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Jain A, Mishra AK, Hurkat P, Shilpi S, Mody N, Jain SK. Navigating liver cancer: Precision targeting for enhanced treatment outcomes. Drug Deliv Transl Res 2025:10.1007/s13346-024-01780-x. [PMID: 39847205 DOI: 10.1007/s13346-024-01780-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/18/2024] [Indexed: 01/24/2025]
Abstract
Cancer treatments such as surgery and chemotherapy have several limitations, including ineffectiveness against large or persistent tumors, high relapse rates, drug toxicity, and non-specificity of therapy. Researchers are exploring advanced strategies for treating this life-threatening disease to address these challenges. One promising approach is targeted drug delivery using prodrugs or surface modification with receptor-specific moieties for active or passive targeting. While various drug delivery systems have shown potential for reaching hepatic cells, nano-carriers offer significant size, distribution, and targetability advantages. Engineered nanocarriers can be customized to achieve effective and safe targeting of tumors by manipulating physical characteristics such as particle size or attaching receptor-specific ligands. This method is particularly advantageous in treating liver cancer by targeting specific hepatocyte receptors and enzymatic pathways for both passive and active therapeutic strategies. It highlights the epidemiology of liver cancer and provides an in-depth analysis of the various targeting approaches, including prodrugs, liposomes, magneto-liposomes, micelles, glycol-dendrimers, magnetic nanoparticles, chylomicron-based emulsion, and quantum dots surface modification with receptor-specific moieties. The insights from this review can be immensely significant for preclinical and clinical researchers working towards developing effective treatments for liver cancer. By utilizing these novel strategies, we can overcome the limitations of conventional therapies and offer better outcomes for liver cancer patients.
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Affiliation(s)
- Ankit Jain
- Department of Pharmacy, Birla Institute of Technology and Science (BITS), Pilani Campus, Pilani, Rajasthan, 333031, India.
| | - Ashwini Kumar Mishra
- Department of Pharmaceutics, School of Pharmacy & Technology Management, SVKM'S NMIMS Deemed-to-be University, Shirpur, Maharashtra, 425405, India
- Central Ayurveda Research Institute, Jhansi, Uttar Pradesh, 284003, India
| | - Pooja Hurkat
- Dr. Hari Singh Gour Central University, Sagar, 470003, MP, India
| | - Satish Shilpi
- School of Pharmaceuticals and Population Health Informatics, FOP, DIT University, Dehradun, Uttarakahnad, India
| | - Nishi Mody
- Dr. Hari Singh Gour Central University, Sagar, 470003, MP, India
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Chehelgerdi M, Behdarvand Dehkordi F, Chehelgerdi M, Kabiri H, Salehian-Dehkordi H, Abdolvand M, Salmanizadeh S, Rashidi M, Niazmand A, Ahmadi S, Feizbakhshan S, Kabiri S, Vatandoost N, Ranjbarnejad T. Exploring the promising potential of induced pluripotent stem cells in cancer research and therapy. Mol Cancer 2023; 22:189. [PMID: 38017433 PMCID: PMC10683363 DOI: 10.1186/s12943-023-01873-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Accepted: 09/27/2023] [Indexed: 11/30/2023] Open
Abstract
The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. The formation of cancer is a multifaceted process influenced by genetic, epigenetic, and environmental factors. iPSCs offer a distinctive platform for investigating the origin of cancer, paving the way for novel approaches to cancer treatment, drug testing, and tailored medical interventions. This review article will provide an overview of the science behind iPSCs, the current limitations and challenges in iPSC-based cancer therapy, the ethical and social implications, and the comparative analysis with other stem cell types for cancer treatment. The article will also discuss the applications of iPSCs in tumorigenesis, the future of iPSCs in tumorigenesis research, and highlight successful case studies utilizing iPSCs in tumorigenesis research. The conclusion will summarize the advancements made in iPSC-based tumorigenesis research and the importance of continued investment in iPSC research to unlock the full potential of these cells.
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Affiliation(s)
- Matin Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Fereshteh Behdarvand Dehkordi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Mohammad Chehelgerdi
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran.
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran.
| | - Hamidreza Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | | | - Mohammad Abdolvand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Sharareh Salmanizadeh
- Department of Cell and Molecular Biology and Microbiology, Faculty of Biological Science and Technology, University of Isfahan, Hezar-Jereeb Street, Isfahan, 81746-73441, Iran
| | - Mohsen Rashidi
- Department Pharmacology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
- The Health of Plant and Livestock Products Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Anoosha Niazmand
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saba Ahmadi
- Department of Molecular and Medical Genetics, Tbilisi State Medical University, Tbilisi, Georgia
| | - Sara Feizbakhshan
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
| | - Saber Kabiri
- Novin Genome (NG) Lab, Research and Development Center for Biotechnology, Shahrekord, Iran
- Young Researchers and Elite Club, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Nasimeh Vatandoost
- Pediatric Inherited Diseases Research Center, Research Institute for Primordial Prevention of Non-Communicable Disease, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Tayebeh Ranjbarnejad
- Department of Genetics and Molecular Biology, School of Medicine, Isfahan University of Medical Science, Isfahan, Iran
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Chen L, Zhang N, Huang Y, Zhang Q, Fang Y, Fu J, Yuan Y, Chen L, Chen X, Xu Z, Li Y, Izawa H, Xiang C. Multiple Dimensions of using Mesenchymal Stem Cells for Treating Liver Diseases: From Bench to Beside. Stem Cell Rev Rep 2023; 19:2192-2224. [PMID: 37498509 DOI: 10.1007/s12015-023-10583-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/26/2023] [Indexed: 07/28/2023]
Abstract
Liver diseases impose a huge burden worldwide. Although hepatocyte transplantation has long been considered as a potential strategy for treating liver diseases, its clinical implementation has created some obvious limitations. As an alternative strategy, cell therapy, particularly mesenchymal stem cell (MSC) transplantation, is widely used in treating different liver diseases, including acute liver disease, acute-on-chronic liver failure, hepatitis B/C virus, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, alcoholic liver disease, liver fibrosis, liver cirrhosis, and hepatocellular carcinoma. Here, we summarize the status of MSC transplantation in treating liver diseases, focusing on the therapeutic mechanisms, including differentiation into hepatocyte-like cells, immunomodulating function with a variety of immune cells, paracrine effects via the secretion of various cytokines and extracellular vesicles, and facilitation of homing and engraftment. Some improved perspectives and current challenges are also addressed. In summary, MSCs have great potential in the treatment of liver diseases based on their multi-faceted characteristics, and more accurate mechanisms and novel therapeutic strategies stemming from MSCs will facilitate clinical practice.
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Affiliation(s)
- Lijun Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Ning Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yuqi Huang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Qi Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yangxin Fang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Jiamin Fu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Yin Yuan
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Lu Chen
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Xin Chen
- Department of Hematology, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310027, People's Republic of China
| | - Zhenyu Xu
- Innovative Precision Medicine (IPM) Group, Hangzhou, Zhejiang, 311215, People's Republic of China
| | - Yifei Li
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China
| | - Hiromi Izawa
- Jingugaien Woman Life Clinic, Jingu-Gaien 3-39-5 2F, Shibuya-Ku, Tokyo, Japan
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, National Medical Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, 310003, People's Republic of China.
- Research Units of Infectious Disease and Microecology, Chinese Academy of Medical Sciences, Hangzhou, Zhejiang, 310003, People's Republic of China.
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Liu W, Gao L, Hou X, Feng S, Yan H, Pan H, Zhang S, Yang X, Jiang J, Ye F, Zhao Q, Wei L, Han Z. TWEAK Signaling-Induced ID1 Expression Drives Malignant Transformation of Hepatic Progenitor Cells During Hepatocarcinogenesis. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2023; 10:e2300350. [PMID: 37085918 PMCID: PMC10288241 DOI: 10.1002/advs.202300350] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Revised: 03/14/2023] [Indexed: 05/03/2023]
Abstract
The malignant transformation of hepatic progenitor cells (HPCs) in the inflammatory microenvironment is the root cause of hepatocarcinogenesis. However, the potential molecular mechanisms are still elusive. The HPCs subgroup is identified by single-cell RNA (scRNA) sequencing and the phenotype of HPCs is investigated in the primary HCC model. Bulk RNA sequencing (RNA-seq) and proteomic analyses are also performed on HPC-derived organoids. It is found that tumors are formed from HPCs in peritumor tissue at the 16th week in a HCC model. Furthermore, it is confirmed that the macrophage-derived TWEAK/Fn14 promoted the expression of inhibitor of differentiation-1 (ID1) in HPCs via NF-κB signaling and a high level of ID1 induced aberrant differentiation of HPCs. Mechanistically, ID1 suppressed differentiation and promoted proliferation in HPCs through the inhibition of HNF4α and Rap1GAP transcriptions. Finally, scRNA sequencing of HCC patients and investigation of clinical specimens also verified that the expression of ID1 is correlated with aberrant differentiation of HPCs into cancer stem cells, patients with high levels of ID1 in HPCs showed a poorer prognosis. This study provides important intervention targets and a theoretical basis for the clinical diagnosis and treatment of HCC.
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Affiliation(s)
- Wenting Liu
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Lu Gao
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Xiaojuan Hou
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Shiyao Feng
- Department of UrologySecond Affiliated HospitalAnhui Medical UniversityHefei230601P. R. China
| | - Haixin Yan
- Department of UrologySecond Affiliated HospitalAnhui Medical UniversityHefei230601P. R. China
| | - Hongyu Pan
- Department of Hepatic SurgeryThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
| | - Shichao Zhang
- Department of Hepatic SurgeryThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
| | - Xue Yang
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Jinghua Jiang
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Fei Ye
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Qiudong Zhao
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Lixin Wei
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
| | - Zhipeng Han
- Tumor Immunology and Gene Therapy CenterThird Affiliated Hospital of Naval Medical UniversityShanghai200438P. R. China
- Key Laboratory on Signaling Regulation and Targeting Therapy of Liver Cancer of Ministry of EducationEastern Hepatobiliary Surgery Hospital/National Center for Liver CancerNaval Medical UniversityShanghai200438P. R. China
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Liu S, Bu X, Kan A, Luo L, Xu Y, Chen H, Lin X, Lai Z, Wen D, Huang L, Shi M. SP1-induced lncRNA DUBR promotes stemness and oxaliplatin resistance of hepatocellular carcinoma via E2F1-CIP2A feedback. Cancer Lett 2022; 528:16-30. [PMID: 34958891 DOI: 10.1016/j.canlet.2021.12.026] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/20/2022]
Abstract
Oxaliplatin-based chemotherapy is widely used to treat advanced hepatocellular carcinoma (HCC), but many patients develop drug resistance that leads to tumor recurrence. Cancer stem cells (CSCs) are known to contribute to chemoresistance, the underlying mechanism, however, remains largely unknown. In this study, we discovered a specificity protein 1 (SP1)-induced long noncoding RNA--DPPA2 upstream binding RNA (DUBR) and its high expression in HCC tissues and liver CSCs. DUBR was associated with HCC progression and poor chemotherapy response. Moreover, DUBR facilitated the stemness and oxaliplatin resistance of HCC in vitro and in vivo. Mechanistically, DUBR upregulated cancerous inhibitor of protein phosphatase 2A (CIP2A) expression through E2F1-mediated transcription regulation. DUBR also exerted function by binding microRNA (miR)-520d-5p as a competing endogenous RNA to upregulate CIP2A at mRNA level. CIP2A, in turn, stabilized E2F1 protein and activated the Notch1 signaling pathway, thereby increasing the stemness feature of HCC and leading to chemoresistance. In conclusion, we identified SP1/DUBR/E2F1-CIP2A as a critical axis to activate the Notch1 signaling pathway and promote stemness and chemoresistance of HCC. Therefore, DUBR could be a potential target in HCC treatment.
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Affiliation(s)
- S Liu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xy Bu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Anna Kan
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - L Luo
- State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Yj Xu
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Hl Chen
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Xj Lin
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Zc Lai
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Ds Wen
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Lc Huang
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - M Shi
- Department of Hepatobiliary Oncology, Sun Yat-sen University Cancer Center, Guangzhou, China; State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China.
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Yu W, Ma Y, Shrivastava SK, Srivastava RK, Shankar S. Chronic alcohol exposure induces hepatocyte damage by inducing oxidative stress, SATB2 and stem cell‐like characteristics, and activating lipogenesis. J Cell Mol Med 2022; 26:2119-2131. [PMID: 35152538 PMCID: PMC8980954 DOI: 10.1111/jcmm.17235] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2021] [Revised: 01/25/2022] [Accepted: 01/31/2022] [Indexed: 12/12/2022] Open
Abstract
Alcohol is a risk factor for hepatocellular carcinoma (HCC). However, the molecular mechanism by which chronic alcohol consumption contributes to HCC is not well understood. The purpose of the study was to demonstrate the effects of chronic ethanol exposure on the damage of human normal hepatocytes. Our data showed that chronic exposure of hepatocytes with ethanol induced changes similar to transformed hepatocytes that is, exhibited colonies and anchorage‐independent growth. These damaged hepatocytes contained high levels of reactive oxygen species (ROS) and showed induction of the SATB2 gene. Furthermore, damaged hepatocytes gained the phenotypes of CSCs which expressed stem cell markers (CD133, CD44, CD90, EpCAM, AFP and LGR5), and pluripotency maintaining factors (Sox‐2, POU5F1/Oct4 and KLF‐4). Ethanol exposure also induced Nanog, a pluripotency maintaining transcription factor that functions in concert with Oct4 and SOX‐2. Furthermore, ethanol induced expression of EMT‐related transcription factors (Snail, Slug and Zeb1), N‐Cadherin, and inhibited E‐cadherin expression in damaged hepatocytes. Ethanol enhanced recruitment of SATB2 to promoters of Bcl‐2, Nanog, c‐Myc, Klf4 and Oct4. Ethanol also induced activation of the Wnt/TCF‐LEF1 pathway and its targets (Bcl‐2, Cyclin D1, AXIN2 and Myc). Finally, ethanol induced hepatocellular steatosis, SREBP1 transcription, and modulated the expression of SREBP1c, ACAC, ACLY, FASN, IL‐1β, IL‐6, TNF‐α, GPC3, FLNB and p53. These data suggest that chronic alcohol consumption may contribute towards the development of HCC by damaging normal hepatocytes with the generation of inflammatory environment, induction of SATB2, stem cell‐like characteristics, and cellular steatosis.
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Affiliation(s)
- Wei Yu
- Kansas City VA Medical Center Kansas City Missouri USA
| | - Yiming Ma
- Kansas City VA Medical Center Kansas City Missouri USA
| | - Sushant K. Shrivastava
- Department of Pharmaceutics Indian Institute of Technology Banaras Hindu University Varanasi U.P. India
| | - Rakesh K. Srivastava
- Kansas City VA Medical Center Kansas City Missouri USA
- Department of Genetics Louisiana State University Health Sciences Center New Orleans Louisina USA
- Stanley S. Scott Cancer Center Department of Genetics Louisiana State University Health Sciences Center New Orleans Louisina USA
- A.B. Freeman School of Business Tulane University New Orleans Louisina USA
| | - Sharmila Shankar
- Kansas City VA Medical Center Kansas City Missouri USA
- John W. Deming Department of Medicine Tulane University School of Medicine New Orleans Louisina USA
- Southeast Louisiana Veterans Health Care System New Orleans Louisina USA
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Shu Y, Xu Q, Xu Y, Tao Q, Shao M, Cao X, Chen Y, Wu Z, Chen M, Zhou Y, Zhou P, Shi Y, Bu H. Loss of Numb promotes hepatic progenitor expansion and intrahepatic cholangiocarcinoma by enhancing Notch signaling. Cell Death Dis 2021; 12:966. [PMID: 34667161 PMCID: PMC8526591 DOI: 10.1038/s41419-021-04263-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Revised: 09/26/2021] [Accepted: 10/06/2021] [Indexed: 02/05/2023]
Abstract
Numb, a stem cell fate determinant, acts as a tumor suppressor and is closely related to a wide variety of malignancies. Intrahepatic cholangiocarcinoma (iCCA) originates from hepatic progenitors (HPCs); however, the role of Numb in HPC malignant transformation and iCCA development is still unclear. A retrospective cohort study indicated that Numb was frequently decreased in tumor tissues and suggests poor prognosis in iCCA patients. Consistently, in a chemically induced iCCA mouse model, Numb was downregulated in tumor cells compared to normal cholangiocytes. In diet-induced chronic liver injury mouse models, Numb ablation significantly promoted histological impairment, HPC expansion, and tumorigenesis. Similarly, Numb silencing in cultured iCCA cells enhanced cell spheroid growth, invasion, metastasis, and the expression of stem cell markers. Mechanistically, Numb was found to bind to the Notch intracellular domain (NICD), and Numb ablation promoted Notch signaling; this effect was reversed when Notch signaling was blocked by γ-secretase inhibitor treatment. Our results suggested that loss of Numb plays an important role in promoting HPC expansion, HPC malignant transformation, and, ultimately, iCCA development in chronically injured livers. Therapies targeting suppressed Numb are promising for the treatment of iCCA.
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Affiliation(s)
- Yuke Shu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qing Xu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yahong Xu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Qing Tao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Mingyang Shao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Xiaoyue Cao
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yuwei Chen
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Zhenru Wu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Menglin Chen
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Yongjie Zhou
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
- Laboratory of Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, China
| | - Ping Zhou
- Department of Pathology, Sichuan Tumor Hospital, Chengdu, 610041, China
| | - Yujun Shi
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China.
- Laboratory of Transplantation, West China Hospital, Sichuan University, Chengdu, 610041, China.
| | - Hong Bu
- Institute of Clinical Pathology, Key Laboratory of Transplant Engineering and Immunology, NHC, West China Hospital, Sichuan University, Chengdu, 610041, China
- Department of Pathology, West China Hospital, Sichuan University, Chengdu, 610041, China
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8
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Narayanan S, Au VB, Khakpoor A, Yan C, Ahl PJ, Kaliaperumal N, Lee B, Xiang WW, Wang J, Lee C, Tay A, Lim SG, Connolly JE. Bayesian analysis of cytokines and chemokine identifies immune pathways of HBsAg loss during chronic hepatitis B treatment. Sci Rep 2021; 11:7455. [PMID: 33811250 PMCID: PMC8018960 DOI: 10.1038/s41598-021-86836-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Accepted: 03/19/2021] [Indexed: 12/13/2022] Open
Abstract
Our objective was to examine differences in cytokine/chemokine response in chronic hepatitis B(CHB) patients to understand the immune mechanism of HBsAg loss (functional cure) during antiviral therapy. We used an unbiased machine learning strategy to unravel the immune pathways in CHB nucleo(t)side analogue-treated patients who achieved HBsAg loss with peg-interferon-α(peg-IFN-α) add-on or switch treatment in a randomised clinical trial. Cytokines/chemokines from plasma were compared between those with/without HBsAg loss, at baseline, before and after HBsAg loss. Peg-IFN-α treatment resulted in higher levels of IL-27, IL-12p70, IL-18, IL-13, IL-4, IL-22 and GM-CSF prior to HBsAg loss. Probabilistic network analysis of cytokines, chemokines and soluble factors suggested a dynamic dendritic cell driven NK and T cell immune response associated with HBsAg loss. Bayesian network analysis showed a dominant myeloid-driven type 1 inflammatory response with a MIG and I-TAC central module contributing to HBsAg loss in the add-on arm. In the switch arm, HBsAg loss was associated with a T cell activation module exemplified by high levels of CD40L suggesting T cell activation. Our findings show that more than one immune pathway to HBsAg loss was found with peg-IFN-α therapy; by myeloid-driven Type 1 response in one instance, and T cell activation in the other.
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Affiliation(s)
- Sriram Narayanan
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Veonice Bijin Au
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Atefeh Khakpoor
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Cheng Yan
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Patricia J Ahl
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Nivashini Kaliaperumal
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore
| | - Bernett Lee
- Singapore Immunology Network, A*STAR REs, Singapore, Singapore
| | - Wen Wei Xiang
- IMCB, Tessa Therapeutics Pvt Ltd, Singapore, Singapore
| | - Juling Wang
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Chris Lee
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Amy Tay
- Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Seng Gee Lim
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore.,Division of Gastroenterology and Hepatology, Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - John E Connolly
- Translational Immunology Programme, Institute of Molecular and Cell Biology (IMCB), Agency for Science, Technology, and Research, Singapore (A*STAR) Research Entities (RE), 61 Biopolis Drive, Proteos, Singapore, 138673, Singapore. .,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,Institute of Biomedical Studies, Baylor University, Waco, TX, USA.
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9
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Han B, Mo H, Svarovskaia E, Mateo R. A primary human hepatocyte/hepatic stellate cell co-culture system for improved in vitro HBV replication. Virology 2021; 559:40-45. [PMID: 33813211 DOI: 10.1016/j.virol.2021.03.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/22/2021] [Accepted: 03/22/2021] [Indexed: 11/18/2022]
Abstract
Primary human hepatocytes (PHHs) are considered the gold standard for the in vitro study of HBV replication as they directly reflect the metabolism and functionality of the human liver. However, several limitations of this system include PHH donor-to-donor variability, limited life span and low permissiveness to HBV infection, which precludes long-term infection studies and viral passaging. Here, an easy-to-set-up co-culture platform that combines PHH with hepatic stellate cells (HSCs) was developed. This platform does not rely on chemical supplementation to sustain robust HBV replication and viral antigen secretion making it a more physiologically relevant system for in vitro HBV infection studies compared to the traditional short-lived PHH monocultures.
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Affiliation(s)
- Bin Han
- Gilead Sciences, Inc., Foster City, CA, USA
| | - Hongmei Mo
- Gilead Sciences, Inc., Foster City, CA, USA
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10
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Chen J, Mitra A, Li S, Song S, Nguyen BN, Chen JS, Shin JH, Gough NR, Lin P, Obias V, He AR, Yao Z, Malta TM, Noushmehr H, Latham PS, Su X, Rashid A, Mishra B, Wu RC, Mishra L. Targeting the E3 Ubiquitin Ligase PJA1 Enhances Tumor-Suppressing TGFβ Signaling. Cancer Res 2020; 80:1819-1832. [PMID: 32127355 DOI: 10.1158/0008-5472.can-19-3116] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Revised: 01/17/2020] [Accepted: 02/24/2020] [Indexed: 12/22/2022]
Abstract
RING-finger E3 ligases are instrumental in the regulation of inflammatory cascades, apoptosis, and cancer. However, their roles are relatively unknown in TGFβ/SMAD signaling. SMAD3 and its adaptors, such as β2SP, are important mediators of TGFβ signaling and regulate gene expression to suppress stem cell-like phenotypes in diverse cancers, including hepatocellular carcinoma (HCC). Here, PJA1, an E3 ligase, promoted ubiquitination and degradation of phosphorylated SMAD3 and impaired a SMAD3/β2SP-dependent tumor-suppressing pathway in multiple HCC cell lines. In mice deficient for SMAD3 (Smad3 +/-), PJA1 overexpression promoted the transformation of liver stem cells. Analysis of genes regulated by PJA1 knockdown and TGFβ1 signaling revealed 1,584 co-upregulated genes and 1,280 co-downregulated genes, including many implicated in cancer. The E3 ligase inhibitor RTA405 enhanced SMAD3-regulated gene expression and reduced growth of HCC cells in culture and xenografts of HCC tumors, suggesting that inhibition of PJA1 may be beneficial in treating HCC or preventing HCC development in at-risk patients.Significance: These findings provide a novel mechanism regulating the tumor suppressor function of TGFβ in liver carcinogenesis.
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Affiliation(s)
- Jian Chen
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
| | - Abhisek Mitra
- Pfizer Inc. Integrative Biotechnology Group, Pearl River, New York
| | - Shulin Li
- Department of Pediatrics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Shumei Song
- Department of GI Medical Oncology-Research, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bao-Ngoc Nguyen
- Center for Translational Medicine, Department of Surgery, George Washington University, Washington, D.C
| | - Jiun-Sheng Chen
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ji-Hyun Shin
- Department of Gastroenterology, Hepatology, and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Nancy R Gough
- Center for Translational Medicine, Department of Surgery, George Washington University, Washington, D.C.,BioSerendipity, LLC, Elkridge, Maryland
| | - Paul Lin
- Department of Surgery, George Washington University, Washington, D.C
| | - Vincent Obias
- Department of Surgery, George Washington University, Washington, D.C
| | - Aiwu Ruth He
- Department of Medicine and Oncology, Georgetown University, Lombardi Comprehensive Cancer Center Washington, D.C
| | - Zhixing Yao
- Department of Biochemistry and Molecular Biology, Howard University, Washington, D.C
| | - Tathiane M Malta
- Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan
| | - Houtan Noushmehr
- Department of Neurosurgery, Henry Ford Hospital, Detroit, Michigan
| | - Patricia S Latham
- Department of Pathology, George Washington University, Washington, D.C
| | - Xiaoping Su
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Asif Rashid
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Bibhuti Mishra
- Center for Translational Medicine, Department of Surgery, George Washington University, Washington, D.C
| | - Ray-Chang Wu
- Department of Biochemistry & Molecular Biology, George Washington University, Washington, D.C
| | - Lopa Mishra
- Center for Translational Medicine, Department of Surgery, George Washington University, Washington, D.C. .,Gastroenterology, Hepatology, and Nutrition Section, VA Medical Center, Washington, D.C
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11
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Meta-Analysis of Human and Mouse Biliary Epithelial Cell Gene Profiles. Cells 2019; 8:cells8101117. [PMID: 31547151 PMCID: PMC6829476 DOI: 10.3390/cells8101117] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 09/03/2019] [Accepted: 09/18/2019] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Chronic liver diseases are frequently accompanied with activation of biliary epithelial cells (BECs) that can differentiate into hepatocytes and cholangiocytes, providing an endogenous back-up system. Functional studies on BECs often rely on isolations of an BEC cell population from healthy and/or injured livers. However, a consensus on the characterization of these cells has not yet been reached. The aim of this study was to compare the publicly available transcriptome profiles of human and mouse BECs and to establish gene signatures that can identify quiescent and activated human and mouse BECs. METHODS We used publicly available transcriptome data sets of human and mouse BECs, compared their profiles and analyzed co-expressed genes and pathways. By merging both human and mouse BEC-enriched genes, we obtained a quiescent and activation gene signature and tested them on BEC-like cells and different liver diseases using gene set enrichment analysis. In addition, we identified several genes from both gene signatures to identify BECs in a scRNA sequencing data set. RESULTS Comparison of mouse BEC transcriptome data sets showed that the isolation method and array platform strongly influences their general profile, still most populations are highly enriched in most genes currently associated with BECs. Pathway analysis on human and mouse BECs revealed the KRAS signaling as a new potential pathway in BEC activation. We established a quiescent and activated BEC gene signature that can be used to identify BEC-like cells and detect BEC enrichment in alcoholic hepatitis, non-alcoholic steatohepatitis (NASH) and peribiliary sclerotic livers. Finally, we identified a gene set that can distinguish BECs from other liver cells in mouse and human scRNAseq data. CONCLUSIONS Through a meta-analysis of human and mouse BEC gene profiles we identified new potential pathways in BEC activation and created unique gene signatures for quiescent and activated BECs. These signatures and pathways will help in the further characterization of this progenitor cell type in mouse and human liver development and disease.
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12
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Crema A, Ledda M, Fioretti D, Lolli MG, Sanchez M, Carico E, Marchese R, Rinaldi M, Lisi A. Combination of cord blood-derived human hepatic progenitors and hepatogenic factors strongly improves recovery after acute liver injury in mice through modulation of the Wnt/β-catenin signaling. J Tissue Eng Regen Med 2019; 13:1031-1043. [PMID: 30942524 DOI: 10.1002/term.2854] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2018] [Revised: 03/15/2019] [Accepted: 03/15/2019] [Indexed: 01/10/2023]
Abstract
Cell therapy represents a promising alternative strategy for end-stage liver disease, and hepatic progenitors are the best candidates. The possibility to maximize the paracrine effects of transplanted cells represents a great potential benefit for cell therapy success. We studied how cell type and microenvironment modulate the Wnt/β-catenin signaling in vitro and in vivo. In vitro, the onset of hepatocyte commitment was characterized by the presence of nuclear truncated β-catenin. In vivo, we analyzed the effect of human hepatic progenitors on damage recovery and functional regeneration in a mouse model of acute liver injury, either in combination or in absence of a selected mix of hepatogenic factors. Animals injected with human hepatic progenitors and hepatogenic factors showed improved engraftment triggering the Wnt/β-catenin signaling cascade. Human hepatic progenitors expressing the human oval cell marker OV6 displayed a consistent colocalization with β-catenin and colocalized with Wnt1 main ligand of the canonical pathway. Wnt5a, on the contrary, was expressed in distinct liver cell populations. Epithelial mesenchymal transition-related markers showed enhanced expression and wider distribution, and the hepato-mesenchymal population Thy1 + CK19- was also present. Control animals injected with hepatogenic factors alone exhibited higher β-catenin, decreased Wnt5a levels, and persistent proliferation of the hepato-mesenchymal population. In conclusion, the combination of human hepatic progenitors with selected hepatogenic factors creates a positive synergy with local microenvironment, ameliorates cell engraftment, stimulates and accelerates regenerative process, and improves the rescue of hepatic function by modulating the Wnt/βcatenin signaling and activating hepato-mesenchymal population.
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Affiliation(s)
- Annalisa Crema
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Mario Ledda
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Daniela Fioretti
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Maria Grazia Lolli
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Massimo Sanchez
- Core Facilities, Cytometry Unit, Istituto Superiore di Sanità, Rome, Italy
| | - Elisabetta Carico
- Department of Clinical and Molecular Medicine, Sapienza University, Sant'Andrea Hospital, Rome, Italy
| | | | - Monica Rinaldi
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
| | - Antonella Lisi
- Institute of Translational Pharmacology (IFT), Department of Biomedical Sciences, National Research Council (CNR), Rome, Italy
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13
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Zhang J, Han C, Ungerleider N, Chen W, Song K, Wang Y, Kwon H, Ma W, Wu T. A Transforming Growth Factor-β and H19 Signaling Axis in Tumor-Initiating Hepatocytes That Regulates Hepatic Carcinogenesis. Hepatology 2019; 69:1549-1563. [PMID: 30014520 PMCID: PMC6335184 DOI: 10.1002/hep.30153] [Citation(s) in RCA: 63] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/03/2018] [Accepted: 06/23/2018] [Indexed: 02/06/2023]
Abstract
Functions of transforming growth factor-β (TGF-β) in the liver vary depending on specific cell types and their temporal response to TGF-β during different stages of hepatocarcinogenesis (HCG). Through analysis of tumor tissues from hepatocellular carcinoma (HCC) patients, we were able to cluster hepatic epithelial cell-derived TGF-β gene signatures in association with distinct clinical prognoses. To delineate the role of hepatic epithelial TGF-β signaling in HCC development, we used an experimental system in which tumor-initiating hepatocytes (TICs) were isolated from TGF-β receptor II floxed mice (Tgfbr2fl/fl ) and transplanted into syngeneic C57BL/6J mice by splenic injection. Recipient mice were then administered Cre-expressing adenovirus (Ad-Cre) to inactivate Tgfbr2 in transplanted TICs. After latency, Tgfbr2-inactivated TICs formed larger and more tumor nodules in recipient livers compared to TICs without Tgfbr2 inactivation. In vitro analyses revealed that treatment of cultured TICs with TGF-β inhibited expression of progenitor cell factors (including SRY (sex determining region Y)-box 2 [Sox2]). RNA sequencing (RNA-seq) analysis identified H19 as one of the most up-regulated long noncoding RNA (lncRNA) in association with Tgfbr2 inactivation in TICs. Tgfbr2 inactivation by Ad-Cre led to a 5-fold increase of H19 expression in TICs. Accordingly, TGF-β treatment reduced H19 expression. We observed that forced overexpression of Sox2 in TICs increased transcription of H19, whereas knockdown of Sox2 decreased it. Furthermore, depletion of H19 reduced the progenitor property of TICs in vitro and decreased their tumorigenic potential in vivo. Finally, we observed a low level of H19 mRNA expression in human HCC tissues from patients with the epithelial TGF-β gene signature in association with favorable prognosis. Conclusion: Our findings describe a TGF-β and H19 signaling axis by Sox2 in TICs that importantly regulates HCG.
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Affiliation(s)
- Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
| | - Nathan Ungerleider
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
| | - Weina Chen
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
| | - Ying Wang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
| | - Hyunjoo Kwon
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
| | - Wenbo Ma
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
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14
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Zhang J, Pei Y, Yang W, Yang W, Chen B, Zhao X, Long S. Cytoglobin ameliorates the stemness of hepatocellular carcinoma via coupling oxidative-nitrosative stress signals. Mol Carcinog 2018; 58:334-343. [PMID: 30365183 DOI: 10.1002/mc.22931] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 09/22/2018] [Accepted: 10/23/2018] [Indexed: 12/18/2022]
Abstract
Cancer stem cells (CSCs) account for tumor self-renewal and heterogeneity. Oxidative-nitrosative stress (ONS) is an independent etiologic factor throughout tumorigenesis. Emerging evidences indicated that the interaction of ONS with CSCs contributes to tumor progression and resistance to chemoradiotherapy. Cytoglobin (Cygb) is a member of human hexacoordinate hemoglobin family and acts as a dynamic mediator of redox homeostasis. We observed that Cygb is significantly deregulated in human hepatocellular carcinoma (HCC) tissue and its decrease aggravates the growth of liver cancer stem cells (LCSCs) and increases the subpopulation of CD133(+) LCSCs. Cygb restoration inhibits HCC proliferation and LCSC growth, and decreases the subpopulation of CD133 (+) LCSCs in vitro. We found that Cygb absence promotes LCSC phenotypes and PI3 K/AKT activation, whereas Cygb restoration inhibits LCSC phenotypes and PI3 K/AKT activation. Furthermore, exogenous antioxidants can eliminate the inhibitory effect of Cygb to LCSC growth and phenotypes, as well as PI3 K/AKT activation. Collectively, this study demonstrated that cytoglobin functions as a tumor suppressor and targets CSCs at an ONS-dependent manner. Thus, Cygb restoration could be a novel and promising therapeutic strategy against HCC with aberrant ROS/RNS accumulation.
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Affiliation(s)
- Jun Zhang
- Department of Pathology, the Affiliated Hospital of Guizhou Medical University, Guiyang, PR China.,Department of Pathology, Graduate School of Medicine, Guizhou Medical University, Guiyang, PR China.,Key Laboratory of Adult Stem Cell Transformation Research, Chinese Academy of Medical Sciences/Stem Cell and Tissue Engineering Research Center, Guizhou Medical University, Guiyang, PR China
| | - YuanYuan Pei
- Department of Pathology, the Affiliated Hospital of Guizhou Medical University, Guiyang, PR China
| | - Wen Yang
- Department of Pathology, the Affiliated Hospital of Guizhou Medical University, Guiyang, PR China
| | - WenXiu Yang
- Department of Pathology, the Affiliated Hospital of Guizhou Medical University, Guiyang, PR China.,Department of Pathology, Graduate School of Medicine, Guizhou Medical University, Guiyang, PR China
| | - BoXin Chen
- Department of Immunology, Basic School of Medicine, Guizhou Medical University, Guiyang, PR China
| | - Xing Zhao
- Department of Immunology, Basic School of Medicine, Guizhou Medical University, Guiyang, PR China
| | - Shiqi Long
- Department of Immunology, Basic School of Medicine, Guizhou Medical University, Guiyang, PR China
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15
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Khambu B, Huda N, Chen X, Antoine DJ, Li Y, Dai G, Köhler UA, Zong WX, Waguri S, Werner S, Oury TD, Dong Z, Yin XM. HMGB1 promotes ductular reaction and tumorigenesis in autophagy-deficient livers. J Clin Invest 2018; 128:2419-2435. [PMID: 29558368 DOI: 10.1172/jci91814] [Citation(s) in RCA: 83] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2016] [Accepted: 03/13/2018] [Indexed: 12/13/2022] Open
Abstract
Autophagy is important for liver homeostasis, and the deficiency leads to injury, inflammation, ductular reaction (DR), fibrosis, and tumorigenesis. It is not clear how these events are mechanistically linked to autophagy deficiency. Here, we reveal the role of high-mobility group box 1 (HMGB1) in two of these processes. First, HMGB1 was required for DR, which represents the expansion of hepatic progenitor cells (HPCs) implicated in liver repair and regeneration. DR caused by hepatotoxic diets (3,5-diethoxycarbonyl-1,4-dihydrocollidine [DDC] or choline-deficient, ethionine-supplemented [CDE]) also depended on HMGB1, indicating that HMGB1 may be generally required for DR in various injury scenarios. Second, HMGB1 promoted tumor progression in autophagy-deficient livers. Receptor for advanced glycation end product (RAGE), a receptor for HMGB1, was required in the same two processes and could mediate the proliferative effects of HMBG1 in isolated HPCs. HMGB1 was released from autophagy-deficient hepatocytes independently of cellular injury but depended on NRF2 and the inflammasome, which was activated by NRF2. Pharmacological or genetic activation of NRF2 alone, without disabling autophagy or causing injury, was sufficient to cause inflammasome-dependent HMGB1 release. In conclusion, HMGB1 release is a critical mechanism in hepatic pathogenesis under autophagy-deficient conditions and leads to HPC expansion as well as tumor progression.
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Affiliation(s)
- Bilon Khambu
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Nazmul Huda
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Xiaoyun Chen
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Daniel J Antoine
- MRC Center for Inflammation Research, The Queen's Medical Research Institute, The University of Edinburgh, United Kingdom
| | - Yong Li
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Guoli Dai
- Department of Biology, Purdue University School of Science, Indianapolis, Indiana, USA
| | - Ulrike A Köhler
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Wei-Xing Zong
- Department of Chemical Biology, Ernest Mario School of Pharmacy, Rutgers University, New Brunswick, New Jersey, USA
| | - Satoshi Waguri
- Department of Anatomy and Histology, Fukushima Medical University, School of Medicine, Fukushima, Japan
| | - Sabine Werner
- Department of Biology, Institute of Molecular Health Sciences, Swiss Federal Institute of Technology (ETH) Zurich, Zurich, Switzerland
| | - Tim D Oury
- Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
| | - Zheng Dong
- Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan, China.,Department of Cellular Biology and Anatomy, Medical College of Georgia at Augusta University and Charlie Norwood VA Medical Center, Augusta, Georgia, USA
| | - Xiao-Ming Yin
- Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, Indiana, USA
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16
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Noncoding RNAs in liver cancer stem cells: The big impact of little things. Cancer Lett 2018; 418:51-63. [DOI: 10.1016/j.canlet.2018.01.001] [Citation(s) in RCA: 36] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2017] [Revised: 12/21/2017] [Accepted: 01/03/2018] [Indexed: 12/12/2022]
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17
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Qiu L, Li H, Fu S, Chen X, Lu L. Surface markers of liver cancer stem cells and innovative targeted-therapy strategies for HCC. Oncol Lett 2018; 15:2039-2048. [PMID: 29434903 PMCID: PMC5776936 DOI: 10.3892/ol.2017.7568] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2017] [Accepted: 11/02/2017] [Indexed: 12/20/2022] Open
Abstract
Liver cancer stem cells (LCSCs) have important roles in the occurrence, development, recurrence, therapy resistance and metastasis of hepatocellular carcinoma (HCC). Therefore, intensive studies are undergoing to identify the mechanisms by which LCSCs contribute to HCC invasion and metastasis, and to design more efficient treatments for this disease. With continuous efforts in LCSC research over the years, therapies targeting LCSCs are thought to have great potential for the clinical treatment and prognosis of liver cancer. Novel LCSC surface markers are continuously discovered and several have been used in targeted therapies to reduce HCC recurrence, metastasis, and drug resistance following tumor resection. The present review describes the surface markers characterizing LCSCs and the recent progress in therapies targeting these markers, including antibodies and polypeptides.
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Affiliation(s)
- Lige Qiu
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
| | - Hailiang Li
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
- Department of Otolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
| | - Sirui Fu
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
| | - Xiaofang Chen
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
- Department of Otolaryngology Head and Neck Surgery, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong 510280, P.R. China
- Stem Cell and Regenerative Medicine Laboratory, Beijing Institute of Transfusion Medicine, Beijing 100850, P.R. China
| | - Ligong Lu
- Department of Intervention, Zhuhai People's Hospital, Zhuhai Hospital Affiliated with Jinan University, Zhuhai, Guangdong 519000, P.R. China
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18
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Acquisition of Cholangiocarcinoma Traits during Advanced Hepatocellular Carcinoma Development in Mice. THE AMERICAN JOURNAL OF PATHOLOGY 2017; 188:656-671. [PMID: 29248454 DOI: 10.1016/j.ajpath.2017.11.013] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2017] [Revised: 11/01/2017] [Accepted: 11/21/2017] [Indexed: 02/06/2023]
Abstract
Past studies have identified hepatic tumors with mixed hepatocellular carcinoma (HCC) and cholangiocarcinoma (CC) characteristics that have a more aggressive behavior and a poorer prognosis than classic HCC. Whether this pathologic heterogeneity is due to a cell of origin of bipotent liver progenitors or the plasticity of cellular constituents comprising these tumors remains debated. In this study, we investigated the potential acquisition of CC-like traits during advanced development of HCC in mice. Primary and rare high-grade HCC developed in a genetic mouse model. A mouse model of highly efficient HCC invasion and metastasis by orthotopic transplantation of liver cancer organoids propagated from primary tumors in the genetic model was further developed. Invasive/metastatic tumors developed in both models closely recapitulated advanced human HCC and displayed a striking acquisition of CC-related pathologic and molecular features, which was absent in the primary HCC tumors. Our study directly demonstrates the pathologic evolution of HCC during advanced tumor development, providing the first evidence that tumors with mixed HCC and CC features, or at least a subset of these tumors, represent a more advanced developmental stage of HCC. Finally, liver cancer organoid-generated high-grade tumors exhibited significantly increased extracellular vesicle secretion, suggesting that identifying tumor-specific extracellular vesicle proteins in plasma may be a promising tool for liver cancer detection.
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19
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Yu L, Chen S, Luo N, He S. The C-terminus domain of the hepatitis B virus x protein stimulates the proliferation of mouse foetal hepatic progenitor cells, although it is not required for the formation of spheroids. Int J Mol Med 2017. [PMID: 28627604 PMCID: PMC5505023 DOI: 10.3892/ijmm.2017.3026] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
The hepatitis B virus X (HBx) protein is an important factor in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC). The C-terminal region of HBx plays a major role in the replication of HBV. Notably, HBx promotes the expansion and tumourigenesis of hepatic progenitor cells (HPCs) in mice. However, it remains unclear as to whether the C-terminal region of HBx is required for the stimulation fo the proliferation of mouse foetal HPCs (FHPCs). In our study, we used EpCAM+, CD133+ and CD49f+ FHPCs, which are bipotential clonogenic cells. These FHPCs transformed into mature hepatocytes and cholangiocytes when cultured under conditions that facilitate differentiation. Compared with the FHPCs grown as monolayers, spherical cell proliferation occurred more rapidly. Furthermore, spherically cultured FHPCs can grow in semi-solid agar and tend to maintain the morphology and characteristics of stem cells compared with growth in rat tail collagen. Notably, we also demonstrate that the C-terminus of HBx stimulates the proliferation of FHPCs, but is not required for the formation of spheroids, similar to hepatic cancer stem cells. These findings enhance our understanding of the HBx-induced tumourigenicity of FHPCs and may aid in the treatment of HCC.
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Affiliation(s)
- Liming Yu
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Shu Chen
- Department of Hematology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
| | - Na Luo
- Department of ICU, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, P.R. China
| | - Song He
- Department of Gastroenterology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing 400010, P.R. China
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20
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Tummala KS, Brandt M, Teijeiro A, Graña O, Schwabe RF, Perna C, Djouder N. Hepatocellular Carcinomas Originate Predominantly from Hepatocytes and Benign Lesions from Hepatic Progenitor Cells. Cell Rep 2017; 19:584-600. [PMID: 28423321 PMCID: PMC5409928 DOI: 10.1016/j.celrep.2017.03.059] [Citation(s) in RCA: 102] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2015] [Revised: 02/08/2017] [Accepted: 03/21/2017] [Indexed: 12/20/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is an aggressive primary liver cancer. However, its origin remains a debated question. Using human data and various hepatocarcinogenesis mouse models, we show that, in early stages, transformed hepatocytes, independent of their proliferation status, activate hepatic progenitor cell (HPC) expansion. Genetic lineage tracing of HPCs and hepatocytes reveals that, in all models, HCC originates from hepatocytes. However, whereas in various models tumors do not emanate from HPCs, tracking of progenitors in a model mimicking human hepatocarcinogenesis indicates that HPCs can generate benign lesions (regenerative nodules and adenomas) and aggressive HCCs. Mechanistically, galectin-3 and α-ketoglutarate paracrine signals emanating from oncogene-expressing hepatocytes instruct HPCs toward HCCs. α-Ketoglutarate preserves an HPC undifferentiated state, and galectin-3 maintains HPC stemness, expansion, and aggressiveness. Pharmacological or genetic blockage of galectin-3 reduces HCC, and its expression in human HCC correlates with poor survival. Our findings may have clinical implications for liver regeneration and HCC therapy.
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Affiliation(s)
- Krishna S Tummala
- Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Marta Brandt
- Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Ana Teijeiro
- Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Osvaldo Graña
- Structural Biology and Biocomputing Programme, Bioinformatics Unit, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Cristian Perna
- Department of Pathology, Hospital Universitario Ramón y Cajal, IRYCIS, Madrid 28034, Spain
| | - Nabil Djouder
- Cancer Cell Biology Programme, Growth Factors, Nutrients and Cancer Group, Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid 28029, Spain.
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Liu Y, Liu H, Yang L, Wu Q, Liu W, Fu Q, Zhang W, Zhang H, Xu J, Gu J. Loss of N-Acetylgalactosaminyltransferase-4 Orchestrates Oncogenic MicroRNA-9 in Hepatocellular Carcinoma. J Biol Chem 2017; 292:3186-3200. [PMID: 28062574 PMCID: PMC5336155 DOI: 10.1074/jbc.m116.751685] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2016] [Revised: 12/25/2016] [Indexed: 01/10/2023] Open
Abstract
Deregulated expression of N-acetylgalactosaminyltransferases (GALNTs), which is responsible for the initial step of mucin-type O-glycosylation, could produce abnormal truncated O-glycans and thereby exert pivotal functions during malignant transformation. GALNT4 is one of the few isoforms preferring to catalyze partial GalNAc-glycosylated substrates and modify the sites not utilized by other known GALNTs. This study aims to evaluate the impact of GALNT4 expression on malignant transformation of hepatocellular carcinoma (HCC). Immunohistochemistry and in situ hybridization analysis were performed to assess GALNT4 and miR-9 level in clinical specimens, respectively. GALNT4 expression is markedly repressed in primary HCC tissues, and reduced expression of GALNT4 is significantly associated with adverse survival of patients with HCC. Functional investigations demonstrate that repressed GALNT4 could promote migration, invasion, anoikis resistance, and stemness of HCC cells in vitro as well as tumor growth in vivo The wild-type GALNT4 could modify O-linked glycosylation on EGFR and thus modulate the activity of EGFR. A luciferase activity assay further identified microRNA-9 (miR-9) as the crucial specific arbitrator for GALNT4 expression in HCC cells. Furthermore, restoring GALNT4 expression attenuates miR-9-mediated oncogenic functions. Kaplan-Meier survival analysis indicates that the miR-9/GALNT4 expression signature yields promising prognostic significance to refine the risk stratification of patients with HCC. In conclusion, this study establishes the miR-9/GALNT4 axis as a potential adverse prognostic factor and therapeutic target for HCC patients.
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Affiliation(s)
- Yidong Liu
- Departments of Biochemistry and Molecular Biology
| | - Haiou Liu
- Shanghai Key Laboratory of Female Reproductive Endocrine Related Diseases, Hospital of Obstetrics and Gynecology, Fudan University, Shanghai 200032, China
| | - Liu Yang
- Departments of Biochemistry and Molecular Biology
| | - Qian Wu
- Departments of Biochemistry and Molecular Biology
| | - Weisi Liu
- Departments of Biochemistry and Molecular Biology
| | - Qiang Fu
- Departments of Biochemistry and Molecular Biology
| | - Weijuan Zhang
- Immunology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
| | | | - Jiejie Xu
- Departments of Biochemistry and Molecular Biology.
| | - Jianxin Gu
- Departments of Biochemistry and Molecular Biology.
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Shiota G, Itaba N. Progress in stem cell-based therapy for liver disease. Hepatol Res 2017; 47:127-141. [PMID: 27188253 DOI: 10.1111/hepr.12747] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/13/2016] [Revised: 05/03/2016] [Accepted: 05/12/2016] [Indexed: 12/16/2022]
Abstract
Liver transplantation has been accepted as a useful therapeutic approach for patients with end-stage liver disease. However, the mismatch between the great demand for liver transplants and the number of available donor organs underscores the urgent need for alternative therapeutic strategies for patients with acute and chronic liver failure. The rapidly growing knowledge on stem cell biology has opened new avenues toward stem cell-based therapy for liver disease. As stem cells have capacity for high proliferation and multipotent differentiation, the characteristics of stem cells fit the cell therapy. Several types of cells have been investigated as possible sources of liver regeneration: mesenchymal stem cells, hematopoietic stem cells, liver progenitor cells, induced pluripotent stem cells, and bone marrow mononuclear cells. In vitro and in vivo experiments revealed that these cells have great potential as candidates of stem cell therapy. We reviewed the reports on clinical trials of cell therapy for liver disease that have been recently undertaken using mesenchymal stem cells, hematopoietic stem cells, bone marrow mononuclear cells, and liver progenitor cells. These reports have heterogeneity of description of trial design, types of infused cells, patient population, and efficacy of therapies. We addressed these reports from these viewpoints and clarified their significance. We hope that this review article will provide a perspective on the available approaches based on stem cell-based therapy for liver disease.
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Affiliation(s)
- Goshi Shiota
- Division of Molecular and Genetic Medicine, Graduate School of Medicine, Tottori University, Yonago, Japan
| | - Noriko Itaba
- Departments of Genetic Medicine and Regenerative Therapeutics, Graduate School of Medicine, Tottori University, Yonago, Japan
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23
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Khawar MB, Azam F, Sheikh N, Abdul Mujeeb K. How Does Interleukin-22 Mediate Liver Regeneration and Prevent Injury and Fibrosis? J Immunol Res 2016; 2016:2148129. [PMID: 28050571 PMCID: PMC5168458 DOI: 10.1155/2016/2148129] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 10/13/2016] [Accepted: 10/25/2016] [Indexed: 12/20/2022] Open
Abstract
Interleukin-22 (IL-22) is a pluripotent T cell-derived cytokine which is a member of IL-10 cytokine family. It is the only interleukin produced by immune cells but does not target immune system components. IL-22 is mainly produced by dendritic cells (DCs) and TH17, TH22, NK, and NKT cells and targets a number of body tissues including liver, pancreas, and other epithelial tissues. It provokes a series of downstream signaling pathways upon binding with IL-22R complex which protects liver damage through STAT3 activation. IL-22BP is an inhibitor of IL-22 which has 20-1000x more affinity to bind with IL-22 compared to IL-22R1 that inhibits IL-22 activity. Its level was found to be positively correlated with the severity of liver damage and fibrosis. So, the present review is an effort to reveal the exact mechanism lying in the hepatoprotective activity of IL-22 and some of its future therapeutic implications.
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Affiliation(s)
- Muhammad Babar Khawar
- Cell & Molecular Biology Lab, Department of Zoology, University of the Punjab, Lahore, Pakistan
| | - Fareeha Azam
- Cell & Molecular Biology Lab, Department of Zoology, University of the Punjab, Lahore, Pakistan
| | - Nadeem Sheikh
- Cell & Molecular Biology Lab, Department of Zoology, University of the Punjab, Lahore, Pakistan
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24
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Xing LB, Gao YT. Progress in research of surface markers of liver cancer stem cells. Shijie Huaren Xiaohua Zazhi 2016; 24:4231-4237. [DOI: 10.11569/wcjd.v24.i31.4231] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
In recent years, cancer stem cell theory, in which a tumor is considered to consist of a handful of tumor stem cells and most common tumor cells, has been put forward by many scientists, which helps researchers to understand cancer from a new perspective. Isolating tumor stem cells is based mainly on their markers and in this way, many kinds of cancer stem cell markers have been confirmed, including live cancer stem cells. Isolating and identifying live cancer stem cells will provide a new hope for curing cancer. This paper mainly discusses seven liver cancer stem cell surface markers and their clinical significance.
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25
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Matthai SM, Ramakrishna B. Cancer stem cells in hepatocellular carcinoma--an immunohistochemical study with histopathological association. Indian J Med Res 2016; 142:391-8. [PMID: 26609030 PMCID: PMC4683823 DOI: 10.4103/0971-5916.169195] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Background & objectives: Cancer stem cells (CSCs) may be responsible for tumour recurrence and resistance to chemotherapy in hepatocellular carcinoma (HCC). This study was carried out to evaluate the association between histological parameters and liver CSCs (LCSC) in HCC, and to compare distribution of liver CSCs in HCC associated with and without hepatitis B virus (HBV) infection. Methods: Seventy nine tumours (49 surgical resections from 46 patients, and 30 from autopsy) were reviewed. Immunohistochemical staining for the LCSC marker EpCAM (epithelial cell adhesion molecule), liver progenitor cell (LPC) markers CK19 (cytokeratin 19) and neural cell adhesion molecule (NCAM) were performed and were associated with histological features of tumour behaviour. Results: Thirty three tumours (41.8%) showed positive staining for EpCAM. CK19 and NCAM expression were seen in 26 (32.9%) and four (5.1%) tumours, respectively. The expression of EpCAM and CK19 was significantly associated with each other (P<0.001). EpCAM expression was significantly associated with clinical and histological features indicating aggressive tumour behaviour, including younger age of onset, higher serum alpha foetoprotein (AFP) levels, tumour cell dedifferentiation, increased mitotic activity, and vascular invasiveness. There was no significant difference in expression of EpCAM, CK19 and NCAM between HBV positive and negative HCC. Interpretation & conclusions: The LCSC marker EpCAM was expressed in less than half of HCC, was independent of HBV aetiology, and was strongly associated with clinical and histological features of aggressive tumour behaviour. Positive staining for CK19 suggests a possible LPC origin of the EpCAM positive HCCs.
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26
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Mani SKK, Zhang H, Diab A, Pascuzzi PE, Lefrançois L, Fares N, Bancel B, Merle P, Andrisani O. EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes. J Hepatol 2016; 65:888-898. [PMID: 27238755 PMCID: PMC5289705 DOI: 10.1016/j.jhep.2016.05.022] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2015] [Revised: 05/02/2016] [Accepted: 05/17/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND & AIMS Hepatocytes in which the hepatitis B virus (HBV) is replicating exhibit loss of the chromatin modifying polycomb repressive complex 2 (PRC2), resulting in re-expression of specific, cellular PRC2-repressed genes. Epithelial cell adhesion molecule (EpCAM) is a PRC2-repressed gene, normally expressed in hepatic progenitors, but re-expressed in hepatic cancer stem cells (hCSCs). Herein, we investigated the functional significance of EpCAM re-expression in HBV-mediated hepatocarcinogenesis. METHODS Employing molecular approaches (transfections, fluorescence-activated cell sorting, immunoblotting, qRT-PCR), we investigated the role of EpCAM-regulated intramembrane proteolysis (RIP) in HBV replicating cells in vitro, and in liver tumors from HBV X/c-myc mice and chronically HBV infected patients. RESULTS EpCAM undergoes RIP in HBV replicating cells, activating canonical Wnt signaling. Transfection of Wnt-responsive plasmid expressing green fluorescent protein (GFP) identified a GFP + population of HBV replicating cells. These GFP+/Wnt+ cells exhibited cisplatin- and sorafenib-resistant growth resembling hCSCs, and increased expression of pluripotency genes NANOG, OCT4, SOX2, and hCSC markers BAMBI, CD44 and CD133. These genes are referred as EpCAM RIP and Wnt-induced hCSC-like gene signature. Interestingly, this gene signature is also overexpressed in liver tumors of X/c-myc bitransgenic mice. Clinically, a group of HBV-associated hepatocellular carcinomas was identified, exhibiting elevated expression of the hCSC-like gene signature and associated with reduced overall survival post-surgical resection. CONCLUSIONS The hCSC-like gene signature offers promise as prognostic tool for classifying subtypes of HBV-induced HCCs. Since EpCAM RIP and Wnt signaling drive expression of this hCSC-like signature, inhibition of these pathways can be explored as therapeutic strategy for this subtype of HBV-associated HCCs. LAY SUMMARY In this study, we provide evidence for a molecular mechanism by which chronic infection by the hepatitis B virus results in the development of poor prognosis liver cancer. Based on this mechanism our results suggest possible therapeutic interventions.
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Affiliation(s)
- Saravana Kumar Kailasam Mani
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
| | - Hao Zhang
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
| | - Ahmed Diab
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States
| | - Pete E Pascuzzi
- Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States; Purdue University Libraries, Purdue University, West Lafayette, IN 47907, United States
| | - Lydie Lefrançois
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Nadim Fares
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Brigitte Bancel
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Philippe Merle
- Centre de Recherche en Cancérologie de Lyon, UMR INSERM 1052 - CNRS 5286, Lyon Cedex 03, France
| | - Ourania Andrisani
- Department of Basic Medical Sciences, Purdue University, West Lafayette, IN 47907, United States; Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, United States.
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27
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Jiang J, Yang P, Guo Z, Yang R, Yang H, Yang F, Li L, Xiang B. Overexpression of microRNA-21 strengthens stem cell-like characteristics in a hepatocellular carcinoma cell line. World J Surg Oncol 2016; 14:278. [PMID: 27793160 PMCID: PMC5086074 DOI: 10.1186/s12957-016-1028-9] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Accepted: 10/18/2016] [Indexed: 12/17/2022] Open
Abstract
Background Liver cancer stem cells (LCSCs) have been shown to express higher levels of microRNA-21 (miR-21). Here, we examine the possible contributions of miR-21 to the phenotype of LCSCs in culture and in xenograft tumors in nude mice. Methods The hepatocellular carcinoma cell line MHCC-97H was stably transformed with a retroviral vector to establish cells overexpressing miR-21, while a cell line transformed with empty vector served as a negative control. RT-PCR and Western blotting were used to evaluate the effects of miR-21 overexpression on the expression of various LCSC markers, a Transwell assay was used to assess the effects on cell migration and invasion, and a spheroid formation assay was used to examine the effects on clonogenesis. The effects of miR-21 overexpression were also examined in tumors in nude mice. Results An MHCC-97H cell line was constructed that stably overexpresses miR-21 at 7.78 ± 1.51-fold higher levels than the negative control cell line. Expression of the LCSC markers CD13, Ep-CAM, CD90, and OCT4 was significantly higher in the miR-21-overexpressing cell line than in the negative control at both mRNA and protein levels. The overexpressing cell line formed larger, tighter, and more numerous spheroids. Overexpression of miR-21 was associated with greater cell migration and invasion. Tumors of overexpressing cells in nude mice had a significantly larger mean volume after 34 days of growth (773.62 ± 163.46 mm3) than tumors of negative control cells (502.79 ± 33.94 mm3, p = 0.048), as well as greater mean weight (0.422 ± 0.019 vs. 0.346 ± 0.006 g, p = 0.003). Conclusions Overexpression of miR-21 strengthens the phenotype of LCSCs, facilitating invasion, migration, and tumorigenesis in hepatocellular carcinoma.
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Affiliation(s)
- Jinghang Jiang
- Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.,Department of General Surgery, The Second People's Hospital of Jing Men, Jingmen, 448000, Hubei Province, China
| | - Peipei Yang
- Department of General Surgery, The Second People's Hospital of Jing Men, Jingmen, 448000, Hubei Province, China
| | - Zhe Guo
- Department of Thyroid and Breast Surgery, The Central Hospital of Wuhan, Wuhan, 430041, Hubei Province, China
| | - Rirong Yang
- Department of Immunology, School of Preclinical Medicine, Biological Targeting Diagnosis and Therapy Research Center, Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Haojie Yang
- Department of General Surgery, The First People's Hospital of Changde, Changde, 415000, Hunan Province, China
| | - Fuquan Yang
- Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Lequn Li
- Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, China
| | - Bangde Xiang
- Department of Hepatobiliary Surgery, Tumor Hospital of Guangxi Medical University, Nanning, 530021, Guangxi Zhuang Autonomous Region, China.
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Song K, Kwon H, Han C, Zhang J, Dash S, Lim K, Wu T. Active glycolytic metabolism in CD133(+) hepatocellular cancer stem cells: regulation by MIR-122. Oncotarget 2016; 6:40822-35. [PMID: 26506419 PMCID: PMC4747371 DOI: 10.18632/oncotarget.5812] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2015] [Accepted: 09/23/2015] [Indexed: 02/07/2023] Open
Abstract
Although altered metabolic pathway is an important diagnostic maker and therapeutic target in cancer, it is poorly understood in cancer stem cells (CSCs). Here we show that the CD133 (+) hepatocellular CSCs have distinct metabolic properties, characterized by more active glycolysis over oxidative phosphorylation, compared to the CD133 (−) cells. Inhibition of PDK4 and LDHA markedly suppresses CD133 (+) stemness characteristics and overcome resistance to sorafenib (current chemotherapeutic agent for hepatocellular cancer). Addition of glucose or lactate to CD133 (−) cells promotes CSC phenotypes, as evidenced by increased CD133 (+) cell population, elevated stemness gene expression and enhanced spheroid formation. Furthermore, the liver-specific miRNA, miR-122, inhibits CSC phenotypes by regulating glycolysis through targeting PDK4. Our findings suggest that enhanced glycolysis is associated with CD133 (+) stem-like characteristics and that metabolic reprogramming through miR-122 or PDK4 may represent a novel therapeutic approach for the treatment of hepatocellular cancer.
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Affiliation(s)
- Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Hyunjoo Kwon
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
| | - Kyu Lim
- Department of Biochemistry, College of Medicine, Cancer Research Institute and Infection Signaling Network Research Center, Chungnam National University, Daejeon, Korea
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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29
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Tang B, Qi G, Tang F, Yuan S, Wang Z, Liang X, Li B, Yu S, Liu J, Huang Q, Wei Y, Zhai R, Lei B, Yu H, Tomlinson S, He S. Aberrant JMJD3 Expression Upregulates Slug to Promote Migration, Invasion, and Stem Cell-Like Behaviors in Hepatocellular Carcinoma. Cancer Res 2016; 76:6520-6532. [PMID: 27651311 DOI: 10.1158/0008-5472.can-15-3029] [Citation(s) in RCA: 66] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Revised: 08/10/2016] [Accepted: 09/04/2016] [Indexed: 11/16/2022]
Abstract
The Jumonji domain-containing chromatin remodeling factor JMJD3 has important roles in development and cancer. Here, we report a pivotal role for JMJD3 in sustaining the phenotype of aggressive hepatocellular carcinomas. Expression levels of JMJD3 in clinical specimens of hepatocellular carcinoma correlated inversely with patient survival. In hepatocellular carcinoma cells, we found that enforcing its overexpression induced epithelial-mesenchymal transition (EMT), invasive migration, stem cell-like traits, and metastatic properties. Conversely, silencing JMJD3 in hepatocellular carcinoma cells overexpressing it inhibited these aggressive phenotypes. Mechanistically, JMJD3 modulated H3K27me3 in the SLUG gene promoter, a histone mark associated with active SLUG transcription. SLUG silencing blocked JMJD3-induced EMT, stemness, and metastasis. Furthermore, SLUG expression in hepatocellular carcinoma clinical specimens correlated positively with JMJD3 expression. Our results establish JMJD3 as a critical driver of hepatocellular carcinoma stem cell-like and metastatic behaviors, with implications for prognosis and treatment. Cancer Res; 76(22); 6520-32. ©2016 AACR.
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Affiliation(s)
- Bo Tang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Guangying Qi
- Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China.,Department of Pathology and Physiopathology, Guilin Medical University, Guilin, Guangxi, China
| | - Fang Tang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Shengguang Yuan
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Zhenran Wang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Xingsi Liang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Bo Li
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Shuiping Yu
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Jie Liu
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Qi Huang
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Yangchao Wei
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Run Zhai
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Biao Lei
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China.,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
| | - Hongping Yu
- Department of Epidemiology and Statistics, School of Public Health, Guilin Medical College, Guilin, Guangxi, China
| | - Stephen Tomlinson
- Department of Microbiology and Immunology, Darby Children's Research Institute, Medical University of South Carolina, Charleston, South Carolina.,Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, South Carolina
| | - Songqing He
- Department of Hepatobiliary Surgery, Guilin Medical University, Affiliated Hospital, Guilin, Guangxi, China. .,Laboratory of Liver Injury and Repair Molecular Medicine, Guilin Medical University, Guilin, Guangxi, China
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30
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Aloia L, McKie MA, Huch M. Cellular plasticity in the adult liver and stomach. J Physiol 2016; 594:4815-25. [PMID: 27028579 DOI: 10.1113/jp271769] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Accepted: 03/21/2016] [Indexed: 12/21/2022] Open
Abstract
Adult tissues maintain function and architecture through robust homeostatic mechanisms mediated by self-renewing cells capable of generating all resident cell types. However, severe injury can challenge the regeneration potential of such a stem/progenitor compartment. Indeed, upon injury adult tissues can exhibit massive cellular plasticity in order to achieve proper tissue regeneration, circumventing an impaired stem/progenitor compartment. Several examples of such plasticity have been reported in both rapidly and slowly self-renewing organs and follow conserved mechanisms. Upon loss of the cellular compartment responsible for maintaining homeostasis, quiescent or slowly proliferating stem/progenitor cells can acquire high proliferation potential and turn into active stem cells, or, alternatively, mature cells can de-differentiate into stem-like cells or re-enter the cell cycle to compensate for the tissue loss. This extensive cellular plasticity acts as a key mechanism to respond to multiple stimuli in a context-dependent manner, enabling tissue regeneration in a robust fashion. In this review cellular plasticity in the adult liver and stomach will be examined, highlighting the diverse cell populations capable of repairing the damaged tissue.
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Affiliation(s)
- Luigi Aloia
- Wellcome Trust/Cancer Research UK - Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK
| | - Mikel Alexander McKie
- Wellcome Trust/Cancer Research UK - Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.,Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3DY, UK
| | - Meritxell Huch
- Wellcome Trust/Cancer Research UK - Gurdon Institute, Henry Wellcome Building of Cancer and Developmental Biology, University of Cambridge, Tennis Court Road, Cambridge, CB2 1QN, UK.,Wellcome Trust - Medical Research Council Stem Cell Institute, University of Cambridge, Gleeson Building, Tennis Court Road, Cambridge, CB2 1QR, UK.,Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, CB2 3DY, UK
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31
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Clinicopathologic Characteristics of Hepatocellular Carcinoma With Reactive Ductule-like Components, a Subset of Liver Cancer Currently Classified as Combined Hepatocellular-Cholangiocarcinoma With Stem-Cell Features, Typical Subtype. Am J Surg Pathol 2016; 40:608-16. [DOI: 10.1097/pas.0000000000000579] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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32
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Differentiation therapy of hepatocellular carcinoma by inhibiting the activity of AKT/GSK-3β/β-catenin axis and TGF-β induced EMT with sophocarpine. Cancer Lett 2016; 376:95-103. [PMID: 26945965 DOI: 10.1016/j.canlet.2016.01.011] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2015] [Revised: 01/03/2016] [Accepted: 01/06/2016] [Indexed: 12/19/2022]
Abstract
Hepatocellular carcinoma progression is thought to be driven by cancer stem cells (CSCs). No clinical trial has, as yet, shown convincing long-term disease free survival results for the majority of patients in HCC. So it is important to discover new anti-cancer agents. In our study, we chose sophocarpine, which is derived from the foxtail-like sophora herb, for its efficacy to inhibit HCC including CSCs and potential mechanism study. Our results show that sophocarpine could not only reduce HCC cell viability, eliminate HCC and reverse hepatoma cells malignant phenotype, but also reduce the ratio of CSCs and inhibit the sphere formation of CSCs in vitro. In vivo, sophocarpine significantly displayed antitumor effects in subcutaneous xenograft HCC models and orthotopic transplantation tumor models. Further studies showed that sophocarpine could exert anti-tumor effects partly via downregulating the activity of the cancer stem cell related pathways and inhibiting EMT induced by TGF-β.
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33
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Komposch K, Sibilia M. EGFR Signaling in Liver Diseases. Int J Mol Sci 2015; 17:E30. [PMID: 26729094 PMCID: PMC4730276 DOI: 10.3390/ijms17010030] [Citation(s) in RCA: 148] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2015] [Revised: 12/17/2015] [Accepted: 12/21/2015] [Indexed: 02/07/2023] Open
Abstract
The epidermal growth factor receptor (EGFR) is a transmembrane receptor tyrosine kinase that is activated by several ligands leading to the activation of diverse signaling pathways controlling mainly proliferation, differentiation, and survival. The EGFR signaling axis has been shown to play a key role during liver regeneration following acute and chronic liver damage, as well as in cirrhosis and hepatocellular carcinoma (HCC) highlighting the importance of the EGFR in the development of liver diseases. Despite the frequent overexpression of EGFR in human HCC, clinical studies with EGFR inhibitors have so far shown only modest results. Interestingly, a recent study has shown that in human HCC and in mouse HCC models the EGFR is upregulated in liver macrophages where it plays a tumor-promoting function. Thus, the role of EGFR in liver diseases appears to be more complex than what anticipated. Further studies are needed to improve the molecular understanding of the cell-specific signaling pathways that control disease development and progression to be able to develop better therapies targeting major components of the EGFR signaling network in selected cell types. In this review, we compiled the current knowledge of EGFR signaling in different models of liver damage and diseases, mainly derived from the analysis of HCC cell lines and genetically engineered mouse models (GEMMs).
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Affiliation(s)
- Karin Komposch
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
| | - Maria Sibilia
- Institute of Cancer Research, Department of Medicine I, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
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34
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Physiological and Pathological Properties of Interleukin-22 in Liver Diseases. CURRENT PATHOBIOLOGY REPORTS 2015. [DOI: 10.1007/s40139-015-0088-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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35
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Zhu CP, Wang AQ, Zhang HH, Wan XS, Yang XB, Chen SG, Zhao HT. Research progress and prospects of markers for liver cancer stem cells. World J Gastroenterol 2015; 21:12190-12196. [PMID: 26576103 PMCID: PMC4641136 DOI: 10.3748/wjg.v21.i42.12190] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/28/2015] [Revised: 07/10/2015] [Accepted: 08/31/2015] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is a common malignancy and surgery is the main treatment strategy. However, the prognosis is still poor because of high frequencies of postoperative recurrence and metastasis. In recent years, cancer stem cell (CSC) theory has evolved with the concept of stem cells, and has been applied to oncological research. According to cancer stem cell theory, liver cancer can be radically cured only by eradication of liver cancer stem cells (LCSCs). This notion has lead to the isolation and identification of LCSCs, which has become a highly researched area. Analysis of LCSC markers is considered to be the primary method for identification of LCSCs. Here, we provide an overview of the current research progress and prospects of surface markers for LCSCs.
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36
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Wang P, Yang AT, Cong M, Liu TH, Zhang D, Huang J, Tong XF, Zhu ST, Xu Y, Tang SZ, Wang BE, Ma H, Jia JD, You H. EGF Suppresses the Initiation and Drives the Reversion of TGF-β1-induced Transition in Hepatic Oval Cells Showing the Plasticity of Progenitor Cells. J Cell Physiol 2015; 230:2362-70. [PMID: 25739869 DOI: 10.1002/jcp.24962] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2014] [Accepted: 02/17/2015] [Indexed: 12/15/2022]
Abstract
Transforming growth factor-β1 (TGF-β1) induces hepatic progenitors to tumor initiating cells through epithelial-mesenchymal transition (EMT), thus raising an important drawback for stem cell-based therapy. How to block and reverse TGF-β1-induced transition is crucial for progenitors' clinical application and carcinogenic prevention. Rat adult hepatic progenitors, hepatic oval cells, experienced E-cadherin to N-cadherin switch and changed to α-smooth muscle actin (α-SMA) positive cells after TGF-β1 incubation, indicating EMT. When TGF-β1 plus EGF were co-administrated to these cells, EGF dose-dependently suppressed the cadherin switch and α-SMA expression. Interestingly, if EGF was applied to TGF-β1-pretreated cells, the cells that have experienced EMT could return to their epithelial phenotype. Abruption of EGF receptor revealed that EGF exerted its blockage and reversal effects through phosphorylation of ERK1/2 and Akt. These findings suggest an important attribute of EGF on opposing and reversing TGF-β1 effects, indicating the plasticity of hepatic progenitors.
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Affiliation(s)
- Ping Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China.,Municipal Laboratory for Liver Protection and Regulation of Regeneration, Capital Medical University, Beijing, China
| | - Ai-Ting Yang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Min Cong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Tian-Hui Liu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Dong Zhang
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Jian Huang
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Xiao-Fei Tong
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Sheng-Tao Zhu
- Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Yong Xu
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Shu-Zhen Tang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Bao-En Wang
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Hong Ma
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Ji-Dong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
| | - Hong You
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Beijing Key Laboratory of Translational Medicine in Liver Cirrhosis & National Clinical Research Center of Digestive Diseases, Beijing, China
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37
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Promotion of Cancer Stem-Like Cell Properties in Hepatitis C Virus-Infected Hepatocytes. J Virol 2015; 89:11549-56. [PMID: 26355082 DOI: 10.1128/jvi.01946-15] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Accepted: 08/31/2015] [Indexed: 02/07/2023] Open
Abstract
UNLABELLED We have previously reported that hepatitis C virus (HCV) infection of primary human hepatocytes (PHH) induces the epithelial mesenchymal transition (EMT) state and extends hepatocyte life span (S. K. Bose, K. Meyer, A. M. Di Bisceglie, R. B. Ray, and R. Ray, J Virol 86:13621-13628, 2012, http://dx.doi.org/10.1128/JVI.02016-12). These hepatocytes displayed sphere formation on ultralow binding plates and survived for more than 12 weeks. The sphere-forming hepatocytes expressed a number of cancer stem-like cell (CSC) markers, including high levels of the stem cell factor receptor c-Kit. The c-Kit receptor is regarded as one of the CSC markers in hepatocellular carcinoma (HCC). Analysis of c-Kit mRNA displayed a significant increase in the liver biopsy specimens of chronically HCV-infected patients. We also found c-Kit is highly expressed in transformed human hepatocytes (THH) infected in vitro with cell culture-grown HCV genotype 2a. Further studies suggested that HCV core protein significantly upregulates c-Kit expression at the transcriptional level. HCV infection of THH led to a significant increase in the number of spheres displayed on ultralow binding plates and in enhanced EMT and CSC markers and tumor growth in immunodeficient mice. The use of imatinib or dasatinib as a c-Kit inhibitor reduced the level of sphere-forming cells in culture. The sphere-forming cells were sensitive to treatment with sorafenib, a multikinase inhibitor, that is used for HCC treatment. Further, stattic, an inhibitor of the Stat3 molecule, induced sphere-forming cell death. A combination of sorafenib and stattic had a significantly stronger effect, leading to cell death. These results suggested that HCV infection potentiates CSC generation, and selected drugs can be targeted to efficiently inhibit cell growth. IMPORTANCE HCV infection may develop into HCC as an end-stage liver disease. We focused on understanding the mechanism for the risk of HCC from chronic HCV infection and identified targets for treatment. HCV-infected primary and transformed human hepatocytes (PHH or THH) generated CSC. HCV-induced spheres were highly sensitive to cell death from sorafenib and stattic treatment. Thus, our study is highly significant for HCV-associated HCC, with the potential for developing a target-specific strategy for improved therapies.
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38
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β-catenin alteration is rare in hepatocellular carcinoma with steatohepatitic features: immunohistochemical and mutational study. Virchows Arch 2015; 467:535-42. [PMID: 26311355 DOI: 10.1007/s00428-015-1836-2] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 07/29/2015] [Accepted: 08/13/2015] [Indexed: 12/22/2022]
Abstract
Hepatocellular carcinoma (HCC) with steatohepatitic features (steatohepatitic HCC, SH-HCC) is a histological subset of HCC, highly associated with metabolic disease and underlying steatohepatitis. Although it has distinct clinicopathologic characteristics, little is known about the immunophenotype or genetic characteristics of SH-HCC. We conducted an immunohistochemical analysis on a tissue microarray containing 197 HCCs (70 SH-HCCs and 127 conventional HCCs (C-HCCs)), focusing on proteins associated with genetic subtypes of HCC and those associated with non-alcoholic fatty liver disease (NAFLD) or NAFLD-associated HCC. We also investigated CTNNB1 mutations in 84 HCCs (31 SH-HCCs and 53 C-HCCs) to better characterize the SH-HCC. When compared to C-HCC, SH-HCC was characterized by a significantly lower incidence of nuclear accumulation of β-catenin (5.7 vs. 25.2 %, p < 0.001) and by a lower incidence of overexpression (H-score = 300) of glutamine synthetase (4.3 vs. 26.0 %, p < 0.001). Multivariate logistic regression analysis revealed that the low rate of nuclear β-catenin accumulation in SH-HCC was independent of background etiology, including underlying steatohepatitis (p < 0.001). In accordance with the immunohistochemical results, CTNNB1 mutations were less frequent in SH-HCC than C-HCC (3.1 vs. 20.8 %, p < 0.048). Other notable findings included the ubiquitous expression of sonic hedgehog ligand in typical SH-HCC (100 %) and the less frequent expression of progenitor markers, such as SALL4 and EpCAM, in SH-HCC. These results indicate that SH-HCC as a subtype is not only characterized by morphology but also by distinct phenotypic and genetic traits.
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39
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Chen C, Wang G. Mechanisms of hepatocellular carcinoma and challenges and opportunities for molecular targeted therapy. World J Hepatol 2015; 7:1964-1970. [PMID: 26244070 PMCID: PMC4517155 DOI: 10.4254/wjh.v7.i15.1964] [Citation(s) in RCA: 103] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Revised: 06/01/2015] [Accepted: 07/17/2015] [Indexed: 02/06/2023] Open
Abstract
The incidence and mortality of hepatocellular carcinoma (HCC) have fallen dramatically in China and elsewhere over the past several decades. Nonetheless, HCC remains a major public health issue as one of the most common malignant tumors worldwide and one of the leading causes of death caused by cancer in China. Hepatocarcinogenesis is a very complex biological process associated with many environmental risk factors and factors in heredity, including abnormal activation of cellular and molecular signaling pathways such as Wnt/β-catenin, hedgehog, MAPK, AKT, and ERK signaling pathways, and the balance between the activation and inactivation of the proto-oncogenes and anti-oncogenes, and the differentiation of liver cancer stem cells. Molecule-targeted therapy, a new approach for the treatment of liver cancer, blocks the growth of cancer cells by interfering with the molecules required for carcinogenesis and tumor growth, making it both specific and selective. However, there is no one drug completely designed for liver cancer, and further development in the research of liver cancer targeted drugs is now almost stagnant. The purpose of this review is to discuss recent advances in our understanding of the molecular mechanisms underlying the development of HCC and in the development of novel strategies for cancer therapeutics.
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40
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Sur S, Pal D, Banerjee K, Mandal S, Das A, Roy A, Panda CK. Amarogentin regulates self renewal pathways to restrict liver carcinogenesis in experimental mouse model. Mol Carcinog 2015; 55:1138-49. [DOI: 10.1002/mc.22356] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2015] [Revised: 05/28/2015] [Accepted: 06/09/2015] [Indexed: 12/30/2022]
Affiliation(s)
- Subhayan Sur
- Department of Oncogene Regulation; Chittaranjan National Cancer Institute; Kolkata India
| | - Debolina Pal
- Department of Oncogene Regulation; Chittaranjan National Cancer Institute; Kolkata India
| | - Kaustav Banerjee
- Department of Oncogene Regulation; Chittaranjan National Cancer Institute; Kolkata India
| | - Suvra Mandal
- Department of Chemistry; National Research Institute for Ayurvedic Drug Development; Kolkata India
| | - Ashes Das
- Department of Chemistry; National Research Institute for Ayurvedic Drug Development; Kolkata India
| | - Anup Roy
- North Bengal Medical College and Hospital; Darjeeling West Bengal India
| | - Chinmay Kumar Panda
- Department of Oncogene Regulation; Chittaranjan National Cancer Institute; Kolkata India
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41
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Zeng W, Xiao J, Zheng G, Xing F, Tipoe GL, Wang X, He C, Chen ZY, Liu Y. Antioxidant treatment enhances human mesenchymal stem cell anti-stress ability and therapeutic efficacy in an acute liver failure model. Sci Rep 2015; 5:11100. [PMID: 26057841 PMCID: PMC4460871 DOI: 10.1038/srep11100] [Citation(s) in RCA: 61] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2015] [Accepted: 05/12/2015] [Indexed: 02/07/2023] Open
Abstract
One of the major problems influencing the therapeutic efficacy of stem cell therapy is the poor cell survival following transplantation. This is partly attributed to insufficient resistance of transplanted stem cells to oxidative and inflammatory stresses at the injured sites. In the current study, we demonstrated the pivotal role of antioxidant levels in human umbilical cord mesenchymal stem cells (hUCMSCs) dynamic in vitro anti-stress abilities against lipopolysaccharide (LPS)/H2O2 intoxication and in vivo therapeutic efficacy in a murine acute liver failure model induced by D-galactosamine/LPS (Gal/LPS) by either reducing the antioxidant levels with diethyl maleate (DEM) or increasing antioxidant levels with edaravone. Both the anti- and pro-oxidant treatments dramatically influenced the survival, apoptosis, and reactive oxygen species (ROS) production of hUCMSCs through the MAPK-PKC-Nrf2 pathway in vitro. When compared with untreated and DEM-treated cells, edaravone-treated hUCMSCs rescued NOD/SCID mice from Gal/LPS-induced death, significantly improved hepatic functions and promoted host liver regeneration. These effects were probably from increased stem cell homing, promoted proliferation, decreased apoptosis and enhanced secretion of hepatocyte growth factor (HGF) under hepatic stress environment. In conclusion, elevating levels of antioxidants in hUCMSCs with edaravone can significantly influence their hepatic tissue repair capacity.
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Affiliation(s)
- Wen Zeng
- State key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China.,Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Jia Xiao
- State key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China.,Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China.,Department of Anatomy, The University of Hong Kong, Hong Kong, China
| | - Gang Zheng
- Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Feiyue Xing
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - George L Tipoe
- Department of Anatomy, The University of Hong Kong, Hong Kong, China
| | - Xiaogang Wang
- Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, China
| | - Chengyi He
- Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Zhi-Ying Chen
- Laboratory for Gene and Cell Therapy, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen, China
| | - Yingxia Liu
- State key Discipline of Infectious Diseases, Shenzhen Third People's Hospital, Shenzhen, China
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42
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Cen Y, Guo XY, Jiang HX. Interleukin-22 activates JAK-STAT3 pathway: Role in liver disease. Shijie Huaren Xiaohua Zazhi 2015; 23:2228-2233. [DOI: 10.11569/wcjd.v23.i14.2228] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Interleukin (IL)-22 belongs to the IL-10 family and is secreted mainly by Th22 cells. IL-22 binds to IL-22 receptors which are expressed in special tissues and cells, and activates the signal transducer and activator of transcription 3 (STAT3) signal pathway. IL-22 has a role in liver injury primarily through activating the STAT3 signal pathway. In different types of liver injury, IL-22 protects the liver or aggravates liver injury. This paper will review the role of IL-22 in liver disease in terms of activating the STAT3 signal pathway.
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43
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Jörs S, Jeliazkova P, Ringelhan M, Thalhammer J, Dürl S, Ferrer J, Sander M, Heikenwalder M, Schmid RM, Siveke JT, Geisler F. Lineage fate of ductular reactions in liver injury and carcinogenesis. J Clin Invest 2015; 125:2445-57. [PMID: 25915586 DOI: 10.1172/jci78585] [Citation(s) in RCA: 133] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2014] [Accepted: 03/20/2015] [Indexed: 12/13/2022] Open
Abstract
Ductular reactions (DRs) are observed in virtually all forms of human liver disease; however, the histogenesis and function of DRs in liver injury are not entirely understood. It is widely believed that DRs contain bipotential liver progenitor cells (LPCs) that serve as an emergency cell pool to regenerate both cholangiocytes and hepatocytes and may eventually give rise to hepatocellular carcinoma (HCC). Here, we used a murine model that allows highly efficient and specific lineage labeling of the biliary compartment to analyze the histogenesis of DRs and their potential contribution to liver regeneration and carcinogenesis. In multiple experimental and genetic liver injury models, biliary cells were the predominant precursors of DRs but lacked substantial capacity to produce new hepatocytes, even when liver injuries were prolonged up to 12 months. Genetic modulation of NOTCH and/or WNT/β-catenin signaling within lineage-tagged DRs impaired DR expansion but failed to redirect DRs from biliary differentiation toward the hepatocyte lineage. Further, lineage-labeled DRs did not produce tumors in genetic and chemical HCC mouse models. In summary, we found no evidence in our system to support mouse biliary-derived DRs as an LPC pool to replenish hepatocytes in a quantitatively relevant way in injury or evidence that DRs give rise to HCCs.
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44
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Li Y, Liu D, Zong Y, Qi J, Li B, Liu K, Xiao H. Developmental Stage-Specific Hepatocytes Induce Maturation of HepG2 Cells by Rebuilding the Regulatory Circuit. Mol Med 2015; 21:285-95. [PMID: 25879626 DOI: 10.2119/molmed.2014.00173] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2014] [Accepted: 04/14/2015] [Indexed: 12/19/2022] Open
Abstract
On the basis of their characteristics, we presume that developmental stage-specific hepatocytes should have the ability to induce maturation of hepatoma cells. A regulatory circuit formed by hepatocyte nuclear factor (HNF)-4α, HNF-1α, HNF-6 and the upstream stimulatory factor (USF-1) play a key role in the maturation of embryonic hepatocytes; however, it is unclear whether the regulatory circuit mediates the embryonic induction of hepatoma cell maturation. In this study, 12.5-d to 15.5-d mouse embryonic hepatocytes or their medium were used to coculture or treat HepG2 cells, and the induced maturation was evaluated in vitro and in vivo. In the induced HepG2 cells, the components of the regulatory circuit were detected, their cross-regulation was evaluated and HNF-4α RNA interference was performed. We found that 13.5-d to 14.5-d embryonic hepatocytes could induce HepG2 cell maturation, demonstrated by morphological changes, increased maturation markers and decreased c-Myc and α-fetoprotein (AFP) in vitro. The majority of HepG2 tumors were eliminated by 13.5-d embryonic induction in vivo. All components of the regulatory circuit were upregulated and the binding of HNF-4α, HNF-1α, HNF-6 and USF-1 to their target sites was promoted to rebuild the regulatory circuit in the induced HepG2 cells. Moreover, RNA interference targeting HNF-4α, which is the core of the regulatory circuit, attenuated the induced maturation of HepG2 cells with downregulation of the regulatory circuit. These results revealed that developmental stage-specific hepatocytes could induce the maturation of HepG2 cells by rebuilding the regulatory circuit.
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Affiliation(s)
- Yanning Li
- Department of Molecular Biology, Hebei Key Laboratory of Laboratory Animal, Hebei Medical University, Shijiazhuang, China
| | - Demei Liu
- Department of Biochemistry, Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
| | - Yanhong Zong
- Department of Biochemistry, Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
| | - Jinsheng Qi
- Department of Biochemistry, Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
| | - Bin Li
- Department of Biochemistry, Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
| | - Kun Liu
- Department of Biochemistry, Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
| | - Hui Xiao
- Department of Biochemistry, Hebei Key Laboratory of Medical Biotechnology, Hebei Medical University, Shijiazhuang, China
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Brain isoform glycogen phosphorylase as a novel hepatic progenitor cell marker. PLoS One 2015; 10:e0122528. [PMID: 25826279 PMCID: PMC4380311 DOI: 10.1371/journal.pone.0122528] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/04/2014] [Accepted: 02/21/2015] [Indexed: 12/21/2022] Open
Abstract
An appropriate liver-specific progenitor cell marker is a stepping stone in liver regenerative medicine. Here, we report brain isoform glycogen phosphorylase (GPBB) as a novel liver progenitor cell marker. GPBB was identified in a protein complex precipitated by a monoclonal antibody Ligab generated from a rat liver progenitor cell line Lig-8. Immunoblotting results show that GPBB was expressed in two liver progenitor cell lines Lig-8 and WB-F344. The levels of GPBB expression decreased in the WB-F344 cells under sodium butyrate (SB)-induced cell differentiation, consistent with roles of GPBB as a liver progenitor cell marker. Short hairpin RNA (shRNA)-mediated GPBB knockdown followed by glucose deprivation test shows that GPBB aids in liver progenitor cell survival under low glucose conditions. Furthermore, shRNA-mediated GPBB knockdown followed by SB-induced cell differentiation shows that reducing GPBB expression delayed liver progenitor cell differentiation. We conclude that GPBB is a novel liver progenitor cell marker, which facilitates liver progenitor cell survival under low glucose conditions and cell differentiation.
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Shibahara J, Ando S, Hayashi A, Sakamoto Y, Hesegawa K, Kokudo N, Fukayama M. Clinicopathologic characteristics of SALL4-immunopositive hepatocellular carcinoma. SPRINGERPLUS 2014; 3:721. [PMID: 26034695 PMCID: PMC4447768 DOI: 10.1186/2193-1801-3-721] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/07/2014] [Accepted: 12/03/2014] [Indexed: 12/23/2022]
Abstract
The aim of this study was to investigate the clinicopathologic characteristics of sal-like protein 4 (SALL4)-immunopositive hepatocellular carcinoma (HCC). Solitary HCCs that were surgically treated at the University of Tokyo Hospital between 2000 and 2008 were the subject of this study. Diffuse, non-punctate nuclear immunoreactivity to SALL4 was observed in 47 of 337 HCCs (13.9%). Compared to patients with SALL4-negative HCC, patients with SALL4-positive HCC were younger (mean 59.2 years vs. 65.2 years), more frequently female (44.7% vs. 18.3%) and positive for hepatitis B virus angigen (42.6% vs. 18.6%). They had much higher serum levels of alpha-fetoprotein (median 3976.5 ng/ml vs. 14.0 ng/ml) (P < 0.001). Liver function tended to be favourable, as was shown by less indocyanine green retention at 15 minutes (ICG15), in patients with SALL4-positive HCCs (P < 0.001). Histologically, SALL4-positive HCCs exhibited less histological differentiation (P < 0.001) and had a higher frequency of micro- or macrovascular invasion (72.3% vs. 54.1%, P = 0.019) and intrahepatic metastasis (34.0% vs. 19.3%, P = 0.022) than SALL4-negative HCCs. SALL4-positive HCCs were more frequently immunoreactive for cytokeratin 19 (42.6% vs. 11.7%, P < 0.001) and EpCAM (51.1% vs. 8.3%, P < 0.001). The log-rank test indicated short-term disease-free survival (< 1 year) of patients with SALL4-positive HCC was worse than those with SALL4-negative HCC (P = 0.019). Multivariate analyses, however, failed to show the prognostic significance of SALL4 immunoreactivity in HCCs. In conclusion, SALL4-immunopositive HCCs constitute a subset with characteristic patient backgrounds and somewhat aggressive behavior, as was manifested by frequent vascular invasion and intrahepatic metastasis. There was little prognostic significance of SALL4 immunoreactivity in HCCs.
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Affiliation(s)
- Junji Shibahara
- Department of Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Sumiyo Ando
- Department of Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Akimasa Hayashi
- Department of Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
| | - Yoshihiro Sakamoto
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hesegawa
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Norihiro Kokudo
- Hepato-Biliary-Pancreatic Division, Department of Surgery, Graduate School of Medicine, University of Tokyo, Tokyo, Japan
| | - Masashi Fukayama
- Department of Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033 Japan
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Lei YY, Wang WJ, Mei JH, Wang CL. Mitogen-Activated Protein Kinase Signal Transduction in Solid Tumors. Asian Pac J Cancer Prev 2014; 15:8539-48. [DOI: 10.7314/apjcp.2014.15.20.8539] [Citation(s) in RCA: 69] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
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Fernando J, Malfettone A, Cepeda EB, Vilarrasa-Blasi R, Bertran E, Raimondi G, Fabra À, Alvarez-Barrientos A, Fernández-Salguero P, Fernández-Rodríguez CM, Giannelli G, Sancho P, Fabregat I. A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells. Int J Cancer 2014; 136:E161-72. [PMID: 25053293 DOI: 10.1002/ijc.29097] [Citation(s) in RCA: 91] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2014] [Accepted: 07/18/2014] [Indexed: 12/11/2022]
Abstract
The multikinase inhibitor sorafenib is the only effective drug in advanced cases of hepatocellular carcinoma (HCC). However, response differs among patients and effectiveness only implies a delay. We have recently described that sorafenib sensitizes HCC cells to apoptosis. In this work, we have explored the response to this drug of six different liver tumor cell lines to define a phenotypic signature that may predict lack of response in HCC patients. Results have indicated that liver tumor cells that show a mesenchymal-like phenotype, resistance to the suppressor effects of transforming growth factor beta (TGF-β) and high expression of the stem cell marker CD44 were refractory to sorafenib-induced cell death in in vitro studies, which correlated with lack of response to sorafenib in nude mice xenograft models of human HCC. In contrast, epithelial-like cells expressing the stem-related proteins EpCAM or CD133 were sensitive to sorafenib-induced apoptosis both in vitro and in vivo. A cross-talk between the TGF-β pathway and the acquisition of a mesenchymal-like phenotype with up-regulation of CD44 expression was found in the HCC cell lines. Targeted CD44 knock-down in the mesenchymal-like cells indicated that CD44 plays an active role in protecting HCC cells from sorafenib-induced apoptosis. However, CD44 effect requires a TGF-β-induced mesenchymal background, since the only overexpression of CD44 in epithelial-like HCC cells is not sufficient to impair sorafenib-induced cell death. In conclusion, a mesenchymal profile and expression of CD44, linked to activation of the TGF-β pathway, may predict lack of response to sorafenib in HCC patients.
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Affiliation(s)
- Joan Fernando
- Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Spain
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Pan CX, Tang J, Wang XY, Wu FR, Ge JF, Chen FH. Role of interleukin-22 in liver diseases. Inflamm Res 2014; 63:519-25. [PMID: 24623532 PMCID: PMC4050291 DOI: 10.1007/s00011-014-0727-3] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2013] [Revised: 02/05/2014] [Accepted: 02/24/2014] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION Interleukin (IL)-22, originally referred to as IL-TIF for IL-10-related T cell-derived inducible factor, is a member of the IL-10-like cytokine family. IL-22 is highly expressed by Th17 cells and is tightly linked to chronic inflammation, including inflammatory bowel disease and local intestinal inflammation among others. MATERIALS AND METHODS A PubMed and Web of Science databases search was performed for studies providing evidences on the role of IL-22 in liver diseases. CONCLUSION IL-22 plays an important role in ameliorating liver injury in many rodent models by targeting hepatocytes that express high levels of IL-22 receptor 1 and IL-10 receptor 2. This review concisely summarizes the role of IL-22 in the development progression of liver disease of different etiologies. It is focused mainly on the IL-22 intracellular signaling and its influence on liver diseases.
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Affiliation(s)
- Chun-xiao Pan
- School of Pharmacy, Anhui Medical University, 81 Mei-shan Road, Hefei, 230032 China
| | - Jie Tang
- School of Pharmacy, Anhui Medical University, 81 Mei-shan Road, Hefei, 230032 China
| | - Xiao-yu Wang
- School of Pharmacy, Anhui Medical University, 81 Mei-shan Road, Hefei, 230032 China
| | - Fan-rong Wu
- School of Pharmacy, Anhui Medical University, 81 Mei-shan Road, Hefei, 230032 China
| | - Jin-fang Ge
- School of Pharmacy, Anhui Medical University, 81 Mei-shan Road, Hefei, 230032 China
| | - Fei-hu Chen
- School of Pharmacy, Anhui Medical University, 81 Mei-shan Road, Hefei, 230032 China
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Nadal-Ginard B, Ellison GM, Torella D. The cardiac stem cell compartment is indispensable for myocardial cell homeostasis, repair and regeneration in the adult. Stem Cell Res 2014; 13:615-30. [PMID: 24838077 DOI: 10.1016/j.scr.2014.04.008] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2014] [Revised: 02/24/2014] [Accepted: 04/18/2014] [Indexed: 02/07/2023] Open
Abstract
Resident cardiac stem cells in embryonic, neonatal and adult mammalian heart have been identified by different membrane markers and transcription factors. However, despite a flurry of publications no consensus has been reached on the identity and actual regenerative effects of the adult cardiac stem cells. Intensive research on the adult mammalian heart's capacity for self-renewal of its muscle cell mass has led to a consensus that new cardiomyocytes (CMs) are indeed formed throughout adult mammalian life albeit at a disputed frequency. The physiological significance of this renewal, the origin of the new CMs, and the rate of adult CM turnover are still highly debated. Myocyte replacement, particularly after injury, was originally attributed to differentiation of a stem cell compartment. More recently, it has been reported that CMs are mainly replaced by the division of pre-existing post-mitotic CMs. These latter results, if confirmed, would shift the target of regenerative therapy toward boosting mature CM cell-cycle re-entry. Despite this controversy, it is documented that the adult endogenous c-kit(pos) cardiac stem cells (c-kit(pos) eCSCs) participate in adaptations to myocardial stress, and, when transplanted into the myocardium, regenerate most cardiomyocytes and microvasculature lost in an infarct. Nevertheless, the in situ myogenic potential of adult c-kit(pos) cardiac cells has been questioned. To revisit the regenerative potential of c-kit(pos) eCSCs, we have recently employed experimental protocols of severe diffuse myocardial damage in combination with several genetic murine models and cell transplantation approaches showing that eCSCs are necessary and sufficient for CM regeneration, leading to complete cellular, anatomical, and functional myocardial recovery. Here we will review the available data on adult eCSC biology and their regenerative potential placing it in the context of the different claimed mechanisms of CM replacement. These data are in agreement with and have reinforced our view that most CMs are replaced by de novo CM formation through the activation, myogenic commitment and specification of the eCSC cohort.
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Affiliation(s)
- Bernardo Nadal-Ginard
- Department of Physiology, School of Biomedical Sciences, King's College, London, UK; Centre for Stem Cells & Regenerative Medicine, King's College, London, UK.
| | - Georgina M Ellison
- Department of Physiology, School of Biomedical Sciences, King's College, London, UK; Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy; Centre for Stem Cells & Regenerative Medicine, King's College, London, UK
| | - Daniele Torella
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro 88100, Italy.
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