC, which displayed upregulated proliferation pathways regulated by HIF1A. A CSC signature of 107 genes was then developed using Weighted Gene Co-expression Network Analysis (WGCNA). Notably, HCC patients with high CSC levels exhibited an accumulation of SPP1+ macrophages (Macro_SPP1) expressing metalloproteinases (MMP9, MMP12, and MMP7) regulated by HIF1A, suggesting a hypoxic tumor region connecting Macro_SPP1 and CSC. Both CSC and Macro_SPP1 correlated with worse prognosis and undesirable immunotherapy response. Spatial analysis revealed the co-location of CSC and Macro_SPP1, with CD8 T cells excluded from the tumor region. The co-location area and non-tumor area of boundary exhibited a high level of hypoxia, with the HAVRC2 checkpoint highly expressed. Within the co-location area, the SPP1 signaling pathway was most active in cell-cell communication, with SPP1-CD44 and SPP1-ITGA/ITGB identified as the main ligand-receptor pairs. This study successfully constructed a CSC signature and demonstrated the co-location of CSC and Macro_SPP1 in a hypoxic region that exacerbates the tumor microenvironment in HCC.
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Affiliation(s)
- Guangyu Fan
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs; No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Tongji Xie
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs; No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Lin Li
- Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100021, China
| | - Le Tang
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs; No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China
| | - Xiaohong Han
- Clinical Pharmacology Research Center, Peking Union Medical College Hospital, State Key Laboratory of Complex Severe and Rare Diseases, NMPA Key Laboratory for Clinical Research and Evaluation of Drug, Beijing Key Laboratory of Clinical PK & PD Investigation for Innovative Drugs, Chinese Academy of Medical Sciences & Peking Union Medical College; No.1, Shuaifuyuan, Dongcheng District, Beijing, 100730, China.
| | - Yuankai Shi
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing Key Laboratory of Clinical Study on Anticancer Molecular Targeted Drugs; No. 17 Panjiayuan Nanli, Chaoyang District, Beijing, 100021, China.
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Cuesta ÁM, Palao N, Bragado P, Gutierrez-Uzquiza A, Herrera B, Sánchez A, Porras A. New and Old Key Players in Liver Cancer. Int J Mol Sci 2023; 24:17152. [PMID: 38138981 PMCID: PMC10742790 DOI: 10.3390/ijms242417152] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
Liver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also be candidates in specific cases, as discussed here. HCC usually develops in a context of chronic inflammation, fibrosis, and cirrhosis, although the role of fibrosis is controversial. The interplay between hepatocytes, immune cells and hepatic stellate cells is a key issue. This review summarizes critical aspects of the liver tumor microenvironment paying special attention to platelets as new key players, which exert both pro- and anti-tumor effects, determined by specific contexts and a tight regulation of platelet signaling. Additionally, the relevance of specific signaling pathways, mainly HGF/MET, EGFR and TGF-β is discussed. HGF and TGF-β are produced by different liver cells and platelets and regulate not only tumor cell fate but also HPCs, inflammation and fibrosis, these being key players in these processes. The role of C3G/RAPGEF1, required for the proper function of HGF/MET signaling in HCC and HPCs, is highlighted, due to its ability to promote HCC growth and, regulate HPC fate and platelet-mediated actions on liver cancer.
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Affiliation(s)
- Ángel M. Cuesta
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Nerea Palao
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Paloma Bragado
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Alvaro Gutierrez-Uzquiza
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Blanca Herrera
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD-ISCIII), 28040 Madrid, Spain
| | - Aránzazu Sánchez
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD-ISCIII), 28040 Madrid, Spain
| | - Almudena Porras
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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Jiang M, Ren J, Belmonte JCI, Liu GH. Hepatocyte reprogramming in liver regeneration: Biological mechanisms and applications. FEBS J 2023; 290:5674-5688. [PMID: 37556833 DOI: 10.1111/febs.16930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2023] [Revised: 07/17/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023]
Abstract
The liver is one of the few organs that retain the capability to regenerate in adult mammals. This regeneration process is mainly facilitated by the dynamic behavior of hepatocytes, which are the major functional constituents in the liver. In response to liver injury, hepatocytes undergo remarkable alterations, such as reprogramming, wherein they lose their original identity and acquire properties from other cells. This phenomenon of hepatocyte reprogramming, coupled with hepatocyte expansion, plays a central role in liver regeneration, and its underlying mechanisms are complex and multifaceted. Understanding the fate of reprogrammed hepatocytes and the mechanisms of their conversion has significant implications for the development of innovative therapeutics for liver diseases. Herein, we review the plasticity of hepatocytes in response to various forms of liver injury, with a focus on injury-induced hepatocyte reprogramming. We provide a comprehensive summary of current knowledge on the molecular and cellular mechanisms governing hepatocyte reprogramming, specifically in the context of liver regeneration, providing insight into potential applications of this process in the treatment of liver disorders, including chronic liver diseases and liver cancer.
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Affiliation(s)
- Mengmeng Jiang
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
| | - Jie Ren
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Key Laboratory of RNA Science and Engineering, CAS Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences and China National Center for Bioinformation, Beijing, China
- Sino-Danish College, University of Chinese Academy of Sciences, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- School of Future Technology, University of Chinese Academy of Sciences, Beijing, China
| | | | - Guang-Hui Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China
- Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beijing, China
- Beijing Institute for Stem Cell and Regenerative Medicine, Beijing, China
- Aging Biomarker Consortium, Beijing, China
- University of Chinese Academy of Sciences, Beijing, China
- Advanced Innovation Center for Human Brain Protection, and National Clinical Research Center for Geriatric Disorders, Xuanwu Hospital Capital Medical University, Beijing, China
- Aging Translational Medicine Center, International Center for Aging and Cancer, Xuanwu Hospital, Capital Medical University, Beijing, China
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Fu X, Zhang Y, Luo Q, Ju Y, Song G. Targeting the mechano-microenvironment and liver cancer stem cells: a promising therapeutic strategy for liver cancer. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0229. [PMID: 38009775 PMCID: PMC10690881 DOI: 10.20892/j.issn.2095-3941.2023.0229] [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: 06/24/2023] [Accepted: 10/30/2023] [Indexed: 11/29/2023] Open
Abstract
Over the past 2 decades, cancer stem cells (CSCs) have been identified as the root cause of cancer occurrence, progression, chemoradioresistance, recurrence, and metastasis. Targeting CSCs is a novel therapeutic strategy for cancer management and treatment. Liver cancer (LC) is a malignant disease that can endanger human health. Studies are increasingly suggesting that changes in the liver mechanical microenvironment are a primary driver triggering the occurrence and development of liver cancer. In this review, we summarize current understanding of the roles of the liver mechano-microenvironment and liver cancer stem cells (LCSCs) in liver cancer progression. We also discuss the relationship between the mechanical heterogeneity of liver cancer tissues and LCSC recruitment and metastasis. Finally, we highlight potential mechanosensitive molecules in LCSCs and mechanotherapy in liver cancer. Understanding the roles and regulatory mechanisms of the mechano-microenvironment and LCSCs may provide fundamental insights into liver cancer progression and aid in further development of novel therapeutic strategies.
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Affiliation(s)
- Xiaorong Fu
- School of Biology and Engineering, Guizhou Medical University, Guiyang 550000, China
- College of Bioengineering, Chongqing University, Chongqing 400030, China
- Department of Mechanical Science and Engineering, Nagoya University, Nagoya 4648603, Japan
| | - Yi Zhang
- Department of Mechanical Science and Engineering, Nagoya University, Nagoya 4648603, Japan
| | - Qing Luo
- College of Bioengineering, Chongqing University, Chongqing 400030, China
| | - Yang Ju
- Department of Mechanical Science and Engineering, Nagoya University, Nagoya 4648603, Japan
| | - Guanbin Song
- College of Bioengineering, Chongqing University, Chongqing 400030, China
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Pandkar MR, Sinha S, Samaiya A, Shukla S. Oncometabolite lactate enhances breast cancer progression by orchestrating histone lactylation-dependent c-Myc expression. Transl Oncol 2023; 37:101758. [PMID: 37572497 PMCID: PMC10425713 DOI: 10.1016/j.tranon.2023.101758] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 07/22/2023] [Accepted: 08/07/2023] [Indexed: 08/14/2023] Open
Abstract
Due to the enhanced glycolytic rate, cancer cells generate lactate copiously, subsequently promoting the lactylation of histones. While previous studies have explored the impact of histone lactylation in modulating gene expression, the precise role of this epigenetic modification in regulating oncogenes is largely unchartered. In this study, using breast cancer cell lines and their mutants exhibiting lactate-deficient metabolome, we have identified that an enhanced rate of aerobic glycolysis supports c-Myc expression via promoter-level histone lactylation. Interestingly, c-Myc further transcriptionally upregulates serine/arginine splicing factor 10 (SRSF10) to drive alternative splicing of MDM4 and Bcl-x in breast cancer cells. Moreover, our results reveal that restricting the activity of critical glycolytic enzymes affects the c-Myc-SRSF10 axis to subside the proliferation of breast cancer cells. Our findings provide novel insights into the mechanisms by which aerobic glycolysis influences alternative splicing processes that collectively contribute to breast tumorigenesis. Furthermore, we also envisage that chemotherapeutic interventions attenuating glycolytic rate can restrict breast cancer progression by impeding the c-Myc-SRSF10 axis.
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Affiliation(s)
- Madhura R Pandkar
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, India. https://twitter.com/https://twitter.com/MadhuraPandkar
| | - Sommya Sinha
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, India. https://twitter.com/https://twitter.com/sinha_sommya
| | - Atul Samaiya
- Department of Surgical Oncology, Bansal Hospital, Bhopal, Madhya Pradesh 462016, India
| | - Sanjeev Shukla
- Department of Biological Sciences, Indian Institute of Science Education and Research Bhopal, Bhopal, Madhya Pradesh 462066, India.
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Domènech Omella J, Cortesi EE, Verbinnen I, Remmerie M, Wu H, Cubero FJ, Roskams T, Janssens V. A Novel Mouse Model of Combined Hepatocellular-Cholangiocarcinoma Induced by Diethylnitrosamine and Loss of Ppp2r5d. Cancers (Basel) 2023; 15:4193. [PMID: 37627221 PMCID: PMC10453342 DOI: 10.3390/cancers15164193] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 08/11/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
Primary liver cancer (PLC) can be classified in hepatocellular (HCC), cholangiocarcinoma (CCA), and combined hepatocellular-cholangiocarcinoma (cHCC-CCA). The molecular mechanisms involved in PLC development and phenotype decision are still not well understood. Complete deletion of Ppp2r5d, encoding the B56δ subunit of Protein Phosphatase 2A (PP2A), results in spontaneous HCC development in mice via a c-MYC-dependent mechanism. In the present study, we aimed to examine the role of Ppp2r5d in an independent mouse model of diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Ppp2r5d deletion (heterozygous and homozygous) accelerated HCC development, corroborating its tumor-suppressive function in liver and suggesting Ppp2r5d may be haploinsufficient. Ppp2r5d-deficient HCCs stained positively for c-MYC, consistent with increased AKT activation in pre-malignant and tumor tissues of Ppp2r5d-deficient mice. We also found increased YAP activation in Ppp2r5d-deficient tumors. Remarkably, in older mice, Ppp2r5d deletion resulted in cHCC-CCA development in this model, with the CCA component showing increased expression of progenitor markers (SOX9 and EpCAM). Finally, we observed an upregulation of Ppp2r5d in tumors from wildtype and heterozygous mice, revealing a tumor-specific control mechanism of Ppp2r5d expression, and suggestive of the involvement of Ppp2r5d in a negative feedback regulation restricting tumor growth. Our study highlights the tumor-suppressive role of mouse PP2A-B56δ in both HCC and cHCC-CCA, which may have important implications for human PLC development and targeted treatment.
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Affiliation(s)
- Judit Domènech Omella
- Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), 3000 Leuven, Belgium; (J.D.O.); (I.V.); (M.R.)
| | - Emanuela E. Cortesi
- Translational Cell & Tissue Research, University of Leuven (KU Leuven), 3000 Leuven, Belgium; (E.E.C.); (T.R.)
| | - Iris Verbinnen
- Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), 3000 Leuven, Belgium; (J.D.O.); (I.V.); (M.R.)
| | - Michiel Remmerie
- Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), 3000 Leuven, Belgium; (J.D.O.); (I.V.); (M.R.)
| | - Hanghang Wu
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (F.J.C.)
| | - Francisco J. Cubero
- Department of Immunology, Ophthalmology & ENT, Complutense University School of Medicine, 28040 Madrid, Spain; (H.W.); (F.J.C.)
- Health Research Institute Gregorio Marañón (IiSGM), 28007 Madrid, Spain
- Centre for Biomedical Research, Network on Liver and Digestive Diseases (CIBEREHD), 28029 Madrid, Spain
| | - Tania Roskams
- Translational Cell & Tissue Research, University of Leuven (KU Leuven), 3000 Leuven, Belgium; (E.E.C.); (T.R.)
- Department of Pathology, University Hospitals Leuven (UZ Leuven), 3000 Leuven, Belgium
| | - Veerle Janssens
- Laboratory of Protein Phosphorylation & Proteomics, Department of Cellular & Molecular Medicine, University of Leuven (KU Leuven), 3000 Leuven, Belgium; (J.D.O.); (I.V.); (M.R.)
- KU Leuven Cancer Institute (LKI), 3000 Leuven, Belgium
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20
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Kaps L, Limeres MJ, Schneider P, Svensson M, Zeyn Y, Fraude S, Cacicedo ML, Galle PR, Gehring S, Bros M. Liver Cell Type-Specific Targeting by Nanoformulations for Therapeutic Applications. Int J Mol Sci 2023; 24:11869. [PMID: 37511628 PMCID: PMC10380755 DOI: 10.3390/ijms241411869] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/21/2023] [Accepted: 07/21/2023] [Indexed: 07/30/2023] Open
Abstract
Hepatocytes exert pivotal roles in metabolism, protein synthesis and detoxification. Non-parenchymal liver cells (NPCs), largely comprising macrophages, dendritic cells, hepatic stellate cells and liver sinusoidal cells (LSECs), serve to induce immunological tolerance. Therefore, the liver is an important target for therapeutic approaches, in case of both (inflammatory) metabolic diseases and immunological disorders. This review aims to summarize current preclinical nanodrug-based approaches for the treatment of liver disorders. So far, nano-vaccines that aim to induce hepatitis virus-specific immune responses and nanoformulated adjuvants to overcome the default tolerogenic state of liver NPCs for the treatment of chronic hepatitis have been tested. Moreover, liver cancer may be treated using nanodrugs which specifically target and kill tumor cells. Alternatively, nanodrugs may target and reprogram or deplete immunosuppressive cells of the tumor microenvironment, such as tumor-associated macrophages. Here, combination therapies have been demonstrated to yield synergistic effects. In the case of autoimmune hepatitis and other inflammatory liver diseases, anti-inflammatory agents can be encapsulated into nanoparticles to dampen inflammatory processes specifically in the liver. Finally, the tolerance-promoting activity especially of LSECs has been exploited to induce antigen-specific tolerance for the treatment of allergic and autoimmune diseases.
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Affiliation(s)
- Leonard Kaps
- I. Department of Medicine, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - María José Limeres
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Paul Schneider
- I. Department of Medicine, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Malin Svensson
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Yanira Zeyn
- Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Silvia Fraude
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Maximiliano L Cacicedo
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Peter R Galle
- I. Department of Medicine, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Stephan Gehring
- Children's Hospital, University Medical Center, Langenbeckstrasse 1, 55131 Mainz, Germany
| | - Matthias Bros
- Department of Dermatology, University Medical Center Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany
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21
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Qin XY, Furutani Y, Yonezawa K, Shimizu N, Kato-Murayama M, Shirouzu M, Xu Y, Yamano Y, Wada A, Gailhouste L, Shrestha R, Takahashi M, Keillor JW, Su T, Yu W, Fujii S, Kagechika H, Dohmae N, Shirakami Y, Shimizu M, Masaki T, Matsuura T, Suzuki H, Kojima S. Targeting transglutaminase 2 mediated exostosin glycosyltransferase 1 signaling in liver cancer stem cells with acyclic retinoid. Cell Death Dis 2023; 14:358. [PMID: 37308486 DOI: 10.1038/s41419-023-05847-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/22/2023] [Accepted: 05/02/2023] [Indexed: 06/14/2023]
Abstract
Transglutaminase 2 (TG2) is a multifunctional protein that promotes or suppresses tumorigenesis, depending on intracellular location and conformational structure. Acyclic retinoid (ACR) is an orally administered vitamin A derivative that prevents hepatocellular carcinoma (HCC) recurrence by targeting liver cancer stem cells (CSCs). In this study, we examined the subcellular location-dependent effects of ACR on TG2 activity at a structural level and characterized the functional role of TG2 and its downstream molecular mechanism in the selective depletion of liver CSCs. A binding assay with high-performance magnetic nanobeads and structural dynamic analysis with native gel electrophoresis and size-exclusion chromatography-coupled multi-angle light scattering or small-angle X-ray scattering showed that ACR binds directly to TG2, induces oligomer formation of TG2, and inhibits the transamidase activity of cytoplasmic TG2 in HCC cells. The loss-of-function of TG2 suppressed the expression of stemness-related genes, spheroid proliferation and selectively induced cell death in an EpCAM+ liver CSC subpopulation in HCC cells. Proteome analysis revealed that TG2 inhibition suppressed the gene and protein expression of exostosin glycosyltransferase 1 (EXT1) and heparan sulfate biosynthesis in HCC cells. In contrast, high levels of ACR increased intracellular Ca2+ concentrations along with an increase in apoptotic cells, which probably contributed to the enhanced transamidase activity of nuclear TG2. This study demonstrates that ACR could act as a novel TG2 inhibitor; TG2-mediated EXT1 signaling is a promising therapeutic target in the prevention of HCC by disrupting liver CSCs.
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Affiliation(s)
- Xian-Yang Qin
- Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan.
| | - Yutaka Furutani
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kento Yonezawa
- Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, Japan
- Center for Digital Green-innovation, Nara Institute of Science and Technology, Takayama, Ikoma, Nara, Japan
| | - Nobutaka Shimizu
- Photon Factory, Institute of Materials Structure Science, High Energy Accelerator Research Organization (KEK), Tsukuba, Ibaraki, Japan
| | - Miyuki Kato-Murayama
- Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan
| | - Mikako Shirouzu
- Laboratory for Protein Functional and Structural Biology, RIKEN Center for Biosystems Dynamics Research, Yokohama, Kanagawa, Japan
| | - Yali Xu
- Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
- School of Medicine, Nanjing University, Nanjing, Jiangsu, China
| | - Yumiko Yamano
- Laboratory of Organic Chemistry for Life Science, Kobe Pharmaceutical University, Kobe, Hyogo, Japan
| | - Akimori Wada
- Laboratory of Organic Chemistry for Life Science, Kobe Pharmaceutical University, Kobe, Hyogo, Japan
| | - Luc Gailhouste
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan
- Laboratory for Brain Development and Disorders, RIKEN Center for Brain Science, Saitama, Japan
| | - Rajan Shrestha
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan
- Department of Pharmacy, Kathmandu University, Dhulikhel, Kavre, Nepal
| | - Masataka Takahashi
- Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Jeffrey W Keillor
- Department of Chemistry and Biomolecular Sciences, University of Ottawa, Ottawa, ON, Canada
| | - Ting Su
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan
- School of Medicine, Nanjing University, Nanjing, Jiangsu, China
| | - Wenkui Yu
- School of Medicine, Nanjing University, Nanjing, Jiangsu, China
| | - Shinya Fujii
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
| | - Hiroyuki Kagechika
- Institute of Biomaterials and Bioengineering, Tokyo Medical and Dental University, Tokyo, Japan
| | - Naoshi Dohmae
- Biomolecular Characterization Unit, RIKEN Center for Sustainable Resource Science, Wako, Saitama, Japan
| | - Yohei Shirakami
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Masahito Shimizu
- Department of Gastroenterology, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Takahiro Masaki
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tomokazu Matsuura
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan
- Department of Laboratory Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Harukazu Suzuki
- Laboratory for Cellular Function Conversion Technology, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Soichi Kojima
- Liver Cancer Prevention Research Unit, RIKEN Cluster for Pioneering Research, Wako, Saitama, Japan
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22
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Tao Q, Ji H, Zhou Y, Shu Y, Chen Y, Shao M, Wu Z, Chen M, Lv T, Shi Y. HDAC3 Controls Liver Homeostasis More by Facilitating Deoxyribonucleic Acid Damage Repair than by Regulating Transcription in Hepatocytes. J Transl Med 2023; 103:100120. [PMID: 36801398 DOI: 10.1016/j.labinv.2023.100120] [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: 09/20/2022] [Revised: 01/18/2023] [Accepted: 02/14/2023] [Indexed: 02/19/2023] Open
Abstract
By controlling DNA damage repair and regulating gene transcription, the critical epigenetic regulator histone deacetylase 3 (HDAC3) plays pivotal roles in liver cancer and liver regeneration; however, the role of HDAC3 in liver homeostasis has not been fully elucidated. In this study, we found that HDAC3-deficient livers developed a defective morphology and metabolism with an increasing degree of DNA damage in the hepatocytes along the portal-central axis of the lobule. Most strikingly, in the Alb-CreERT:Hdac3-/- mice, it was demonstrated that HDAC3 ablation did not impair liver homeostasis in terms of histologic characteristics, function, proliferation, or gene profiles prior to the profound accumulation of DNA damage. Next, we identified that the hepatocytes in the portal area, which carried less DNA damage than those in the central area, repopulated the hepatic lobule by active regeneration and movement toward the center. As a result, the liver became more viable after each surgery. Furthermore, in vivo tracing of keratin-19-expressing hepatic progenitor cells, which lacked HDAC3, showed that the hepatic progenitor cells gave rise to newly generated periportal hepatocytes. In hepatocellular carcinoma, HDAC3 deficiency impaired DNA damage response and enhanced radiotherapy sensitivity in vitro and in vivo. Taken together, we demonstrated that HDAC3 deficiency interferes with liver homeostasis, which is more dependent on the accumulation of DNA damage in hepatocytes than on transcriptional dysregulation. Our findings support the hypothesis that selective HDAC3 inhibition has the potential to augment the effect of chemoradiotherapy aimed at inducing DNA damage in cancer therapy.
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Affiliation(s)
- Qing Tao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Hongjie Ji
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China; School of Bioscience and Technology, Weifang Medical University, Weifang, China
| | - Yongjie Zhou
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
| | - Yuke Shu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Yuwei Chen
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Mingyang Shao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Zhenru Wu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Menglin Chen
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China
| | - Tao Lv
- Laboratory of Liver Transplantation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China; Department of Liver Surgery, West China Hospital, Sichuan University, Chengdu, China.
| | - Yujun Shi
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, National Healthcare Corporation, West China Hospital, Sichuan University, Chengdu, China; Laboratory of Liver Transplantation, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China.
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23
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Liang L, Zhang LY, Liu WT, Zong C, Gao L, Li R, Zhao QD, Zhao NP, Wei LX, Zhang L, Han ZP. Babao Dan decreases hepatocarcinogenesis by inhibiting hepatic progenitor cells malignant transformation via down-regulating toll-like receptor 4. Front Oncol 2023; 13:1073859. [PMID: 37251918 PMCID: PMC10213212 DOI: 10.3389/fonc.2023.1073859] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Accepted: 04/11/2023] [Indexed: 05/31/2023] Open
Abstract
Background Babao Dan (BBD) is a traditional Chinese medicine that has been widely used as a complementary and alternative medicine to treat chronic liver diseases. In this study, we aimed to observe the effect of BBD on the incidence of diethylnitrosamine (DEN)-initiated hepatocellular carcinoma formation in rats and explored its possible mechanism. Methods To verify this hypothesis, BBD was administrated to rats at a dose of 0.5g/kg body weight per two days from the 9th to 12th week in HCC-induced by DEN. Liver injury biomarkers and hepatic inflammatory parameters were evaluated by histopathology as well as serum and hepatic content analysis. We applied immunohistochemical analysis to investigate the expression of CK-19 and SOX-9 in liver tissues. The expression of TLR4 was determined by immunohistochemical, RT-PCR, and western blot analysis. Furthermore, we also detected the efficacy of BBD against primary HPCs neoplastic transformation induced by LPS. Results We observed that DEN could induce hepatocarcinogenesis, and BBD could obviously decrease the incidence. The biochemical and histopathological examination results confirmed that BBD could protect against liver injury and decrease inflammatory infiltration. Immunohistochemistry staining results showed that BBD could effectively inhibit the ductal reaction and the expression of TLR4. The results showed that BBD-serumcould obviously inhibit primary HPCs neoplastic transformation induced by regulating the TLR4/Ras/ERK signaling pathway. Conclusion In summary, our results indicate that BBD has potential applications in the prevention and treatment of HCC, which may be related to its effect on hepatic progenitor cells malignant transformation via inhibiting the TLR4/Ras/ERK signaling pathway.
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Affiliation(s)
- Lei Liang
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
- Department of Hepatobiliary, Pancreatic and Minimal Invasive Surgery, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, Zhejiang, China
- Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Hangzhou, China
| | - Lu-Yao Zhang
- Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
- School of Pharmacy, Anhui Medical University, Hefei, China
| | - Wen-Ting Liu
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chen Zong
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Lu Gao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Rong Li
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Qiu-Dong Zhao
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Na-Ping Zhao
- Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Li-Xin Wei
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Li Zhang
- Clinical Research Unit, Changhai Hospital, Naval Medical University, Shanghai, China
- Department of Clinical Pharmacology, The Second Hospital of Anhui Medical University, Hefei, China
| | - Zhi-Peng Han
- Tumor Immunology and Gene Therapy Center, Third Affiliated Hospital of Naval Medical University, Shanghai, China
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24
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Dong ZR, Cai JB, Shi GM, Yang YF, Huang XY, Zhang C, Dong RZ, Wei CY, Li T, Ke AW, Fan J. Oncogenic miR-93-5p/Gal-9 axis drives CD8 (+) T-cell inactivation and is a therapeutic target for hepatocellular carcinoma immunotherapy. Cancer Lett 2023; 564:216186. [PMID: 37105392 DOI: 10.1016/j.canlet.2023.216186] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Revised: 04/08/2023] [Accepted: 04/11/2023] [Indexed: 04/29/2023]
Abstract
Evading immune destruction is an emerging hallmark of cancer and a potential key step in tumorigenesis. Immune checkpoint blocker (ICB)-based combination therapies revolutionize the landscape of systemic therapy for HCC. However, the molecular underpinnings governing immune evasion and responses remain unclear. Our study aims to find new regulatory molecules that drive HCC immune escape and tumorigenesis and find new promising immunotherapeutic approaches for HCC. In our study, laser capture microdissection (LCM) and miRNA sequencing combined with in vitro and in vivo experiments identified miR-93-5p as a crucial initiating oncogene during liver progenitor cell (LPC) malignant transformation and immune escape. Mechanistically, miR-93-5p could directly target canonical tumour suppressors such as APC to promote LPC malignant transformation and hepatocarcinogenesis. More importantly, miR-93-5p could induce deviant GAL-9 augmentation to inactivate infiltrated CD8(+) T cells and induce immune evasion by targeting several epigenetic regulators, such as AEBP2, and then regulating H3K4me3/H3K27me3 bivalency. Experiments in C57BL/6 mice demonstrated that blockade of Gal-9 abrogated miR-93-5p-induced HCC progression and improved their prognosis. Clinically, we identified a unique subtype of HCC closely associated with high GAL-9 expression and anti-PD1 treatment resistance. Our study highlights the pivotal role of the miR-93-5p/Gal-9 axis in driving HCC immune escape and tumorigenesis. Blocking GAL-9 is an effective and promising immunotherapeutic approach for HCC.
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Affiliation(s)
- Zhao-Ru Dong
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250012, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China.
| | - Jia-Bin Cai
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China
| | - Guo-Ming Shi
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China
| | - Ya-Fei Yang
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250012, China
| | - Xiao-Yong Huang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China
| | - Chi Zhang
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China
| | - Rui-Zhao Dong
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China
| | - Chuan-Yuan Wei
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China
| | - Tao Li
- Department of General Surgery, Qilu Hospital, Shandong University, Jinan, 250012, China.
| | - Ai-Wu Ke
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China.
| | - Jia Fan
- Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, 200032, China; Key Laboratory of Carcinogenesis and Cancer Invasion (Fudan University), Ministry of Education, Shanghai, 200032, China.
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25
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Ezhilarasan D. Unraveling the pathophysiologic role of galectin-3 in chronically injured liver. J Cell Physiol 2023; 238:673-686. [PMID: 36745560 DOI: 10.1002/jcp.30956] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 01/04/2023] [Accepted: 01/12/2023] [Indexed: 02/07/2023]
Abstract
Galectin-3 (Gal-3) previously referred to as S-type lectins, is a soluble protein that specifically binds to β-galactoside carbohydrates with high specificity. Gal-3 plays a pivotal role in a variety of pathophysiological processes such as cell proliferation, inflammation, differentiation, angiogenesis, transformation and apoptosis, pre-mRNA splicing, metabolic syndromes, fibrosis, and host defense. The role of Gal-3 has also been implicated in liver diseases. Gal-3 is activated upon a hepatotoxic insult to the liver and its level has been shown to be upregulated in fatty liver diseases, inflammation, nonalcoholic steatohepatitis, fibrosis, cholangitis, cirrhosis, and hepatocellular carcinoma (HCC). Gal-3 directly interacts with the NOD-like receptor family, pyrin domain containing 3, and activates the inflammasome in macrophages of the liver. In the chronically injured liver, Gal-3 secreted by injured hepatocytes and immune cells, activates hepatic stellate cells (HSCs) in a paracrine fashion to acquire a myofibroblast like collagen-producing phenotype. Activated HSCs in the fibrotic liver secrete Gal-3 which acts via autocrine signaling to exacerbate extracellular matrix synthesis and fibrogenesis. In the stromal microenvironment, Gal-3 activates cancer cell proliferation, migration, invasiveness, and metastasis. Clinically, increased serum levels and Gal-3 expression were observed in the liver tissue of nonalcoholic steatohepatitis, fibrotic/cirrhotic, and HCC patients. The pathological role of Gal-3 has been experimentally and clinically reported in the progression of chronic liver disease. Therefore, this review discusses the pathological role of Gal-3 in the progression of chronic liver diseases.
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Affiliation(s)
- Devaraj Ezhilarasan
- Department of Pharmacology, Molecular Medicine and Toxicology Lab, Saveetha Dental College, Saveetha Institute of Medical and Technical Sciences, Chennai, Tamil Nadu, India
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26
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Rigual MDM, Sánchez Sánchez P, Djouder N. Is liver regeneration key in hepatocellular carcinoma development? Trends Cancer 2023; 9:140-157. [PMID: 36347768 DOI: 10.1016/j.trecan.2022.10.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 10/05/2022] [Accepted: 10/10/2022] [Indexed: 11/08/2022]
Abstract
The liver is the largest organ of the mammalian body and has the remarkable ability to fully regenerate in order to maintain tissue homeostasis. The adult liver consists of hexagonal lobules, each with a central vein surrounded by six portal triads localized in the lobule border containing distinct parenchymal and nonparenchymal cells. Because the liver is continuously exposed to diverse stress signals, several sophisticated regenerative processes exist to restore its functional status following impairment. However, these stress signals can affect the liver's capacity to regenerate and may lead to the development of hepatocellular carcinoma (HCC), one of the most aggressive liver cancers. Here, we review the mechanisms of hepatic regeneration and their potential to influence HCC development.
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Affiliation(s)
- María Del Mar Rigual
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Paula Sánchez Sánchez
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid, ES-28029, Spain.
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27
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Gromowski T, Lukacs-Kornek V, Cisowski J. Current view of liver cancer cell-of-origin and proposed mechanisms precluding its proper determination. Cancer Cell Int 2023; 23:3. [PMID: 36609378 PMCID: PMC9824961 DOI: 10.1186/s12935-022-02843-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2022] [Accepted: 12/30/2022] [Indexed: 01/09/2023] Open
Abstract
Hepatocellular carcinoma and intrahepatic cholangiocarcinoma are devastating primary liver cancers with increasing prevalence in many parts of the world. Despite intense investigation, many aspects of their biology are still largely obscure. For example, numerous studies have tackled the question of the cell-of-origin of primary liver cancers using different experimental approaches; they have not, however, provided a clear and undisputed answer. Here, we will review the evidence from animal models supporting the role of all major types of liver epithelial cells: hepatocytes, cholangiocytes, and their common progenitor as liver cancer cell-of-origin. Moreover, we will also propose mechanisms that promote liver cancer cell plasticity (dedifferentiation, transdifferentiation, and epithelial-to-mesenchymal transition) which may contribute to misinterpretation of the results and which make the issue of liver cancer cell-of-origin particularly complex.
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Affiliation(s)
- Tomasz Gromowski
- grid.5522.00000 0001 2162 9631Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland
| | - Veronika Lukacs-Kornek
- grid.10388.320000 0001 2240 3300Institute of Experimental Immunology, University Hospital of the Rheinische Friedrich-Wilhelms-University, Bonn, Germany
| | - Jaroslaw Cisowski
- Department of General Biochemistry, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University, Krakow, Poland.
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Rare Inherited Cholestatic Disorders and Molecular Links to Hepatocarcinogenesis. Cells 2022; 11:cells11162570. [PMID: 36010647 PMCID: PMC9406938 DOI: 10.3390/cells11162570] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 08/05/2022] [Accepted: 08/12/2022] [Indexed: 11/16/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common primary liver cancer affecting adults and the second most common primary liver cancer affecting children. Recent years have seen a significant increase in our understanding of the molecular changes associated with HCC. However, HCC is a complex disease, and its molecular pathogenesis, which likely varies by aetiology, remains to be fully elucidated. Interestingly, some inherited cholestatic disorders that manifest in childhood are associated with early HCC development. This review will thus explore how three genes that are associated with liver disease in childhood (ABCB11, TJP2 and VPS33B) might play a role in the initiation and progression of HCC. Specifically, chronic bile-induced damage (caused by ABCB11 changes), disruption of intercellular junction formation (caused by TJP2 changes) and loss of normal apical–basal cell polarity (caused by VPS33B changes) will be discussed as possible mechanisms for HCC development.
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Zhou L, Yu KH, Wong TL, Zhang Z, Chan CH, Loong JH, Che N, Yu HJ, Tan KV, Tong M, Ngan ES, Ho JW, Ma S. Lineage tracing and single-cell analysis reveal proliferative Prom1+ tumour-propagating cells and their dynamic cellular transition during liver cancer progression. Gut 2022; 71:1656-1668. [PMID: 34588223 DOI: 10.1136/gutjnl-2021-324321] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Accepted: 09/19/2021] [Indexed: 12/14/2022]
Abstract
OBJECTIVE Hepatocellular carcinoma (HCC) has high intratumoral heterogeneity, which contributes to therapeutic resistance and tumour recurrence. We previously identified Prominin-1 (PROM1)/CD133 as an important liver cancer stem cell (CSC) marker in human HCC. The aim of this study was to investigate the heterogeneity and properties of Prom1+ cells in HCC in intact mouse models. DESIGN We established two mouse models representing chronic fibrotic HCC and rapid steatosis-related HCC. We performed lineage tracing post-HCC induction using Prom1C-L/+; Rosa26tdTomato/+ mice, and targeted depletion using Prom1C-L/+; Rosa26DTA/+ mice. Single-cell RNA sequencing (scRNA-seq) was carried out to analyse the transcriptomic profile of traced Prom1+ cells. RESULTS Prom1 in HCC tumours marks proliferative tumour-propagating cells with CSC-like properties. Lineage tracing demonstrated that these cells display clonal expansion in situ in primary tumours. Labelled Prom1+ cells exhibit increasing tumourigenicity in 3D culture and allotransplantation, as well as potential to form cancers of differential lineages on transplantation. Depletion of Prom1+ cells impedes tumour growth and reduces malignant cancer hallmarks in both HCC models. scRNA-seq analysis highlighted the heterogeneity of Prom1+ HCC cells, which follow a trajectory to the dedifferentiated status with high proliferation and stem cells traits. Conserved gene signature of Prom1 linage predicts poor prognosis in human HCC. The activated oxidant detoxification underlies the protective mechanism of dedifferentiated transition and lineage propagation. CONCLUSION Our study combines in vivo lineage tracing and scRNA-seq to reveal the heterogeneity and dynamics of Prom1+ HCC cells, providing insights into the mechanistic role of malignant CSC-like cells in HCC progression.
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Affiliation(s)
- Lei Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Ken Ho Yu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, Hong Kong SAR, China
| | - Tin Lok Wong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Zhao Zhang
- Department of Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Chun Ho Chan
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Jane Hc Loong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Noelia Che
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Hua Jian Yu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Kel Vin Tan
- Department of Diagnostic Radiology, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Man Tong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
| | - Elly S Ngan
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China
| | - Joshua Wk Ho
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China .,Laboratory of Data Discovery for Health Limited (D24H), Hong Kong Science Park, Hong Kong SAR, China
| | - Stephanie Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China .,Department of Clinical Oncology, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong SAR, China
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30
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López-Torres CD, Torres-Mena JE, Castro-Gil MP, Villa-Treviño S, Arellanes-Robledo J, Del Pozo-Yauner L, Pérez-Carreón JI. Downregulation of Indolethylamine N-methyltransferase is an early event in the rat hepatocarcinogenesis and is associated with poor prognosis in hepatocellular carcinoma patients. J Gene Med 2022; 24:e3439. [PMID: 35816441 DOI: 10.1002/jgm.3439] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/25/2022] [Accepted: 07/07/2022] [Indexed: 11/10/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers worldwide, often preceded by cirrhosis and usually diagnosed at advanced stages; therefore, identifying molecular changes at early stages is an attractive strategy for detection and timely treatment. Here, we investigated the progressive transcriptomic changes during experimental hepatocarcinogenesis to identify novel early tumor markers in an HCC model induced by chronic administration of sublethal doses of diethylnitrosamine. An analysis of differentially expressed genes showed that four processes associated with oxidation-reduction and detoxification were significantly overrepresented during hepatocarcinogenesis progression, of which the Nuclear Factor, Erythroid 2 Like 2 (NRF2) pathway showed several dysregulated genes. Interestingly, we also identified 91 genes dysregulated at early HCC stages, but the expression of the indolethylamine N-methyltransferase gene (Inmt), as well as the level of its encoding protein, were strongly downregulated. INMT was increased in perivenular hepatocytes of normal livers but decreased in livers of experimental HCC. Furthermore, a gene expression and survival analysis performed using data from the liver hepatocellular carcinoma project of The Cancer Genome Atlas Program revealed that INMT is also significantly downregulated in human HCC and is associated with poor overall survival. In conclusion, by performing a transcriptome analysis of the HCC progression, we identified that INMT is early downregulated in the rat hepatocarcinogenesis and is associated with poor prognosis in human HCC, suggesting that INMT downregulation may be a promising prognostic marker for HCC in high-risk populations.
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Affiliation(s)
- Carlos David López-Torres
- Laboratorio de Enfermedades Hepáticas. Instituto Nacional de Medicina Genómica. Ciudad de México, México
| | | | - María Paulette Castro-Gil
- Laboratorio de Enfermedades Hepáticas. Instituto Nacional de Medicina Genómica. Ciudad de México, México
| | - Saúl Villa-Treviño
- Departamento de Biología Celular. Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional. Ciudad de México, México
| | - Jaime Arellanes-Robledo
- Laboratorio de Enfermedades Hepáticas. Instituto Nacional de Medicina Genómica. Ciudad de México, México.,Dirección de Cátedras. Consejo Nacional de Ciencia y Tecnología. Ciudad de México, México
| | - Luis Del Pozo-Yauner
- Department of Pathology, College of Medicine, University of South Alabama. Alabama, USA
| | - Julio Isael Pérez-Carreón
- Laboratorio de Enfermedades Hepáticas. Instituto Nacional de Medicina Genómica. Ciudad de México, México
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Zhu H, Liu D, Cheng L, Liu J, Wang G, Li H, Zhang Y, Mi H, Zhang S, Shu K, Yu X. Prognostic Value and Biological Function of Galectins in Malignant Glioma. Front Oncol 2022; 12:834307. [PMID: 35814469 PMCID: PMC9263596 DOI: 10.3389/fonc.2022.834307] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 05/24/2022] [Indexed: 12/22/2022] Open
Abstract
Malignant glioma is the most common solid tumor of the adult brain, with high lethality and poor prognosis. Hence, identifying novel and reliable biomarkers can be advantageous for diagnosing and treating glioma. Several galectins encoded by LGALS genes have recently been reported to participate in the development and progression of various tumors; however, their detailed role in glioma progression remains unclear. Herein, we analyzed the expression and survival curves of all LGALS across 2,217 patients with glioma using The Cancer Genome Atlas (TCGA), Chinese Glioma Genome Atlas (CGGA), and Rembrandt databases. By performing multivariate Cox analysis, we built a survival model containing LGALS1, LGALS3, LGALS3BP, LGALS8, and LGALS9 using TCGA database. The prognostic power of this panel was assessed using CGGA and Rembrandt datasets. ESTIMATE and CIBERSORT algorithms confirmed that patients in high-risk groups exhibited significant stromal and immune cell infiltration, immunosuppression, mesenchymal subtype, and isocitrate dehydrogenase 1 (IDH1) wild type. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), CancerSEA, and Gene Set Enrichment Analysis (GSEA) showed that pathways related to hypoxia, epithelial-to-mesenchymal transition (EMT), stemness, and inflammation were enriched in the high-risk group. To further elucidate the function of LGALS in glioma, we performed immunohistochemical staining of tissue microarrays (TMAs), Western blotting, and cell viability, sphere formation, and limiting dilution assays following lentiviral short hairpin RNA (shRNA)-mediated LGALS knockdown. We observed that LGALS expression was upregulated in gliomas at both protein and mRNA levels. LGALS could promote the stemness maintenance of glioma stem cells (GSCs) and positively correlate with M2-tumor-associated macrophages (TAMs) infiltration. In conclusion, we established a reliable survival model for patients with glioma based on LGALS expression and revealed the essential roles of LGALS genes in tumor growth, immunosuppression, stemness maintenance, pro-neural to mesenchymal transition, and hypoxia in glioma.
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Affiliation(s)
- Hongtao Zhu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dan Liu
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Lidong Cheng
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jingdian Liu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guanghui Wang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Li
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yang Zhang
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hailong Mi
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Suojun Zhang
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kai Shu
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Kai Shu, ; Xingjiang Yu,
| | - Xingjiang Yu
- Department of Histology and Embryology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
- *Correspondence: Kai Shu, ; Xingjiang Yu,
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32
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Liu P, Zhou Q, Li J. Integrated Multi-Omics Data Analysis Reveals Associations Between Glycosylation and Stemness in Hepatocellular Carcinoma. Front Oncol 2022; 12:913432. [PMID: 35814473 PMCID: PMC9259879 DOI: 10.3389/fonc.2022.913432] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 05/25/2022] [Indexed: 12/14/2022] Open
Abstract
Background Glycosylation plays an essential role in driving the progression and treatment resistance of hepatocellular carcinoma (HCC). However, its function in regulating the acquisition and maintenance of the cancer stemness-like phenotype in HCC remains largely unknown. There is also very little known about how CAD and other potential glycosylation regulators may influence stemness. This study explores the relationship between glycosylation and stemness in HCC. Methods Gene set variance analysis (GSVA) was used to assess the TCGA pan-cancer enrichment in glycosylation-related pathways. Univariate, LASSO, and multivariate COX regression were then used to identify prognostic genes in the TCGA-LIHC and construct a prognostic signature. HCC patients were classified into high- and low-risk subgroups based on the signature. The relationship between gene expression profiles and stemness was confirmed using bulk and single-cell RNA-sequencing data. The role of CAD and other genes in regulating the stemness of HCC was also validated by RT-qPCR, CCK-8, and colony formation assay. Copy number variation (CNV), immune infiltration, and clinical features were further analyzed in different subgroups and subsequent gene expression profiles. Sensitive drugs were also screened. Results In the pan-cancer analysis, HCC was shown to have specific glycosylation alterations. Five genes, CAD, SLC51B, LGALS3, B3GAT3, and MT3, identified from 572 glycosylation-related genes, were used to construct a gene signature and predict HCC patient survival in the TCGA cohort. The results demonstrated a significant positive correlation between patients in the high-risk group and both elevated gene expression and HCC dedifferentiation status. A significant reduction in the stemness-related markers, CD24, CD44, CD20, FOXM1, and EpCAM, was found after the knockdown of CAD and other genes in HepG2 and Huh7 cells. Frequent mutations increased CNVs, immune-suppressive responses, and poor prognosis were also associated with the high-risk profile. The ICGC-LIRI-JP cohort confirmed a similar relationship between glycosylation-related subtypes and stemness. Finally, 84 sensitive drugs were screened for abnormal glycosylation of HCC, and carfilzomib was most highly correlated with CAD. Conclusions Glycosylation-related molecular subtypes are associated with HCC stemness and disease prognosis. These results provide new directions for further research on the relationship between glycosylation and stemness phenotypes.
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Affiliation(s)
- Peiyan Liu
- Department of Hepatology, Second People’s Clinical College of Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People’s Hospital, Tianjin, China
| | - Qi Zhou
- Department of Gastroenterology, The Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Liver Disease Research, Guangzhou, China
| | - Jia Li
- Department of Hepatology, Second People’s Clinical College of Tianjin Medical University, Tianjin, China
- Department of Hepatology, Tianjin Second People’s Hospital, Tianjin, China
- *Correspondence: Jia Li,
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Xie ZQ, Li HX, Hou XJ, Huang MY, Zhu ZM, Wei LX, Tang CX. Capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of hepatic progenitor cells via SIRT1/SOX2 signaling pathway. Cancer Med 2022; 11:4283-4296. [PMID: 35674129 DOI: 10.1002/cam4.4777] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 11/11/2022] Open
Abstract
BACKGROUND & AIMS Capsaicin, a functional component of chili pepper, possesses anti-inflammatory, analgesic, and anti-cancer properties. This study aimed to determine the property of capsaicin against hepatocarcinogenesis in vivo and investigate the role of the SIRT1/SOX2 pathway in the mode of action of capsaicin in hepatic progenitor cells (HPCs), which is related to hepatocarcinogenesis. MATERIALS & METHODS We prepared a diethylnitrosamine-induced liver cancer model in rats to examine hepatocarcinogenesis, and delivered liposomal capsaicin through the subcutaneous transposition of the spleen to the liver. Liver sections from rats and hepatocarcinoma patients were stained for the markers of HPCs or SIRT1/SOX2 signaling. SIRT1/SOX2 signalling expression was measured using immunoprecipitation and western blot. RESULTS We found that capsaicin significantly inhibited hepatocarcinogenesis. Notably, capsaicin inhibited HPCs activation in vivo but did not induce apoptosis in the normal hepatic progenitor cell line in rats in vitro. This suggests that capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of HPCs. Moreover, capsaicin can induce this inhibition by reducing the stability of SOX2. SIRT1 is overexpressed in liver cancer and acts as a tumor promoter via SOX2 deacetylation. Using immunoprecipitation, we identified direct binding between SIRT1 and SOX2. The capsaicin treatment resulted in SIRT1 downregulation which reduced deacetylation, and increased nuclear export as well as subsequent ubiquitous degradation of SOX2. CONCLUSIONS Altogether, we report that capsaicin suppresses hepatocarcinogenesis by inhibiting the stemness of HPCs via SIRT1/SOX2 signaling. It may serve as a promising therapeutic candidate for liver cancer.
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Affiliation(s)
- Zhi-Qin Xie
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
| | - Hong-Xia Li
- Department of Pathology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
| | - Xiao-Juan Hou
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai City, China
| | - Mei-Yuan Huang
- Department of Pathology, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
| | - Ze-Min Zhu
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
| | - Li-Xin Wei
- Tumor Immunology and Gene Therapy Center, Eastern Hepatobiliary Surgery Hospital, The Second Military Medical University, Shanghai City, China
| | - Cai-Xi Tang
- Department of Hepatobiliary and Pancreatic Surgery, Zhuzhou Hospital Affiliated to Xiangya School of Medicine, Central South University, Zhuzhou City, Hunan Province, China
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Medler J, Kucka K, Wajant H. Tumor Necrosis Factor Receptor 2 (TNFR2): An Emerging Target in Cancer Therapy. Cancers (Basel) 2022; 14:cancers14112603. [PMID: 35681583 PMCID: PMC9179537 DOI: 10.3390/cancers14112603] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2022] [Revised: 05/19/2022] [Accepted: 05/22/2022] [Indexed: 12/12/2022] Open
Abstract
Despite the great success of TNF blockers in the treatment of autoimmune diseases and the identification of TNF as a factor that influences the development of tumors in many ways, the role of TNFR2 in tumor biology and its potential suitability as a therapeutic target in cancer therapy have long been underestimated. This has been fundamentally changed with the identification of TNFR2 as a regulatory T-cell (Treg)-stimulating factor and the general clinical breakthrough of immunotherapeutic approaches. However, considering TNFR2 as a sole immunosuppressive factor in the tumor microenvironment does not go far enough. TNFR2 can also co-stimulate CD8+ T-cells, sensitize some immune and tumor cells to the cytotoxic effects of TNFR1 and/or acts as an oncogene. In view of the wide range of cancer-associated TNFR2 activities, it is not surprising that both antagonists and agonists of TNFR2 are considered for tumor therapy and have indeed shown overwhelming anti-tumor activity in preclinical studies. Based on a brief summary of TNFR2 signaling and the immunoregulatory functions of TNFR2, we discuss here the main preclinical findings and insights gained with TNFR2 agonists and antagonists. In particular, we address the question of which TNFR2-associated molecular and cellular mechanisms underlie the observed anti-tumoral activities of TNFR2 agonists and antagonists.
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35
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Garrido A, Kim E, Teijeiro A, Sánchez Sánchez P, Gallo R, Nair A, Matamala Montoya M, Perna C, Vicent GP, Muñoz J, Campos-Olivas R, Melms JC, Izar B, Schwabe RF, Djouder N. Histone acetylation of bile acid transporter genes plays a critical role in cirrhosis. J Hepatol 2022; 76:850-861. [PMID: 34958836 PMCID: PMC8934297 DOI: 10.1016/j.jhep.2021.12.019] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 12/01/2021] [Accepted: 12/10/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND & AIMS Owing to the lack of genetic animal models that adequately recreate key clinical characteristics of cirrhosis, the molecular pathogenesis of cirrhosis has been poorly characterized, and treatments remain limited. Hence, we aimed to better elucidate the pathological mechanisms of cirrhosis using a novel murine model. METHODS We report on the first murine genetic model mimicking human cirrhosis induced by hepatocyte-specific elimination of microspherule protein 1 (MCRS1), a member of non-specific lethal (NSL) and INO80 chromatin-modifier complexes. Using this genetic tool with other mouse models, cell culture and human samples, combined with quantitative proteomics, single nuclei/cell RNA sequencing and chromatin immunoprecipitation assays, we investigated mechanisms of cirrhosis. RESULTS MCRS1 loss in mouse hepatocytes modulates the expression of bile acid (BA) transporters - with a pronounced downregulation of Na+-taurocholate cotransporting polypeptide (NTCP) - concentrating BAs in sinusoids and thereby activating hepatic stellate cells (HSCs) via the farnesoid X receptor (FXR), which is predominantly expressed in human and mouse HSCs. Consistently, re-expression of NTCP in mice reduces cirrhosis, and genetic ablation of FXR in HSCs suppresses fibrotic marks in mice and in vitro cell culture. Mechanistically, deletion of a putative SANT domain from MCRS1 evicts histone deacetylase 1 from its histone H3 anchoring sites, increasing histone acetylation of BA transporter genes, modulating their expression and perturbing BA flow. Accordingly, human cirrhosis displays decreased nuclear MCRS1 and NTCP expression. CONCLUSIONS Our data reveal a previously unrecognized function of MCRS1 as a critical histone acetylation regulator, maintaining gene expression and liver homeostasis. MCRS1 loss induces acetylation of BA transporter genes, perturbation of BA flow, and consequently, FXR activation in HSCs. This axis represents a central and universal signaling event in cirrhosis, which has significant implications for cirrhosis treatment. LAY SUMMARY By genetic ablation of MCRS1 in mouse hepatocytes, we generate the first genetic mouse model of cirrhosis that recapitulates human features. Herein, we demonstrate that the activation of the bile acid/FXR axis in liver fibroblasts is key in cirrhosis development.
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Affiliation(s)
- Amanda Garrido
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
| | - Eunjeong Kim
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
| | - Ana Teijeiro
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
| | - Paula Sánchez Sánchez
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
| | - Rosa Gallo
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
| | - Ajay Nair
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - María Matamala Montoya
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
| | - Cristian Perna
- Department of Pathology, Hospital Universitario Ramón y Cajal (IRYCIS), Madrid, 28034, Spain
| | - Guillermo P Vicent
- Molecular Biology Institute of Barcelona, Consejo Superior de Investigaciones Científicas (IBMB-CSIC), Barcelona, 08028, Spain
| | - Javier Muñoz
- Biotechnology Programme, Proteomics Core Unit, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain; Present address: Biocruces Bizkaia Health Research Institute. Ikerbasque, Basque Foundation for Science, Bilbao, 48013, Spain
| | - Ramón Campos-Olivas
- Structural Biology Programme, Spectroscopyand Nuclear Magnetic Resonance Unit, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain
| | - Johannes C Melms
- Department of Medicine, Division of Hematology and Oncology, Irving Medical Center, Columbia University, New York, NY 10032, USA
| | - Benjamin Izar
- Department of Medicine, Division of Hematology and Oncology, Irving Medical Center, Columbia University, New York, NY 10032, USA
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Nabil Djouder
- Molecular Oncology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional Investigaciones Oncológicas (CNIO), Madrid, 28029, Spain.
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Holczbauer Á, Wangensteen KJ, Shin S. Cellular origins of regenerating liver and hepatocellular carcinoma. JHEP Rep 2022; 4:100416. [PMID: 35243280 PMCID: PMC8873941 DOI: 10.1016/j.jhepr.2021.100416] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 11/30/2021] [Accepted: 12/02/2021] [Indexed: 02/08/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the predominant primary cancer arising from the liver and is one of the major causes of cancer-related mortality worldwide. The cellular origin of HCC has been a topic of great interest due to conflicting findings regarding whether it originates in hepatocytes, biliary cells, or facultative stem cells. These cell types all undergo changes during liver injury, and there is controversy about their contribution to regenerative responses in the liver. Most HCCs emerge in the setting of chronic liver injury from viral hepatitis, fatty liver disease, alcohol, and environmental exposures. The injuries are marked by liver parenchymal changes such as hepatocyte regenerative nodules, biliary duct cellular changes, expansion of myofibroblasts that cause fibrosis and cirrhosis, and inflammatory cell infiltration, all of which may contribute to carcinogenesis. Addressing the cellular origin of HCC is the key to identifying the earliest events that trigger it. Herein, we review data on the cells of origin in regenerating liver and HCC and the implications of these findings for prevention and treatment. We also review the origins of childhood liver cancer and other rare cancers of the liver.
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Aissa AF, Tryndyak VP, de Conti A, Rita Thomazela Machado A, Tuttis K, da Silva Machado C, Hernandes LC, Wellington da Silva Santos P, Mara Serpeloni J, P Pogribny I, Maria Greggi Antunes L. Epigenetic changes induced in mice liver by methionine-supplemented and methionine-deficient diets. Food Chem Toxicol 2022; 163:112938. [PMID: 35314295 DOI: 10.1016/j.fct.2022.112938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Revised: 03/10/2022] [Accepted: 03/16/2022] [Indexed: 02/07/2023]
Abstract
A diet deficient in donors of methyl group, such as methionine, affects DNA methylation and hepatic lipid metabolism. Methionine also affects other epigenetic mechanisms, such as microRNAs. We investigated the effects of methionine-supplemented or methionine-deficient diets on the expression of chromatin-modifying genes, global DNA methylation, the expression and methylation of genes related to lipid metabolism, and the expression of microRNAs in mouse liver. Female Swiss albino mice were fed a control diet (0.3% methionine), a methionine-supplemented diet (2% methionine), and a methionine-deficient diet (0% methionine) for 10 weeks. The genes most affected by the methionine-supplemented diet were associated with histone and DNA methyltransferases activity, while the methionine-deficient diet mostly altered the expression of histone methyltransferases genes. Both diets altered the global DNA methylation and the expression and gene-specific methylation of the lipid metabolism gene Apoa5. Both diets altered the expression of several liver homeostasis-related microRNAs, including miR-190b-5p, miR-130b-3p, miR-376c-3p, miR-411-5p, miR-29c-3p, miR-295-3p, and miR-467d-5p, with the methionine-deficient diet causing a more substantial effect. The effects of improper amounts of methionine in the diet on liver pathologies may involve a cooperative action of chromatin-modifying genes, which results in an aberrant pattern of global and gene-specific methylation, and microRNAs responsible for liver homeostasis.
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Affiliation(s)
- Alexandre Ferro Aissa
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Volodymyr P Tryndyak
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Aline de Conti
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Ana Rita Thomazela Machado
- Departament of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Katiuska Tuttis
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Carla da Silva Machado
- Department of Genetics, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Lívia Cristina Hernandes
- Departament of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Patrick Wellington da Silva Santos
- Departament of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil
| | - Juliana Mara Serpeloni
- Department of General Biology, Center of Biological Sciences, State University of Londrina (UEL), Londrina, PR, Brazil
| | - Igor P Pogribny
- Division of Biochemical Toxicology, National Center for Toxicological Research, U.S. Food and Drug Administration, Jefferson, AR, USA
| | - Lusânia Maria Greggi Antunes
- Departament of Clinical Analysis, Toxicology and Food Science, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, SP, Brazil.
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Guo Y, Luo J, Zou H, Liu C, Deng L, Li P. Context-dependent transcriptional regulations of YAP/TAZ in cancer. Cancer Lett 2022; 527:164-173. [PMID: 34952145 DOI: 10.1016/j.canlet.2021.12.019] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 11/20/2021] [Accepted: 12/13/2021] [Indexed: 02/07/2023]
Abstract
As the downstream effectors of Hippo pathway, YAP/TAZ are identified to participate in organ growth, regeneration and tumorigenesis. However, owing to lack of a DNA-binding domain, YAP/TAZ usually act as coactivators and cooperate with other transcription factors or partners to mediate their transcriptional outputs. In this article, we first present an overview of the core components and the upstream regulators of Hippo-YAP/TAZ signaling in mammals, and then systematically summarize the identified transcription factors or partners that are responsible for the downstream transcriptional output of YAP/TAZ in various cancers.
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Affiliation(s)
- Yibo Guo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Juan Luo
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Hailin Zou
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Chenxin Liu
- Key Laboratory for Green Chemical Process of Ministry of Education, Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Hubei Engineering Research Center for Advanced Fine Chemicals, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, Hubei, 430205, People's Republic of China
| | - Liang Deng
- Department of General Surgery, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China
| | - Peng Li
- Scientific Research Center, The Seventh Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518107, Guangdong, People's Republic of China; Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen, 518107, Guangdong, People's Republic of China.
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Cancer stem cells in hepatocellular carcinoma - from origin to clinical implications. Nat Rev Gastroenterol Hepatol 2022; 19:26-44. [PMID: 34504325 DOI: 10.1038/s41575-021-00508-3] [Citation(s) in RCA: 239] [Impact Index Per Article: 79.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 07/26/2021] [Indexed: 02/06/2023]
Abstract
Hepatocellular carcinoma (HCC) is an aggressive disease with a poor clinical outcome. The cancer stem cell (CSC) model states that tumour growth is powered by a subset of tumour stem cells within cancers. This model explains several clinical observations in HCC (as well as in other cancers), including the almost inevitable recurrence of tumours after initial successful chemotherapy and/or radiotherapy, as well as the phenomena of tumour dormancy and treatment resistance. The past two decades have seen a marked increase in research on the identification and characterization of liver CSCs, which has encouraged the design of novel diagnostic and treatment strategies for HCC. These studies revealed novel aspects of liver CSCs, including their heterogeneity and unique immunobiology, which are suggestive of opportunities for new research directions and potential therapies. In this Review, we summarize the present knowledge of liver CSC markers and the regulators of stemness in HCC. We also comprehensively describe developments in the liver CSC field with emphasis on experiments utilizing single-cell transcriptomics to understand liver CSC heterogeneity, lineage-tracing and cell-ablation studies of liver CSCs, and the influence of the CSC niche and tumour microenvironment on liver cancer stemness, including interactions between CSCs and the immune system. We also discuss the potential application of liver CSC-based therapies for treatment of HCC.
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40
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She J, Sheng R, Qin ZH. Pharmacology and Potential Implications of Nicotinamide Adenine Dinucleotide Precursors. Aging Dis 2021; 12:1879-1897. [PMID: 34881075 PMCID: PMC8612620 DOI: 10.14336/ad.2021.0523] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Accepted: 05/23/2021] [Indexed: 12/21/2022] Open
Abstract
Coenzyme I (nicotinamide adenine dinucleotide, NAD+/NADH) and coenzyme II (nicotinamide adenine dinucleotide phosphate, NADP+/NADPH) are involved in various biological processes in mammalian cells. NAD+ is synthesised through the de novo and salvage pathways, whereas coenzyme II cannot be synthesised de novo. NAD+ is a precursor of coenzyme II. Although NAD+ is synthesised in sufficient amounts under normal conditions, shortage in its supply due to over consumption and its decreased synthesis has been observed with increasing age and under certain disease conditions. Several studies have proved that in a wide range of tissues, such as liver, skin, muscle, pancreas, and fat, the level of NAD+ decreases with age. However, in the brain tissue, the level of NADH gradually increases and that of NAD+ decreases in aged people. The ratio of NAD+/NADH indicates the cellular redox state. A decrease in this ratio affects the cellular anaerobic glycolysis and oxidative phosphorylation functions, which reduces the ability of cells to produce ATP. Therefore, increasing the exogenous NAD+ supply under certain disease conditions or in elderly people may be beneficial. Precursors of NAD+ have been extensively explored and have been reported to effectively increase NAD+ levels and possess a broad range of functions. In this review article, we discuss the pharmacokinetics and pharmacodynamics of NAD+ precursors.
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Affiliation(s)
- Jing She
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| | - Rui Sheng
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
| | - Zheng-Hong Qin
- Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Neuropsychiatric Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
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El Raziky M, Abdel Hafez H, Elsharkawy A, Moneer TA, EL-Sheikh SM, Maher RM, Sharaf SA. Serum level of cytokeratin 19 as a diagnostic and prognostic marker in patients with HCV-related hepatocellular carcinoma. EGYPTIAN LIVER JOURNAL 2021. [DOI: 10.1186/s43066-021-00125-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Abstract
Abstract
Background
The heterogeneous nature of human hepatocellular carcinoma (HCC) impedes both treatment strategies and prognostic predictions. Several markers have been proposed for the diagnosis of HCC. Cytoskeleton-associated proteins have been known as cellular integrators in neoplasm formation. Hepatic progenitor cells are thought to express alpha-fetoprotein (AFP) and hematopoietic as well as biliary markers such as cytokeratin 19 (CK 19) and cytokeratin 7. The aim of this study was to verify the role of serum CK 19 alone or in combination with AFP as a diagnostic marker of HCC and to assess the changes in its levels after ablation of HCV-related HCC to evaluate its role as a predictor marker for recurrence of HCC after ablation. The study was conducted on 102 HCV-related cirrhotic patients categorized into three different groups according to the clinical, laboratory, and radiological evaluation: group I—62 patients with early or intermediate HCC who underwent locoregional intervention, group II—20 patients with advanced HCC not fit for any intervention apart from best supportive treatment, and group III—20 cirrhotic patients with no evidence of HCC as proved by two imaging techniques.
Results
The mean serum levels of CK 19 were 6.5 ± 5.7, 10.5 ± 12.5, and 6.8 ± 2.8 ng/ml in groups I, II, and III, respectively, with no significant difference between groups. Sensitivity, specificity, positive, and negative predictive values of combined AFP and human CK 19 at cutoff levels of 25.5 ng/ml and 6.25 ng/ml were 93.9%, 45%, 87.5%, and 64.3%, respectively. In group I patients, CK 19 levels were comparable in patients with ablated focal lesion and those who did not at baseline; then, it was significantly higher in ablated patients than in patients with residual tumor 1 and 6 months after the intervention.
Conclusions
Combination of both AFP and CK 19 levels could increase the diagnostic accuracy of suspected HCCs. CK 19 levels are good predictors of ablation/recurrence in patients who underwent interventional procedures minimizing the need for follow-up imaging modalities.
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Karakülah G, Yandim C. Identification of differentially expressed genomic repeats in primary hepatocellular carcinoma and their potential links to biological processes and survival. Turk J Biol 2021; 45:599-612. [PMID: 34803457 PMCID: PMC8574195 DOI: 10.3906/biy-2104-13] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2021] [Accepted: 06/19/2021] [Indexed: 11/05/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the deadliest cancers. Research on HCC so far primarily focused on genes and provided limited information on genomic repeats, which constitute more than half of the human genome and contribute to genomic stability. In line with this, repeat dysregulation was significantly shown to be pathological in various cancers and other diseases. In this study, we aimed to determine the full repeat expression profile of HCC for the first time. We utilised two independent RNA-seq datasets obtained from primary HCC tumours with matched normal tissues of 20 and 17 HCC patients, respectively. We quantified repeat expressions and analysed their differential expression. We also identified repeats that are cooperatively expressed with genes by constructing a gene coexpression network. Our results indicated that HCC tumours in both datasets harbour 24 differentially expressed repeats and even more elements were coexpressed with genes involved in various metabolic pathways. We discovered that two L1 elements (L1M3b, L1M3de) were downregulated and a handful of HERV subfamily repeats (HERV-Fc1-int, HERV3-int, HERVE_a-int, HERVK11D-int, HERVK14C-int, HERVL18-int) were upregulated with the exception of HERV1_LTRc, which was downregulated. Various LTR elements (LTR32, LTR9, LTR4, LTR52-int, LTR70) and MER elements (MER11C, MER11D, MER57C1, MER9a1, MER74C) were implicated along with few other subtypes including Charlie12, MLT2A2, Tigger15a, Tigger 17b. The only satellite repeat differentially expressed in both datasets was GSATII, whose expression was upregulated in 33 (>90%) out of 37 patients. Notably, GSATII expression correlated with HCC survival genes. Elements discovered here promise future studies to be considered for biomarker and HCC therapy research. The coexpression pattern of the GSATII satellite with HCC survival genes and the fact that it has been upregulated in the vast majority of patients make this repeat particularly stand out for HCC.
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Affiliation(s)
- Gökhan Karakülah
- İzmir Biomedicine and Genome Center (İBG), İzmir Turkey.,İzmir International Biomedicine and Genome Institute (İBG-İzmir), Dokuz Eylül University, İzmir Turkey
| | - Cihangir Yandim
- İzmir Biomedicine and Genome Center (İBG), İzmir Turkey.,Department of Genetics and Bioengineering, Faculty of Engineering, İzmir University of Economics, İzmir Turkey
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Herranz-Montoya I, Park S, Djouder N. A comprehensive analysis of prefoldins and their implication in cancer. iScience 2021; 24:103273. [PMID: 34761191 PMCID: PMC8567396 DOI: 10.1016/j.isci.2021.103273] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
Prefoldins (PFDNs) are evolutionary conserved co-chaperones, initially discovered in archaea but universally present in eukaryotes. PFDNs are prevalently organized into hetero-hexameric complexes. Although they have been overlooked since their discovery and their functions remain elusive, several reports indicate they act as co-chaperones escorting misfolded or non-native proteins to group II chaperonins. Unlike the eukaryotic PFDNs which interact with cytoskeletal components, the archaeal PFDNs can bind and stabilize a wide range of substrates, possibly due to their great structural diversity. The discovery of the unconventional RPB5 interactor (URI) PFDN-like complex (UPC) suggests that PFDNs have versatile functions and are required for different cellular processes, including an important role in cancer. Here, we summarize their functions across different species. Moreover, a comprehensive analysis of PFDNs genomic alterations across cancer types by using large-scale cancer genomic data indicates that PFDNs are a new class of non-mutated proteins significantly overexpressed in some cancer types.
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Affiliation(s)
- Irene Herranz-Montoya
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain
| | - Solip Park
- Computational Cancer Genomics Group, Structural Biology Programme, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain
| | - Nabil Djouder
- Growth Factors, Nutrients and Cancer Group, Molecular Oncology Programme, Centro Nacional de Investigaciones Oncológicas, CNIO, Madrid 28029, Spain
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Bhat M, Clotet-Freixas S, Baciu C, Pasini E, Hammad A, Ivanics T, Reid S, Azhie A, Angeli M, Ghanekar A, Fischer S, Sapisochin G, Konvalinka A. Combined proteomic/transcriptomic signature of recurrence post-liver transplantation for hepatocellular carcinoma beyond Milan. Clin Proteomics 2021; 18:27. [PMID: 34794390 PMCID: PMC8600773 DOI: 10.1186/s12014-021-09333-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Accepted: 11/03/2021] [Indexed: 02/07/2023] Open
Abstract
Background and aims Liver transplantation (LT) can be offered to patients with Hepatocellular carcinoma (HCC) beyond Milan criteria. However, there are currently limited molecular markers on HCC explant histology to predict recurrence, which arises in up to 20% of LT recipients. The goal of our study was to derive a combined proteomic/transcriptomic signature on HCC explant predictive of recurrence post-transplant using unbiased, high-throughput approaches. Methods Patients who received a LT for HCC beyond Milan criteria in the context of hepatitis B cirrhosis were identified. Tumor explants from patients with post-transplant HCC recurrence (N = 7) versus those without recurrence (N = 4) were analyzed by mass spectrometry and gene expression array. Univariate analysis was used to generate a combined proteomic/transcriptomic signature linked to recurrence. Significantly predictive genes and proteins were verified and internally validated by immunoblotting and immunohistochemistry. Results Seventy-nine proteins and 636 genes were significantly differentially expressed in HCC tumors with subsequent recurrence (p < 0.05). Univariate survival analysis identified Aldehyde Dehydrogenase 1 Family Member A1 (ALDH1A1) gene (HR = 0.084, 95%CI 0.01–0.68, p = 0.0152), ALDH1A1 protein (HR = 0.039, 95%CI 0.16–0.91, p = 0.03), Galectin 3 Binding Protein (LGALS3BP) gene (HR = 7.14, 95%CI 1.20–432.96, p = 0.03), LGALS3BP protein (HR = 2.6, 95%CI 1.1–6.1, p = 0.036), Galectin 3 (LGALS3) gene (HR = 2.89, 95%CI 1.01–8.3, p = 0.049) and LGALS3 protein (HR = 2.6, 95%CI 1.2–5.5, p = 0.015) as key dysregulated analytes in recurrent HCC. In concordance with our proteome findings, HCC recurrence was linked to decreased ALDH1A1 and increased LGALS3 protein expression by Western Blot. LGALS3BP protein expression was validated in 29 independent HCC samples. Conclusions Significantly increased LGALS3 and LGALS3BP gene and protein expression on explant were associated with post-transplant recurrence, whereas increased ALDH1A1 was associated with absence of recurrence in patients transplanted for HCC beyond Milan criteria. This combined proteomic/transcriptomic signature could help in predicting HCC recurrence risk and guide post-transplant surveillance. Supplementary Information The online version contains supplementary material available at 10.1186/s12014-021-09333-x.
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Affiliation(s)
- Mamatha Bhat
- Ajmera Transplant Program, University Health Network, Toronto, Canada. .,Division of Gastroenterology and Hepatology, University of Toronto, Toronto, Canada. .,Toronto General Hospital Research Institute, Toronto, Canada. .,Institute of Medical Science, University of Toronto, Toronto, Canada.
| | - Sergi Clotet-Freixas
- Ajmera Transplant Program, University Health Network, Toronto, Canada.,Toronto General Hospital Research Institute, Toronto, Canada
| | - Cristina Baciu
- Ajmera Transplant Program, University Health Network, Toronto, Canada
| | - Elisa Pasini
- Ajmera Transplant Program, University Health Network, Toronto, Canada
| | - Ahmed Hammad
- Ajmera Transplant Program, University Health Network, Toronto, Canada.,Department of General Surgery, Mansoura University, Mansoura, Egypt
| | - Tommy Ivanics
- Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Canada
| | - Shelby Reid
- Institute of Medical Science, University of Toronto, Toronto, Canada
| | - Amirhossein Azhie
- Ajmera Transplant Program, University Health Network, Toronto, Canada
| | - Marc Angeli
- Ajmera Transplant Program, University Health Network, Toronto, Canada
| | - Anand Ghanekar
- Ajmera Transplant Program, University Health Network, Toronto, Canada.,Toronto General Hospital Research Institute, Toronto, Canada.,Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Canada
| | - Sandra Fischer
- Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Canada
| | - Gonzalo Sapisochin
- Ajmera Transplant Program, University Health Network, Toronto, Canada.,Division of Multi-Organ Transplant and HPB Surgical Oncology, Department of General Surgery, University Health Network, Toronto, Canada
| | - Ana Konvalinka
- Ajmera Transplant Program, University Health Network, Toronto, Canada. .,Toronto General Hospital Research Institute, Toronto, Canada. .,Department of Laboratory Medicine and Pathology, University of Toronto, Toronto, Canada. .,Institute of Medical Science, University of Toronto, Toronto, Canada. .,Division of Nephrology, Department of Medicine, University Health Network, Toronto, Canada. .,University Health Network, 585 University Avenue, Room 11-PMB-189, Toronto, ON, M5G 2N2, Canada.
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Single-Cell Transcriptomics Reveals the Expression of Aging- and Senescence-Associated Genes in Distinct Cancer Cell Populations. Cells 2021; 10:cells10113126. [PMID: 34831349 PMCID: PMC8623328 DOI: 10.3390/cells10113126] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/31/2021] [Accepted: 11/09/2021] [Indexed: 12/12/2022] Open
Abstract
The human aging process is associated with molecular changes and cellular degeneration, resulting in a significant increase in cancer incidence with age. Despite their potential correlation, the relationship between cancer- and ageing-related transcriptional changes is largely unknown. In this study, we aimed to analyze aging-associated transcriptional patterns in publicly available bulk mRNA-seq and single-cell RNA-seq (scRNA-seq) datasets for chronic myelogenous leukemia (CML), colorectal cancer (CRC), hepatocellular carcinoma (HCC), lung cancer (LC), and pancreatic ductal adenocarcinoma (PDAC). Indeed, we detected that various aging/senescence-induced genes (ASIGs) were upregulated in malignant diseases compared to healthy control samples. To elucidate the importance of ASIGs during cell development, pseudotime analyses were performed, which revealed a late enrichment of distinct cancer-specific ASIG signatures. Notably, we were able to demonstrate that all cancer entities analyzed in this study comprised cell populations expressing ASIGs. While only minor correlations were detected between ASIGs and transcriptome-wide changes in PDAC, a high proportion of ASIGs was induced in CML, CRC, HCC, and LC samples. These unique cellular subpopulations could serve as a basis for future studies on the role of aging and senescence in human malignancies.
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Sánchez PS, Rigual MDM, Djouder N. Inflammatory and Non-Inflammatory Mechanisms Controlling Cirrhosis Development. Cancers (Basel) 2021; 13:cancers13205045. [PMID: 34680192 PMCID: PMC8534267 DOI: 10.3390/cancers13205045] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Revised: 10/01/2021] [Accepted: 10/03/2021] [Indexed: 12/28/2022] Open
Abstract
Simple Summary The liver is continuously exposed to several harmful factors, subsequently activating sophisticated mechanisms set-up in order to repair and regenerate the damaged liver and hence to prevent its failure. When the injury becomes chronic, the regenerative response becomes perpetual and goes awry, leading to cirrhosis with a fatal liver dysfunction. Cirrhosis is a well-known risk factor for hepatocellular carcinoma (HCC), the most common, usually lethal, human primary liver neoplasm with very limited therapeutic options. Considering the pivotal role of immune factors in the development of cirrhosis, here we review and discuss the inflammatory pathways and components implicated in the development of cirrhosis. A better understanding of these circuits would help the design of novel strategies to prevent and treat cirrhosis and HCC, two lethal diseases. Abstract Because the liver is considered to be one of the most important metabolic organs in the body, it is continuously exposed to damaging environmental agents. Upon damage, several complex cellular and molecular mechanisms in charge of liver recovery and regeneration are activated to prevent the failure of the organ. When liver injury becomes chronic, the regenerative response goes awry and impairs the liver function, consequently leading to cirrhosis, a liver disorder that can cause patient death. Cirrhosis has a disrupted liver architecture and zonation, along with the presence of fibrosis and parenchymal nodules, known as regenerative nodules (RNs). Inflammatory cues contribute to the cirrhotic process in response to chronic damaging agents. Cirrhosis can progress to HCC, the most common and one of the most lethal liver cancers with unmet medical needs. Considering the essential role of inflammatory pathways in the development of cirrhosis, further understanding of the relationship between immune cells and the activation of RNs and fibrosis would guide the design of innovative therapeutic strategies to ameliorate the survival of cirrhotic and HCC patients. In this review, we will summarize the inflammatory mechanisms implicated in the development of cirrhosis.
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Affiliation(s)
| | | | - Nabil Djouder
- Correspondence: ; Tel.: +34-3-491-732-8000 (ext. 3830); Fax: +34-3-491-224-6914
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Aloia L. The influence of tissue spatial geometry and functional organisation on liver regeneration. Semin Cell Dev Biol 2021; 130:70-78. [PMID: 34563460 DOI: 10.1016/j.semcdb.2021.09.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 08/09/2021] [Accepted: 09/10/2021] [Indexed: 12/14/2022]
Abstract
The adult liver exerts crucial functions, including nutrient metabolism and storage, bile production and drug detoxification. These complex functions expose the liver to constant damage induced by toxins, metabolic intermediates and oxidative stress. However, the adult liver exhibits an exceptional regenerative potential, which allows fast and efficient restoration of tissue architecture and function both after tissue resection and toxic damage. To accomplish its vital role, the liver shows a peculiar tissue architecture into functional units, which follow the gradient of oxygen and nutrients within the parenchyma. Much less is known about the influence of tissue spatial geometry and functional organisation on adult liver regeneration. Here I examine the experimental evidence in mouse models showing that the spatial organisation of the epithelial and mesenchymal compartments plays a key role in liver regeneration and favours the establishment of regenerative adult liver progenitors following liver injury. I also discuss the advantages and limitations of human and mouse 3D hepatic organoid systems, which recapitulate key aspects of liver function and architecture, as models of liver regeneration and disease. Finally, I analyse the role of the YAP/TAZ transcriptional co-activators as a central hub sensing the extra-cellular matrix (ECM), metabolic and epigenetic remodelling that regulate liver regeneration and promote liver disease, such as fibrosis, chronic liver disease and liver cancer. Together, the findings summarised here demonstrate that local physical and functional cellular interactions determined by the liver peculiar spatial geometry, play a crucial role in liver regeneration, and that their alterations have important implications for human liver disease.
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Affiliation(s)
- Luigi Aloia
- MRC Laboratory for Molecular Cell Biology, University College London, Gower Street, London WC1E 6BT, UK
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48
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Yang F, Wan Y, Xu L, Wu Y, Shen X, Wang J, Lu D, Shao C, Zheng S, Niu T, Xu X. MRI-Radiomics Prediction for Cytokeratin 19-Positive Hepatocellular Carcinoma: A Multicenter Study. Front Oncol 2021; 11:672126. [PMID: 34476208 PMCID: PMC8406635 DOI: 10.3389/fonc.2021.672126] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 07/20/2021] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer and has poor prognosis. Cytokeratin (CK)19-positive (CK19+) HCC is especially aggressive; early identification of this subtype and timely intervention can potentially improve clinical outcomes. In the present study, we developed a preoperative gadoxetic acid-enhanced magnetic resonance imaging (MRI)-based radiomics model for noninvasive and accurate classification of CK19+ HCC. A multicenter and time-independent cohort of 257 patients were retrospectively enrolled (training cohort, n = 143; validation cohort A, n = 75; validation cohort B, n = 39). A total of 968 radiomics features were extracted from preoperative multisequence MR images. The maximum relevance minimum redundancy algorithm was applied for feature selection. Multiple logistic regression, support vector machine, random forest, and artificial neural network (ANN) algorithms were used to construct the radiomics model, and the area under the receiver operating characteristic (AUROC) curve was used to evaluate the diagnostic performance of corresponding classifiers. The incidence of CK19+ HCC was significantly higher in male patients. The ANN-derived combined classifier comprising 12 optimal radiomics features showed the best diagnostic performance, with AUROCs of 0.857, 0.726, and 0.790 in the training cohort and validation cohorts A and B, respectively. The combined model based on multisequence MRI radiomics features can be used for preoperative noninvasive and accurate classification of CK19+ HCC, so that personalized management strategies can be developed.
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Affiliation(s)
- Fan Yang
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yidong Wan
- Institute of Translational Medicine, Zhejiang University, Hangzhou, China.,Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Lei Xu
- Institute of Translational Medicine, Zhejiang University, Hangzhou, China.,Department of Radiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yichao Wu
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoyong Shen
- Department of Radiology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Jianguo Wang
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Di Lu
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Chuxiao Shao
- Department of General Surgery, Lishui Central Hospital, Lishui, China
| | - Shusen Zheng
- Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, Shulan Health Hangzhou Hospital, Hangzhou, China
| | - Tianye Niu
- Nucelar & Radiological Engineering and Medical Physics Programs, Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, The Center of Integrated Oncology and Precision Medicine, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Zhejiang University Cancer Center, Hangzhou, China.,NHC Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China.,Institute of Organ Transplantation, Zhejiang University, Hangzhou, China
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Goonetilleke M, Kuk N, Correia J, Hodge A, Moore G, Gantier MP, Yeoh G, Sievert W, Lim R. Addressing the liver progenitor cell response and hepatic oxidative stress in experimental non-alcoholic fatty liver disease/non-alcoholic steatohepatitis using amniotic epithelial cells. Stem Cell Res Ther 2021; 12:429. [PMID: 34321089 PMCID: PMC8317377 DOI: 10.1186/s13287-021-02476-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Accepted: 06/26/2021] [Indexed: 12/29/2022] Open
Abstract
Background Non-alcoholic fatty liver disease is the most common liver disease globally and in its inflammatory form, non-alcoholic steatohepatitis (NASH), can progress to cirrhosis and hepatocellular carcinoma (HCC). Currently, patient education and lifestyle changes are the major tools to prevent the continued progression of NASH. Emerging therapies in NASH target known pathological processes involved in the progression of the disease including inflammation, fibrosis, oxidative stress and hepatocyte apoptosis. Human amniotic epithelial cells (hAECs) were previously shown to be beneficial in experimental models of chronic liver injury, reducing hepatic inflammation and fibrosis. Previous studies have shown that liver progenitor cells (LPCs) response plays a significant role in the development of fibrosis and HCC in mouse models of fatty liver disease. In this study, we examined the effect hAECs have on the LPC response and hepatic oxidative stress in an experimental model of NASH. Methods Experimental NASH was induced in C57BL/6 J male mice using a high-fat, high fructose diet for 42 weeks. Mice received either a single intraperitoneal injection of 2 × 106 hAECs at week 34 or an additional hAEC dose at week 38. Changes to the LPC response and oxidative stress regulators were measured. Results hAEC administration significantly reduced the expansion of LPCs and their mitogens, IL-6, IFNγ and TWEAK. hAEC administration also reduced neutrophil infiltration and myeloperoxidase production with a concurrent increase in heme oxygenase-1 production. These observations were accompanied by a significant increase in total levels of anti-fibrotic IFNβ in mice treated with a single dose of hAECs, which appeared to be independent of c-GAS-STING activation. Conclusions Expansion of liver progenitor cells, hepatic inflammation and oxidative stress associated with experimental NASH were attenuated by hAEC administration. Given that repeated doses did not significantly increase efficacy, future studies assessing the impact of dose escalation and/or timing of dose may provide insights into clinical translation. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02476-6.
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Affiliation(s)
- Mihiri Goonetilleke
- Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia.,The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia
| | - Nathan Kuk
- Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia.,Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
| | - Jeanne Correia
- Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia.,The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia.,Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
| | - Alex Hodge
- Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia.,Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
| | - Gregory Moore
- Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia.,Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
| | - Michael P Gantier
- Department of Molecular and Translational Science, Monash University, Clayton, Victoria, Australia.,Centre for Innate Immunity and Infectious Disease, Hudson Institute of Medical Research, Melbourne, Victoria, Australia
| | - George Yeoh
- Centre for Medical Research, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.,School of Molecular Sciences, The University of Western Australia, Crawley, Western Australia, Australia.,Centre for Cell Therapy and Regenerative Medicine, School of Biomedical Sciences, The University of Western Australia, Crawley, Western Australia, Australia
| | - William Sievert
- Centre for Inflammatory Disease, School of Clinical Sciences, Monash University, Melbourne, Victoria, Australia.,Gastroenterology and Hepatology Unit, Monash Health, Melbourne, Victoria, Australia
| | - Rebecca Lim
- The Ritchie Centre, Hudson Institute of Medical Research, Melbourne, Victoria, Australia. .,Department of Obstetrics and Gynaecology, Monash University, Melbourne, Victoria, Australia.
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50
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Orabi D, Berger NA, Brown JM. Abnormal Metabolism in the Progression of Nonalcoholic Fatty Liver Disease to Hepatocellular Carcinoma: Mechanistic Insights to Chemoprevention. Cancers (Basel) 2021; 13:3473. [PMID: 34298687 PMCID: PMC8307710 DOI: 10.3390/cancers13143473] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is on the rise and becoming a major contributor to the development of hepatocellular carcinoma (HCC). Reasons for this include the rise in obesity and metabolic syndrome in contrast to the marked advances in prevention and treatment strategies of viral HCC. These shifts are expected to rapidly propel this trend even further in the coming decades, with NAFLD on course to become the leading etiology of end-stage liver disease and HCC. No Food and Drug Administration (FDA)-approved medications are currently available for the treatment of NAFLD, and advances are desperately needed. Numerous medications with varying mechanisms of action targeting liver steatosis and fibrosis are being investigated including peroxisome proliferator-activated receptor (PPAR) agonists and farnesoid X receptor (FXR) agonists. Additionally, drugs targeting components of metabolic syndrome, such as antihyperglycemics, have been found to affect NAFLD progression and are now being considered in the treatment of these patients. As NAFLD drug discovery continues, special attention should be given to their relationship to HCC. Several mechanisms in the pathogenesis of NAFLD have been implicated in hepatocarcinogenesis, and therapies aimed at NAFLD may additionally harbor independent antitumorigenic potential. This approach may provide novel prevention and treatment strategies.
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Affiliation(s)
- Danny Orabi
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA;
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
- Department of General Surgery, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Nathan A. Berger
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - J. Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA;
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
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