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Ding Z, Wang L, Sun J, Zheng L, Tang Y, Tang H. Hepatocellular carcinoma: pathogenesis, molecular mechanisms, and treatment advances. Front Oncol 2025; 15:1526206. [PMID: 40265012 PMCID: PMC12011620 DOI: 10.3389/fonc.2025.1526206] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2024] [Accepted: 03/21/2025] [Indexed: 04/24/2025] Open
Abstract
Hepatocellular Carcinoma (HCC), a highly prevalent malignancy, poses a significant global health challenge. Its pathogenesis is intricate and multifactorial, involving a complex interplay of environmental and genetic factors. Viral hepatitis, excessive alcohol consumption, and cirrhosis are known to significantly elevate the risk of developing HCC. The underlying biological processes driving HCC are equally complex, encompassing aberrant activation of molecular signaling pathways, dysregulation of hepatocellular differentiation and angiogenesis, and immune dysfunction. This review delves into the multifaceted nature of HCC, exploring its etiology and the intricate molecular signaling pathways involved in its development. We examine the role of immune dysregulation in HCC progression and discuss the potential of emerging therapeutic strategies, including immune-targeted therapy and tumor-associated macrophage interventions. Additionally, we explore the potential of traditional Chinese medicine (TCM) monomers in inhibiting tumor growth. By elucidating the complex interplay of factors contributing to HCC, this review aims to provide a comprehensive understanding of the disease and highlight promising avenues for future research and therapeutic development.
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Affiliation(s)
- Zhixian Ding
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Lusheng Wang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Jiting Sun
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Lijie Zheng
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Yu Tang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
| | - Heng Tang
- General Clinical Research Center, Wanbei Coal-Electricity Group General Hospital, Suzhou, China
- Laboratory of Inflammation and Repair of Liver Injury and Tumor Immunity, Wanbei Coal-Electricity Group General Hospital, Hefei, China
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Ekpenyong BB, Ubi GM, Kooffreh ME, Umoyen AJ, James CS, Ettah IA, Etangetuk NA, Effiom BE, Okpechi PA, Ejue BP, Ambo OA. Tumor protein 53 gene polymorphism, demographic attributes and associated risk factors among liver cancer patients in Calabar, Nigeria. BMC Cancer 2025; 25:430. [PMID: 40065269 PMCID: PMC11892161 DOI: 10.1186/s12885-025-13803-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Accepted: 02/25/2025] [Indexed: 03/14/2025] Open
Abstract
Mutations in the TP53 gene had been attributed to the development of liver cancer. Hepatocellular carcinoma (HCC) and liver tumour are liver diseases having high mortality rates in several populations. There is no information on the TP53 gene polymorphism among liver diseases patients in Calabar, Nigeria. This study investigated the genetic polymorphism of TP53 among HCC and liver tumour in Calabar. This research was carried out in the University of Calabar Teaching Hospital, Calabar. Blood samples were collected from 35 clinically diagnosed hepatocellular carcinoma and 10 tumour patients and 10 healthy controls. DNA was extracted from all blood samples and Polymerase Chain Reaction (PCR) was performed using specific primers. The PCR amplicons were digested using Hae III restriction enzyme and the genotypic and allelic frequencies was determined. Demographic data among participants showed that males were 68.9% (31), females (31.1%; 14), sex ratio (2.2: 0.5), mean age was 41.51 ± 2.13 years with an odds ratio of 1.25. The distribution of participants according to marital status were 33(73.3%), 10(22.2%), and 2(4.4%) for married, single, and widowed respectively. The participants were from different extractions with varied representations of Yakurr (22.2%, 10), Efik (20%, 9), Boki (13.3%, 6), Ogoja (13.3%, 6), Annang (8.8%, 4), Ibibio (2.2%, 1) and Igbo (2.2%, 1) and respectively. Approximately, 64.7% (30) of the chronic liver diseases were from the Central and Northern part of Cross River State. The risk factors were HCV infection, HBsAg+, alcoholism, smoking, consumption of groundnuts that may have been contaminated with aflatoxin and family history of the disease. PCR product yielded 254 bp and digested PCR product showed homozygous TT mutation (27), heterozygous GT mutation (17) and homozygous GG wild type (1) in cases. The overall TP53 gene mutation frequency was 46.32% (44). The frequency of G allele, T allele, GG, GT and TT were 0.21, 0.79, 0.04, 0.33 and 0.62 respectively among cases, while GG (wild type) was only detected among controls in the study population. The genotypic and allelic frequencies conform to Hardy-Weinberg equilibrium meaning that the forces of evolution were not acting on the locus. There were significant differences in the genotypic proportions of the TP53 gene polymorphism among patients and controls. This study on the TP53 gene polymorphism will serve as baseline information on the molecular etiology of hepatocellular carcinoma and liver tumour in Cross River State.
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Affiliation(s)
- Blessing B Ekpenyong
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
- Department of Plant Science and Biotechnology, University of Cross River State, Calabar, Nigeria
| | - Godwin M Ubi
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria.
| | - M E Kooffreh
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Anthony J Umoyen
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Cecilia S James
- Department of Genetics and Biotechnology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Ivon A Ettah
- Department of Science Laboratory Technology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Nseabasi A Etangetuk
- Department of Science Laboratory Technology, Faculty of Biological Sciences, University of Calabar, Calabar, Nigeria
| | - Bassey E Effiom
- Department of Guidance and Counseling, Faculty of Education, University of Calabar, Calabar, Nigeria
| | - Philip A Okpechi
- Department of Guidance and Counseling, Faculty of Education, University of Calabar, Calabar, Nigeria
| | - Bassey P Ejue
- Department of Guidance and Counseling, Faculty of Education, University of Calabar, Calabar, Nigeria
| | - Ogar A Ambo
- Department of Guidance and Counseling, Faculty of Education, University of Calabar, Calabar, Nigeria
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Chaudhary N, Kiranmayee B. Non-receptor Type PTPases and their Role in Controlling Pathways Related to Diabetes and Liver Cancer Signalling. Curr Pharm Biotechnol 2025; 26:654-664. [PMID: 38424416 DOI: 10.2174/0113892010288624240213072415] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2023] [Revised: 01/22/2024] [Accepted: 02/01/2024] [Indexed: 03/02/2024]
Abstract
The role of non-receptor type Protein Tyrosine Phosphatase (PTPases) in controlling pathways related to diabetes and Hepatocellular Carcinoma (HCC) is significant. The insulin signal transduction pathway is regulated by the steady-state phosphorylation of tyrosyl residues of the insulin receptor and post-receptor substrates. PTPase has been shown to have a physiological role in the regulation of reversible tyrosine phosphorylation. There are several non-receptor type PTPases. PTPase containing the SH-2 domain (SHP-2) and the non-receptor type PTPase (PTP1B; encoded by the PTPN1 gene) are involved in negative regulation of the insulin signaling pathway, thereby indicating that the pathway can be made more efficient by the reduction in the activity of specific PTPases. Reduction in insulin resistance may be achieved by drugs targeting these specific enzymes. The modifications in the receptor and post-receptor events of insulin signal transduction give rise to insulin resistance, and a link between insulin-resistant states and HCC has been established. The cancer cells thrive on higher levels of energy and their growth gets encouraged since insulin-resistant states lead to greater glucose levels. Cancer, hyperglycemia, and hypoglycemia are highly linked through various pathways hence, clarifying the molecular mechanisms through which non-receptor type PTPase regulates the insulin signal transduction is necessary to find an effective target for cancer. Targeting the pathways related to PTPases; both receptor and non-receptor types, may lead to an effective candidate to fight against diabetes and HCC.
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Affiliation(s)
- Nidhee Chaudhary
- Centre for Biotechnology & Biochemical Engineering, Amity Institute Biotechnology, Amity University Uttar Pradesh, Sector-125, Expressway, Noida, 201313, Uttar Pradesh, India
| | - Bellam Kiranmayee
- Centre for Biotechnology & Biochemical Engineering, Amity Institute Biotechnology, Amity University Uttar Pradesh, Sector-125, Expressway, Noida, 201313, Uttar Pradesh, India
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Ju S, Duan X, Wang Y, Zhang M, Bai Y, He X, Wang C, Liu J, Yao W, Zhou C, Xiong B, Zheng C. Blocking TGFβR synergistically enhances anti-tumor effects of anti-PD-1 antibody in a mouse model of incomplete thermal ablation. Int Immunopharmacol 2024; 138:112585. [PMID: 38950456 DOI: 10.1016/j.intimp.2024.112585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 06/20/2024] [Accepted: 06/25/2024] [Indexed: 07/03/2024]
Abstract
The mechanism of early tumor recurrence after incomplete microwave ablation (iMWA) is poorly understood. The anti-programmed cell death protein 1 (anti-PD-1) monotherapy is reported to be ineffective to prevent the progression of residual tumor resulted from iMWA. Transforming growth factor-β (TGFβ) signaling pathway plays an important role in tumorigenesis and development. We assume blocking transforming growth factor-β receptor (TGFβR) after incomplete iMWA may synergistically enhance the effect of anti-PD-1 antibody to prevent the progression of residual tumor. We construct an iMWA model with mice harboring Hepa1-6 derived xenograft. The Tgfb1 expression and phosphorylated-Smad3 protein expression is upregulated in the residual tumor after iMWA. With the application of TGFβR inhibitor SB431542, the cell proliferation potential, the tumor growth, the mRNA expression of epithelial mesenchymal transition (EMT) markers including Cdh2, and Vim, and cancer stem cell marker Epcam, and the infiltrating Treg cells are reduced in the residual tumor tissue. In addition, iMWA combined with TGFβR blocker and anti-PD-1 antibody further decreases the cell proliferation, tumor growth, expression of EMT markers and cancer stem cell marker, and the infiltrating Treg cells in the residual tumor tissue. Blocking TGFβR may alleviate the pro-tumoral effect of tumor microenvironment thereby significantly prevents the progression of residual tumor tissue. Our study indicates that blocking TGFβR may be a novel therapeutic strategy to enhance the effect of anti-PD-1 antibody to prevent residual hepatocellular carcinoma (HCC) progression after iMWA.
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Affiliation(s)
- Shuguang Ju
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Xuhua Duan
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, China
| | - Yingliang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Mengfan Zhang
- Department of Interventional Radiology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou University, Zhengzhou 450000, China
| | - Yaowei Bai
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Xuelian He
- School of Pharmacy, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Chaoyang Wang
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Jiacheng Liu
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Wei Yao
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Chen Zhou
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China
| | - Bin Xiong
- Department of Interventional Radiology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
| | - Chuansheng Zheng
- Department of Radiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Hubei Province Key Laboratory of Molecular Imaging, Wuhan 430022, China.
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Chen L, Ye X, Yang L, Zhao J, You J, Feng Y. Linking fatty liver diseases to hepatocellular carcinoma by hepatic stellate cells. JOURNAL OF THE NATIONAL CANCER CENTER 2024; 4:25-35. [PMID: 39036388 PMCID: PMC11256631 DOI: 10.1016/j.jncc.2024.01.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/05/2024] [Accepted: 01/07/2024] [Indexed: 07/23/2024] Open
Abstract
Hepatic stellate cells (HSCs), a distinct category of non-parenchymal cells in the liver, are critical for liver homeostasis. In healthy livers, HSCs remain non-proliferative and quiescent. However, under conditions of acute or chronic liver damage, HSCs are activated and participate in the progression and regulation of liver diseases such as liver fibrosis, cirrhosis, and liver cancer. Fatty liver diseases (FLD), including nonalcoholic (NAFLD) and alcohol-related (ALD), are common chronic inflammatory conditions of the liver. These diseases, often resulting from multiple metabolic disorders, can progress through a sequence of inflammation, fibrosis, and ultimately, cancer. In this review, we focused on the activation and regulatory mechanism of HSCs in the context of FLD. We summarized the molecular pathways of activated HSCs (aHSCs) in mediating FLD and their role in promoting liver tumor development from the perspectives of cell proliferation, invasion, metastasis, angiogenesis, immunosuppression, and chemo-resistance. We aimed to offer an in-depth discussion on the reciprocal regulatory interactions between FLD and HSC activation, providing new insights for researchers in this field.
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Affiliation(s)
- Liang'en Chen
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Xiangshi Ye
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Lixian Yang
- Cancer Center, Department of Radiation Oncology, Zhejiang Provincial People's Hospital (Hangzhou Medical College), Hangzhou, China
| | - Jiangsha Zhao
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
| | - Jia You
- School of Life Sciences, Westlake University, Hangzhou, China
| | - Yuxiong Feng
- Zhejiang Provincial Key Laboratory of Pancreatic Disease, First Affiliated Hospital, and Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
- Cancer Center, Zhejiang University, Hangzhou, China
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Cuesta ÁM, Palao N, Bragado P, Gutierrez-Uzquiza A, Herrera B, Sánchez A, Porras A. New and Old Key Players in Liver Cancer. Int J Mol Sci 2023; 24:17152. [PMID: 38138981 PMCID: PMC10742790 DOI: 10.3390/ijms242417152] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 11/27/2023] [Accepted: 11/28/2023] [Indexed: 12/24/2023] Open
Abstract
Liver cancer represents a major health problem worldwide with growing incidence and high mortality, hepatocellular carcinoma (HCC) being the most frequent. Hepatocytes are likely the cellular origin of most HCCs through the accumulation of genetic alterations, although hepatic progenitor cells (HPCs) might also be candidates in specific cases, as discussed here. HCC usually develops in a context of chronic inflammation, fibrosis, and cirrhosis, although the role of fibrosis is controversial. The interplay between hepatocytes, immune cells and hepatic stellate cells is a key issue. This review summarizes critical aspects of the liver tumor microenvironment paying special attention to platelets as new key players, which exert both pro- and anti-tumor effects, determined by specific contexts and a tight regulation of platelet signaling. Additionally, the relevance of specific signaling pathways, mainly HGF/MET, EGFR and TGF-β is discussed. HGF and TGF-β are produced by different liver cells and platelets and regulate not only tumor cell fate but also HPCs, inflammation and fibrosis, these being key players in these processes. The role of C3G/RAPGEF1, required for the proper function of HGF/MET signaling in HCC and HPCs, is highlighted, due to its ability to promote HCC growth and, regulate HPC fate and platelet-mediated actions on liver cancer.
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Affiliation(s)
- Ángel M. Cuesta
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Nerea Palao
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Paloma Bragado
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Alvaro Gutierrez-Uzquiza
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
| | - Blanca Herrera
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD-ISCIII), 28040 Madrid, Spain
| | - Aránzazu Sánchez
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
- Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD-ISCIII), 28040 Madrid, Spain
| | - Almudena Porras
- Departamento de Bioquímica y Biología Molecular, Facultad de Farmacia, Universidad Complutense de Madrid (UCM), 28040 Madrid, Spain; (Á.M.C.); (N.P.); (P.B.); (A.G.-U.); (B.H.); (A.S.)
- Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), 28040 Madrid, Spain
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Chen Y, Wang W, Morgan MP, Robson T, Annett S. Obesity, non-alcoholic fatty liver disease and hepatocellular carcinoma: current status and therapeutic targets. Front Endocrinol (Lausanne) 2023; 14:1148934. [PMID: 37361533 PMCID: PMC10286797 DOI: 10.3389/fendo.2023.1148934] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 05/16/2023] [Indexed: 06/28/2023] Open
Abstract
Obesity is a global epidemic and overwhelming evidence indicates that it is a risk factor for numerous cancers, including hepatocellular carcinoma (HCC), the third leading cause of cancer-related deaths worldwide. Obesity-associated hepatic tumorigenesis develops from nonalcoholic fatty liver disease (NAFLD), progressing to nonalcoholic steatohepatitis (NASH), cirrhosis and ultimately to HCC. The rising incidence of obesity is resulting in an increased prevalence of NAFLD and NASH, and subsequently HCC. Obesity represents an increasingly important underlying etiology of HCC, in particular as the other leading causes of HCC such as hepatitis infection, are declining due to effective treatments and vaccines. In this review, we provide a comprehensive overview of the molecular mechanisms and cellular signaling pathways involved in the pathogenesis of obesity-associated HCC. We summarize the preclinical experimental animal models available to study the features of NAFLD/NASH/HCC, and the non-invasive methods to diagnose NAFLD, NASH and early-stage HCC. Finally, since HCC is an aggressive tumor with a 5-year survival of less than 20%, we will also discuss novel therapeutic targets for obesity-associated HCC and ongoing clinical trials.
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Affiliation(s)
- Yinshuang Chen
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Weipeng Wang
- College of Pharmaceutical Sciences, Soochow University, Suzhou, China
| | - Maria P. Morgan
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Tracy Robson
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
| | - Stephanie Annett
- School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, University of Medicine and Health Sciences, Dublin, Ireland
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Mishima E, Conrad M. Nonmetabolic role for CKB in ferroptosis. Nat Cell Biol 2023; 25:633-634. [PMID: 37156911 DOI: 10.1038/s41556-023-01104-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/10/2023]
Affiliation(s)
- Eikan Mishima
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Munich, Germany
| | - Marcus Conrad
- Institute of Metabolism and Cell Death, Helmholtz Zentrum München, Munich, Germany.
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Jothi S, Parumasivam T, Mohtar N. <em>Eurycoma longifolia</em>: an overview on the pharmacological properties for the treatment of common cancer. J Public Health Afr 2023. [PMID: 37492537 PMCID: PMC10365645 DOI: 10.4081/jphia.2023.2495] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/18/2023] Open
Abstract
Eurycoma longifolia plant, the so called Tongkat Ali in Malaysia, is a well grown prominent tree in all Southeast Asia. It is well known among traditional medicine practitioners as a curative plant for many diseases and health conditions. The major quassinoid from the plant is eurycomanone, which exhibits many prominent effects on various cancer cell lines. Numerous studies have shown that eurycomanone inhibits cancerous cell growth and encourages cell death both in vitro and in vivo test. Even though analyses of safety and toxicity have been conducted, there is still a substantial knowledge barrier when it comes to providing a scientific foundation for the molecular mechanism as well as intervention strategy in the living people cancer cell. In a way to offer adequate baseline data for future investigations based on molecular mechanism and intervention, the present work seeks to review the researches conducted to date on this herbal plant.
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Salam SGA, Rashed MM, Ibrahim NA, Rahim EAA, Alsufiani HM, Mansouri RA, Afifi M, Al-Farga A. Cell Growth Inhibition, DNA Fragmentation and Apoptosis-Inducing Properties of Household-Processed Leaves and Seeds of Fenugreek ( Trigonella Foenum-Graecum Linn.) against HepG2, HCT-116, and MCF-7 Cancerous Cell Lines. Curr Issues Mol Biol 2023; 45:936-953. [PMID: 36826005 PMCID: PMC9955320 DOI: 10.3390/cimb45020060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 01/15/2023] [Accepted: 01/17/2023] [Indexed: 01/20/2023] Open
Abstract
Household processing of fenugreek seeds and leaves, including soaking, germination, and boiling of the seeds, and air-drying of the leaves, has improved the levels of human consumption of the bitter seeds and increased the shelf life of fresh leaves, respectively. The potential anticancer activity of either unprocessed or processed fenugreek seeds or leaves and the relative expression of pro-apoptotic and anti-apoptotic genes of the studied cancerous cell lines exposed to IC50 crude extracts was investigated to observe the apoptotic-inducing property of this plant as an anticancer agent. The protein expression of IKK-α and IKK-β, as inhibitors of NF-KB which exhibit a critical function in the regulation of genes involved in chronic inflammatory disorders, were studied in the tested cancerous cell lines. In this study, the anticancer activity of household-processed fenugreek leaves and seeds against HepG2, HCT-116, MCF-7, and VERO cell lines was measured using an MTT assay. DNA fragmentation of both HepG2 and MCF-7 was investigated by using gel electrophoresis. RT-PCR was used to evaluate the relative expression of each p53, caspase-3, Bax, and Bcl-2 genes, whereas ELISA assay determined the expression of caspase-3, TNF-α, and 8-OHDG genes. Western blotting analyzed the protein-expressing levels of IKK-α and IKK-β proteins in each studied cell line. Data showed that at 500 µg mL-1, ADFL had the highest cytotoxicity against the HepG2 and HCT-116 cell lines. Although, each UFS and GFS sample had a more inhibitory effect on MCF-7 cells than ADFL. Gel electrophoresis demonstrated that the IC50 of each ADFL, UFS, and GFS sample induced DNA fragmentation in HepG2 and MCF-7, contrary to untreated cell lines. Gene expression using RT-PCR showed that IC50 doses of each sample induced apoptosis through the up-regulation of the p53, caspase-3, and Bax genes and the down-regulation of the Bcl-2 gene in each studied cell line. The relative expression of TNF-α, 8-OHDG, and caspase-3 genes of each HepG2 and MCF-7 cell line using ELISA assays demonstrated that ADFL, UFS, and GFS samples reduced the expression of TNF-α and 8-OHDG genes but increased the expression of the caspase-3 gene. Protein-expressing levels of IKK-α and IKK-β proteins in each studied cell line, determined using Western blotting, indicated that household treatments decreased IKK-α expression compared to the UFS sample. Moreover, the ADFL and SFS samples had the most activity in the IKK-β expression levels. Among all studied samples, air-dried fenugreek leaves and unprocessed and germinated fenugreek seeds had the most anti-proliferative and apoptotic-inducing properties against human HepG2, MCF-7, and HCT-116 cell lines, as compared to the VERO cell line. So, these crude extracts can be used in the future for developing new effective natural drugs for the treatment of hepatocellular, breast, and colon carcinomas.
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Affiliation(s)
- Shaimaa G. Abdel Salam
- Food Technology Research Institute, Agricultural Research Center, Giza P.O. Box 12613, Egypt
- Biochemistry Department, Faculty of Agriculture, Cairo University, Giza P.O. Box 12613, Egypt
| | - Mohamed M. Rashed
- Biochemistry Department, Faculty of Agriculture, Cairo University, Giza P.O. Box 12613, Egypt
| | - Nabih A. Ibrahim
- Food Technology Research Institute, Agricultural Research Center, Giza P.O. Box 12613, Egypt
| | - Emam A. Abdel Rahim
- Biochemistry Department, Faculty of Agriculture, Cairo University, Giza P.O. Box 12613, Egypt
| | - Hadeil Muhanna Alsufiani
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21959, Saudi Arabia
- Experimental Biochemistry Unit, King Fahd Medical Research Center, King Abdulaziz Unversity, Jeddah 21959, Saudi Arabia
| | - Rasha A. Mansouri
- Biochemistry Department, Faculty of Sciences, King Abdulaziz University, Jeddah 21959, Saudi Arabia
| | - Mohamed Afifi
- Department of Biochemistry, College of Sciences, University of Jeddah, Jeddah 21959, Saudi Arabia
- Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig P.O. Box 44519, Egypt
- Najla Bint Saud Al Saud Center for Distinguished Research in Biotechnology, Jeddah 21577, Saudi Arabia
| | - Ammar Al-Farga
- Department of Biochemistry, College of Sciences, University of Jeddah, Jeddah 21959, Saudi Arabia
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11
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Cytokines and Hepatocellular Carcinoma: Biomarkers of a Deadly Embrace. J Pers Med 2022; 13:jpm13010005. [PMID: 36675666 PMCID: PMC9865677 DOI: 10.3390/jpm13010005] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 12/08/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents a worldwide health matter with a major care burden, high prevalence, and poor prognosis. Its pathogenesis mainly varies depending on the underlying etiological factors, although it develops from liver cirrhosis in the majority of cases. This review summarizes the role of the most interesting soluble factors as biomarkers for early diagnosis and as recommended targets for treatment in accordance with the new challenges in precision medicine. In the premalignant environment, inflammatory cells release a wide range of cytokines, chemokines, growth factors, prostaglandins, and proangiogenic factors, making the liver environment more suitable for hepatocyte tumor progression that starts from acquired genetic mutations. A complex interaction of pro-inflammatory (IL-6, TNF-α) and anti-inflammatory cytokines (TGF-α and -β), pro-angiogenic molecules (including the Angiopoietins, HGF, PECAM-1, HIF-1α, VEGF), different transcription factors (NF-kB, STAT-3), and their signaling pathways are involved in the development of HCC. Since cytokines are expressed and released during the different stages of HCC progression, their measurement, by different available methods, can provide in-depth information on the identification and management of HCC.
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12
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Abu El-Makarem MA, Kamel MF, Mohamed AA, Ali HA, Mohamed MR, Mohamed AEDM, El-Said AM, Ameen MG, Hassnine AA, Hassan HA. Down-regulation of hepatic expression of GHR/STAT5/IGF-1 signaling pathway fosters development and aggressiveness of HCV-related hepatocellular carcinoma: Crosstalk with Snail-1 and type 2 transforming growth factor-beta receptor. PLoS One 2022; 17:e0277266. [PMID: 36374927 PMCID: PMC9662744 DOI: 10.1371/journal.pone.0277266] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Accepted: 10/24/2022] [Indexed: 11/16/2022] Open
Abstract
Background and aims So far, few clinical trials are available concerning the role of growth hormone receptor (GHR)/signal transducer and activator of transcription 5 (STAT5)/insulin like growth factor-1 (IGF-1) axis in hepatocarcinogenesis. The aim of this study was to evaluate the hepatic expression of GHR/STAT5/IGF-1 signaling pathway in hepatocellular carcinoma (HCC) patients and to correlate the results with the clinico-pathological features and disease outcome. The interaction between this signaling pathway and some inducers of epithelial-mesenchymal transition (EMT), namely Snail-1 and type 2 transforming growth factor-beta receptor (TGFBR2) was studied too. Material and methods A total of 40 patients with HCV-associated HCC were included in this study. They were compared to 40 patients with HCV-related cirrhosis without HCC, and 20 healthy controls. The hepatic expression of GHR, STAT5, IGF-1, Snail-1 and TGFBR2 proteins were assessed by immunohistochemistry. Results Compared with cirrhotic patients without HCC and healthy controls, cirrhotic patients with HCC had significantly lower hepatic expression of GHR, STAT5, and IGF-1proteins. They also displayed significantly lower hepatic expression of TGFBR2, but higher expression of Snail-1 versus the non-HCC cirrhotic patients and controls. Serum levels of alpha-fetoprotein (AFP) showed significant negative correlations with hepatic expression of GHR (r = -0.31; p = 0.029) and STAT5 (r = -0.29; p = 0.04). Hepatic expression of Snail-1 also showed negative correlations with GHR, STAT5, and IGF-1 expression (r = -0.55, p = 0.02; r = -0.472, p = 0.035, and r = -0.51, p = 0.009, respectively), whereas, hepatic expression of TGFBR2 was correlated positively with the expression of all these proteins (r = 0.47, p = 0.034; 0.49, p = 0.023, and r = 0.57, p<0.001, respectively). Moreover, we reported that decreased expression of GHR was significantly associated with serum AFP level>100 ng/ml (p = 0.048), increased tumor size (p = 0.02), vascular invasion (p = 0.002), and advanced pathological stage (p = 0.01). Similar significant associations were found between down-regulation of STAT5 expression and AFP level > 100 ng/ml (p = 0.006), vascular invasion (p = 0.009), and advanced tumor stage (p = 0.007). Also, attenuated expression of IGF-1 showed a significant association with vascular invasion (p < 0.001). Intriguingly, we detected that lower expression of GHR, STAT5 and IGF-1 were considered independent predictors for worse outcome in HCC. Conclusion Decreased expression of GHR/STAT5/IGF-1 signaling pathway may have a role in development, aggressiveness, and worse outcome of HCV-associated HCC irrespective of the liver functional status. Snail-1 and TGFBR2 as inducers of EMT may be key players. However, large prospective multicenter studies are needed to validate these results.
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Affiliation(s)
- Mona A. Abu El-Makarem
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
- * E-mail:
| | - Mariana F. Kamel
- Department of Pathology, School of Medicine, Minia University, Minia, Egypt
- Department of Pathology, Minia Oncology Center, Minia, Egypt
| | - Ahmed A. Mohamed
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
| | - Hisham A. Ali
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
| | - Mahmoud R. Mohamed
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
| | | | - Ahmed M. El-Said
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
| | - Mahmoud G. Ameen
- Department of Pathology, South Egypt Cancer Institute, Assuit University, Assuit, Egypt
| | - Alshymaa A. Hassnine
- Department of Tropical Medicine and Gastroenterology, School of Medicine, Minia University, Minia, Egypt
| | - Hatem A. Hassan
- Department of Internal Medicine, School of Medicine, Minia University, Minia, Egypt
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13
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Guo X, Li Y, Wang W, Wang L, Hu S, Xiao X, Hu C, Dai Y, Zhang Y, Li Z, Li J, Ma X, Zeng J. The construction of preclinical evidence for the treatment of liver fibrosis with quercetin: A systematic review and meta-analysis. Phytother Res 2022; 36:3774-3791. [PMID: 35918855 DOI: 10.1002/ptr.7569] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2021] [Revised: 07/06/2022] [Accepted: 07/06/2022] [Indexed: 12/09/2022]
Abstract
Quercetin (3,3',4',5,7-pentahydroxyflavone), a flavonoid, is widely found in fruits and vegetables and exerts broad-spectrum pharmacological effects in the liver. Many studies have explored the bioactivity of quercetin in the treatment of liver fibrosis. Hence, through a systematic review and biological mechanism evaluation, this study aimed to construct a body of preclinical evidence for the treatment of liver fibrosis using quercetin. The literature used in this study was mainly obtained from four databases, and the SYRCLE list (10 items) was used to evaluate the quality of the included literature. A meta-analysis of HA, LN, and other indicators was performed via STATA 15.0 software. Subgroup analyses based on animal species and model protocol were performed to further obtain detailed results. Moreover, the therapeutic mechanism of quercetin was summarized in a directed network form based on a comprehensive search of the literature. After screening, a total of 14 articles (comprising 15 studies) involving 254 animals were included. The results from the analysis showed that the corresponding liver function indexes, such as the levels of HA and LN, were significantly improved in the quercetin group compared with the model group, and liver function, such as the levels of AST and ALT, were also improved in the quercetin group. The species- and model-based subgroup analyses of AST and ALT revealed that quercetin exerts a significant effect. The therapeutic mechanism of quercetin was shown to be related to multiple pathways involving anti-inflammatory and antioxidant activities and lipid accumulation, including regulation of the TGF-β, α-SMA, ROS, and P-AMPK pathways. The results showed that quercetin exerts an obvious effect on liver fibrosis, and more prominent improvement effects on liver function and liver fibrosis indicators were obtained with a dose of 5-200 mg during a treatment course ranging from 4 to 8 weeks. Quercetin might be a promising therapeutic for liver fibrosis.
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Affiliation(s)
- Xiaochuan Guo
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yuanyuan Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Weizheng Wang
- School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Luyao Wang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Sihan Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- School of Acupuncture and Tuina, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiaolin Xiao
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Caiyu Hu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yao Dai
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Yiheng Zhang
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Ziyu Li
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Junlin Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Xiao Ma
- State Key Laboratory of Southwestern Chinese Medicine Resources, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, Chengdu, China
| | - Jinhao Zeng
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, China
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Kumar D, Das M, Oberg A, Sahoo D, Wu P, Sauceda C, Jih L, Ellies LG, Langiewicz MT, Sen S, Webster NJG. Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2105120. [PMID: 35615981 PMCID: PMC9313545 DOI: 10.1002/advs.202105120] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/18/2022] [Indexed: 05/12/2023]
Abstract
Hepatocellular carcinoma (HCC) is the fifth most common cancer worldwide. Serine-arginine rich splicing factor 3 (SRSF3) plays a critical role in hepatocyte function and its loss in mice promotes chronic liver damage and leads to HCC. Hepatocyte-specific SRSF3 knockout mice (SKO mice) also overexpress insulin-like growth factor 2 (IGF2). In the present study, double deletion of Igf2 and Srsf3 (DKO mice) prevents hepatic fibrosis and inflammation, and completely prevents tumor formation, and is associated with decreased proliferation, apoptosis and DNA damage, and restored DNA repair enzyme expression. This is confirmed in vitro, where IGF2 treatment of HepG2 hepatoma cells decreases DNA repair enzyme expression and causes DNA damage. Tumors from the SKO mice also show mutational signatures consistent with homologous recombination and mismatch repair defects. Analysis of frozen human samples shows that SRSF3 protein is decreased sixfold in HCC compared to normal liver tissue but SRSF3 mRNA is increased. Looking at public TCGA data, HCC patients having high SRSF3 mRNA expression show poor survival, as do patients with alterations in known SRSF3-dependent splicing events. The results indicate that IGF2 overexpression in conjunction with reduced SRSF3 splicing activity could be a major cause of DNA damage and driver of liver cancer.
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Affiliation(s)
- Deepak Kumar
- Research and Development ServiceVA San Diego Healthcare SystemSan DiegoCA92161USA
- Division of Endocrinology and Metabolism, Department of MedicineUniversity of California San DiegoLa JollaCA92093USA
| | - Manasi Das
- Division of Endocrinology and Metabolism, Department of MedicineUniversity of California San DiegoLa JollaCA92093USA
| | - Alexis Oberg
- Research and Development ServiceVA San Diego Healthcare SystemSan DiegoCA92161USA
- Division of Endocrinology and Metabolism, Department of MedicineUniversity of California San DiegoLa JollaCA92093USA
| | - Debashis Sahoo
- Division of Genome Information Sciences, Department of PediatricsUniversity of California San DiegoLa JollaCA92093USA
| | - Panyisha Wu
- Research and Development ServiceVA San Diego Healthcare SystemSan DiegoCA92161USA
- Division of Endocrinology and Metabolism, Department of MedicineUniversity of California San DiegoLa JollaCA92093USA
| | - Consuelo Sauceda
- Research and Development ServiceVA San Diego Healthcare SystemSan DiegoCA92161USA
- Division of Endocrinology and Metabolism, Department of MedicineUniversity of California San DiegoLa JollaCA92093USA
| | - Lily Jih
- Research and Development ServiceVA San Diego Healthcare SystemSan DiegoCA92161USA
- Division of Endocrinology and Metabolism, Department of MedicineUniversity of California San DiegoLa JollaCA92093USA
| | - Lesley G. Ellies
- Division of Cancer Biology Research, Department of PathologyUniversity of California San DiegoLa JollaCA92093USA
- Moores Cancer CenterUniversity of California San DiegoLa JollaCA92093USA
| | - Magda T. Langiewicz
- Division of Endocrinology and Metabolism, Department of MedicineUniversity of California San DiegoLa JollaCA92093USA
| | - Supriya Sen
- Division of Endocrinology and Metabolism, Department of MedicineUniversity of California San DiegoLa JollaCA92093USA
| | - Nicholas J. G. Webster
- Research and Development ServiceVA San Diego Healthcare SystemSan DiegoCA92161USA
- Division of Endocrinology and Metabolism, Department of MedicineUniversity of California San DiegoLa JollaCA92093USA
- Moores Cancer CenterUniversity of California San DiegoLa JollaCA92093USA
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15
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Wu H, Liu Y, Liao Z, Mo J, Zhang Q, Zhang B, Zhang L. The role of YAP1 in liver cancer stem cells: proven and potential mechanisms. Biomark Res 2022; 10:42. [PMID: 35672802 PMCID: PMC9171972 DOI: 10.1186/s40364-022-00387-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Accepted: 05/25/2022] [Indexed: 02/08/2023] Open
Abstract
YAP1 (Yes-associated protein 1) is one of the principal factors that mediates oncogenesis by acting as a driver of gene expression. It has been confirmed to play an important role in organ volume control, stem cell function, tissue regeneration, tumorigenesis and tumor metastasis. Recent research findings show that YAP1 is correlated with the stemness of liver cancer stem cells, and liver cancer stem cells are closely associated with YAP1-induced tumor initiation and progression. This article reviews the advancements made in research on the mechanisms by which YAP1 promotes liver cancer stem cells and discusses some potential mechanisms that require further study.
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Affiliation(s)
- Haofeng Wu
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Yachong Liu
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Zhibin Liao
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Jie Mo
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Qiaofeng Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Bixiang Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
| | - Lei Zhang
- Hepatic Surgery Center, Institute of Hepato-Pancreato-Bililary Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
- Department of Hepatobiliary Surgery, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Shanxi Medical University; Shanxi Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Taiyuan, 030032, China.
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16
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Sartorius K, Antwi SO, Chuturgoon A, Roberts LR, Kramvis A. RNA Therapeutic Options to Manage Aberrant Signaling Pathways in Hepatocellular Carcinoma: Dream or Reality? Front Oncol 2022; 12:891812. [PMID: 35600358 PMCID: PMC9115561 DOI: 10.3389/fonc.2022.891812] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Accepted: 04/04/2022] [Indexed: 11/24/2022] Open
Abstract
Despite the early promise of RNA therapeutics as a magic bullet to modulate aberrant signaling in cancer, this field remains a work-in-progress. Nevertheless, RNA therapeutics is now a reality for the treatment of viral diseases (COVID-19) and offers great promise for cancer. This review paper specifically investigates RNAi as a therapeutic option for HCC and discusses a range of RNAi technology including anti-sense oligonucleotides (ASOs), Aptamers, small interfering RNA (siRNA), ribozymes, riboswitches and CRISPR/Cas9 technology. The use of these RNAi based interventions is specifically outlined in three primary strategies, namely, repressing angiogenesis, the suppression of cell proliferation and the promotion of apoptosis. We also discuss some of the inherent chemical and delivery problems, as well as targeting issues and immunogenic reaction to RNAi interventions.
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Affiliation(s)
- Kurt Sartorius
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- Department of Surgery, KZN Kwazulu-Natal (UKZN) Gastrointestinal Cancer Research Centre, Durban, South Africa
| | - Samuel O. Antwi
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Jacksonville, FL, United States
| | - Anil Chuturgoon
- Discipline of Medical Biochemistry, School of Laboratory Medicine and Medical Sciences, College of Health Science, University of KwaZulu-Natal, Durban, South Africa
| | - Lewis R. Roberts
- The Africa Hepatopancreatobiliary Cancer Consortium (AHPBCC), Mayo Clinic, Jacksonville, FL, United States
- Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, United States
| | - Anna Kramvis
- Hepatitis Virus Diversity Research Unit, School of Internal Medicine, University of the Witwatersrand, Johannesburg, South Africa
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17
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Danesh Pouya F, Rasmi Y, Nemati M. Signaling Pathways Involved in 5-FU Drug Resistance in Cancer. Cancer Invest 2022; 40:516-543. [PMID: 35320055 DOI: 10.1080/07357907.2022.2055050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Anti-metabolite drugs prevent the synthesis of essential cell growth compounds. 5-fluorouracil is used as an anti-metabolic drug in various cancers in the first stage of treatment. Unfortunately, in some cancers, 5-fluorouracil has low effectiveness because of its drug resistance. Studies have shown that drug resistance to 5-fluorouracil is due to the activation of specific signaling pathways and increased expressions of enzymes involved in drug metabolites. However, when 5-fluorouracil is used in combination with other drugs, the sensitivity of cancer cells to 5-fluorouracil increases, and the effect of drug resistance is reversed. This study discusses how the function of 5-fluorouracil in JAK/STAT, Wnt, Notch, NF-κB, and hedgehogs in some cancers.
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Affiliation(s)
- Fahima Danesh Pouya
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
| | - Yousef Rasmi
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran.,Cellular and Molecular Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Mohadeseh Nemati
- Department of Biochemistry, School of Medicine, Urmia University of Medical Sciences, Urmia, Iran
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18
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Saisana M, Griffin SM, May FEB. Insulin and the insulin receptor collaborate to promote human gastric cancer. Gastric Cancer 2022; 25:107-123. [PMID: 34554347 PMCID: PMC8732810 DOI: 10.1007/s10120-021-01236-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2021] [Accepted: 08/12/2021] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric adenocarcinoma is common and consequent mortality high. Presentation and mortality are increased in obese individuals, many of whom have elevated circulating insulin concentrations. High plasma insulin concentrations may promote, and increase mortality from, gastric adenocarcinoma. Tumour promotion activities of insulin and its receptor are untested in gastric cancer cells. METHODS Tumour gene amplification and expression were computed from sequencing and microarray data. Associations with patient survival were assessed. Insulin-dependent signal transduction, growth, apoptosis and anoikis were analysed in metastatic cells from gastric adenocarcinoma patients and in cell lines. Receptor involvement was tested by pharmacological inhibition and genetic knockdown. RNA was analysed by RT-PCR and proteins by western transfer and immunofluorescence. RESULTS INSR expression was higher in tumour than in normal gastric tissue. High tumour expression was associated with worse patient survival. Insulin receptor was detected readily in metastatic gastric adenocarcinoma cells and cell lines. Isoforms B and A were expressed. Pharmacological inhibition prevented cell growth and division, and induced caspase-dependent cell death. Rare tumour INS expression indicated tumours would be responsive to pancreatic or therapeutic insulins. Insulin stimulated gastric adenocarcinoma cell PI3-kinase/Akt signal transduction, proliferation, and survival. Insulin receptor knockdown inhibited proliferation and induced programmed cell death. Type I IGF receptor knockdown did not induce cell death. CONCLUSIONS The insulin and IGF signal transduction pathway is dominant in gastric adenocarcinoma. Gastric adenocarcinoma cell survival depends upon insulin receptor. That insulin has direct cancer-promoting effects on tumour cells has implications for clinical management of obese and diabetic cancer patients.
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Affiliation(s)
- Marina Saisana
- grid.1006.70000 0001 0462 7212Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH UK
| | - S. Michael Griffin
- grid.1006.70000 0001 0462 7212Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH UK ,grid.420004.20000 0004 0444 2244Department of Surgery, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, NE1 4LP UK
| | - Felicity E. B. May
- grid.1006.70000 0001 0462 7212Newcastle University Centre for Cancer, Translational and Clinical Research Institute, Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH UK ,grid.1006.70000 0001 0462 7212Department of Pathology, Faculty of Medical Sciences, University of Newcastle-upon-Tyne, Framlington Place, Newcastle-upon-Tyne, NE2 4HH UK ,grid.420004.20000 0004 0444 2244Department of Oncology, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle-upon-Tyne, NE1 4LP UK
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Pocino K, Napodano C, Marino M, Di Santo R, Miele L, De Matthaeis N, Gulli F, Saporito R, Rapaccini GL, Ciasca G, Basile U. A Comparative Study of Serum Angiogenic Biomarkers in Cirrhosis and Hepatocellular Carcinoma. Cancers (Basel) 2021; 14:cancers14010011. [PMID: 35008171 PMCID: PMC8750498 DOI: 10.3390/cancers14010011] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 12/14/2021] [Indexed: 12/29/2022] Open
Abstract
Simple Summary The progression of liver disease is accompanied by pathological angiogenesis, a prerequisite for the development of HCC. In this paper, we analyzed the clinical significance of serum angiogenic markers VEGF, Ang-1, Ang-2, angiopoietin receptor Tie1/2, HGF, and PECAM-1 in 62 patients with liver disease, out of which 33 were diagnosed with HCC and 29 with liver cirrhosis without signs of neoplasia. Biomarkers levels were investigated as a function of “Model for End-Stage Liver Disease” (MELD) score and Fibrosis Index (FI). HCC patients showed higher HGF levels than ones with cirrhosis, while high Ang-1 levels appeared to have a protective role in HCC as well as prognostic significance; we also found a strong correlation between HGF levels, Ang-2, and VEGF levels, further supporting their role in tumor angiogenesis. Due to the complexity of angiogenesis and the small size of the study group, further investigations are widely desired especially in the era of immunotherapy and HCC-targeted anti-angiogenic drugs. Abstract Background: Hepatocellular carcinoma (HCC) is a global health problem associated with chronic liver disease. Its pathogenesis varies according to the underlying etiological factors, although in most cases it develops from liver cirrhosis. The disease progression is accompanied by pathological angiogenesis, which is a prerequisite that favors the development of HCC. Aims: This study aims at contributing to our understanding of the role of angiogenic factors in the progression of liver disease. For this purpose, we evaluate the clinical significance of serum angiogenic markers (VEGF, Ang-1, Ang-2, the angiopoietin receptor Tie1/2, HGF, and PECAM-1) first in cirrhotic and HCC patients separately, and then comparing cirrhotic patients with and without HCC. Materials and Methods: We enrolled 62 patients, out of whom 33 were diagnosed with HCC and 29 with liver cirrhosis without signs of neoplasia. Patients underwent venous blood sampling before and after receiving treatments for the diagnosed disease. Serum markers were evaluated using ELISA assays for Tie1 and the Bio-Plex Multiplex system for the remaining ones. Biomarker levels were investigated as a function of clinical scores for disease staging (MELD and Fibrosis Index, FI). Results: In cirrhotic patients, Ang-1 and Ang-2 correlate with MELD (ρAng-1 = −0.73, p = 2E−5) and FI (ρAng-1 = −0.52, p = 7E−3, ρAng-2 = 0.53, p = 3E−3). A reduction of Ang-2 levels (p = 0.047) and of the Ang-2/Ang-1 ratio (p = 0.031) is observed in cirrhotic patients diagnosed with viral hepatitis after antiviral treatments. In HCC patients, Ang-1 negatively correlates with FI (ρ = −0.63, p = 1E−4), and PECAM-1 positively correlates with MELD (ρ = 0.44, p = 0.01). A significant Ang-1 reduction was observed in deceased patients during the study compared to ones who survived (p = 0.01). In HCC patients, VEGF levels were increased after tumor treatment (p = 0.037). Notably, HGF levels in cirrhotic patients with HCC are significantly raised (p = 0.017) compared to that in those without HCC. Conclusions: Our results suggest that serum angiogenic markers, with emphasis on Ang-1/2, can contribute to the development of quantitative tools for liver disease staging and therapy monitoring. The comparison between cirrhotic patients with and without HCC suggests that HGF levels are potentially useful for monitoring the insurgence of HCC after a cirrhosis diagnosis. High Ang-1 levels in HCC patients appear to have a protective role as well as prognostic significance.
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Affiliation(s)
- Krizia Pocino
- Unità Operativa Complessa di Patologia Clinica, Ospedale Generale di Zona San Pietro Fatebenefratelli, 00189 Rome, Italy; (K.P.); (R.S.)
| | | | - Mariapaola Marino
- Dipartimento di Medicina e Chirurgia Traslazionale, Sezione di Patologia Generale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy
- Correspondence: (M.M.); (U.B.)
| | - Riccardo Di Santo
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (R.D.S.); (G.C.)
| | - Luca Miele
- Dipartimento di Medicina e Chirurgia Traslazionale, Sezione di Medicina Interna, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (L.M.); (N.D.M.); (G.L.R.)
| | - Nicoletta De Matthaeis
- Dipartimento di Medicina e Chirurgia Traslazionale, Sezione di Medicina Interna, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (L.M.); (N.D.M.); (G.L.R.)
| | - Francesca Gulli
- Laboratorio di Patologia Clinica, Ospedale Madre Giuseppina Vannini, 00177 Rome, Italy;
| | - Raffaele Saporito
- Unità Operativa Complessa di Patologia Clinica, Ospedale Generale di Zona San Pietro Fatebenefratelli, 00189 Rome, Italy; (K.P.); (R.S.)
| | - Gian Ludovico Rapaccini
- Dipartimento di Medicina e Chirurgia Traslazionale, Sezione di Medicina Interna, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (L.M.); (N.D.M.); (G.L.R.)
| | - Gabriele Ciasca
- Dipartimento di Neuroscienze, Sezione di Fisica, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (R.D.S.); (G.C.)
| | - Umberto Basile
- Dipartimento di Scienze di Laboratorio e Infettivologiche, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy
- Correspondence: (M.M.); (U.B.)
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The Curious Case of the HepG2 Cell Line: 40 Years of Expertise. Int J Mol Sci 2021; 22:13135. [PMID: 34884942 PMCID: PMC8658661 DOI: 10.3390/ijms222313135;select dbms_pipe.receive_message(chr(115)||chr(108)||chr(113)||chr(84),5) from dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver cancer is the third leading cause of cancer death worldwide. Representing such a dramatic impact on our lives, liver cancer is a significant public health concern. Sustainable and reliable methods for preventing and treating liver cancer require fundamental research on its molecular mechanisms. Cell lines are treated as in vitro equivalents of tumor tissues, making them a must-have for basic research on the nature of cancer. According to recent discoveries, certified cell lines retain most genetic properties of the original tumor and mimic its microenvironment. On the other hand, modern technologies allowing the deepest level of detail in omics landscapes have shown significant differences even between samples of the same cell line due to cross- and mycoplasma infection. This and other observations suggest that, in some cases, cell cultures are not suitable as cancer models, with limited predictive value for the effectiveness of new treatments. HepG2 is a popular hepatic cell line. It is used in a wide range of studies, from the oncogenesis to the cytotoxicity of substances on the liver. In this regard, we set out to collect up-to-date information on the HepG2 cell line to assess whether the level of heterogeneity of the cell line allows in vitro biomedical studies as a model with guaranteed production and quality.
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21
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The Curious Case of the HepG2 Cell Line: 40 Years of Expertise. Int J Mol Sci 2021; 22:13135. [PMID: 34884942 PMCID: PMC8658661 DOI: 10.3390/ijms222313135;select dbms_pipe.receive_message(chr(80)||chr(106)||chr(79)||chr(120),5) from dual--] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Liver cancer is the third leading cause of cancer death worldwide. Representing such a dramatic impact on our lives, liver cancer is a significant public health concern. Sustainable and reliable methods for preventing and treating liver cancer require fundamental research on its molecular mechanisms. Cell lines are treated as in vitro equivalents of tumor tissues, making them a must-have for basic research on the nature of cancer. According to recent discoveries, certified cell lines retain most genetic properties of the original tumor and mimic its microenvironment. On the other hand, modern technologies allowing the deepest level of detail in omics landscapes have shown significant differences even between samples of the same cell line due to cross- and mycoplasma infection. This and other observations suggest that, in some cases, cell cultures are not suitable as cancer models, with limited predictive value for the effectiveness of new treatments. HepG2 is a popular hepatic cell line. It is used in a wide range of studies, from the oncogenesis to the cytotoxicity of substances on the liver. In this regard, we set out to collect up-to-date information on the HepG2 cell line to assess whether the level of heterogeneity of the cell line allows in vitro biomedical studies as a model with guaranteed production and quality.
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22
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Arzumanian VA, Kiseleva OI, Poverennaya EV. The Curious Case of the HepG2 Cell Line: 40 Years of Expertise. Int J Mol Sci 2021; 22:13135. [PMID: 34884942 PMCID: PMC8658661 DOI: 10.3390/ijms222313135] [Citation(s) in RCA: 160] [Impact Index Per Article: 40.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 02/06/2023] Open
Abstract
Liver cancer is the third leading cause of cancer death worldwide. Representing such a dramatic impact on our lives, liver cancer is a significant public health concern. Sustainable and reliable methods for preventing and treating liver cancer require fundamental research on its molecular mechanisms. Cell lines are treated as in vitro equivalents of tumor tissues, making them a must-have for basic research on the nature of cancer. According to recent discoveries, certified cell lines retain most genetic properties of the original tumor and mimic its microenvironment. On the other hand, modern technologies allowing the deepest level of detail in omics landscapes have shown significant differences even between samples of the same cell line due to cross- and mycoplasma infection. This and other observations suggest that, in some cases, cell cultures are not suitable as cancer models, with limited predictive value for the effectiveness of new treatments. HepG2 is a popular hepatic cell line. It is used in a wide range of studies, from the oncogenesis to the cytotoxicity of substances on the liver. In this regard, we set out to collect up-to-date information on the HepG2 cell line to assess whether the level of heterogeneity of the cell line allows in vitro biomedical studies as a model with guaranteed production and quality.
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23
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DNAzymes, Novel Therapeutic Agents in Cancer Therapy: A Review of Concepts to Applications. J Nucleic Acids 2021; 2021:9365081. [PMID: 34760318 PMCID: PMC8575636 DOI: 10.1155/2021/9365081] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 10/06/2021] [Indexed: 11/17/2022] Open
Abstract
The past few decades have witnessed a rapid evolution in cancer drug research which is aimed at developing active biological interventions to regulate cancer-specific molecular targets. Nucleic acid-based therapeutics, including ribozymes, antisense oligonucleotides, small interference RNA (siRNA), aptamer, and DNAzymes, have emerged as promising candidates regulating cancer-specific genes at either the transcriptional or posttranscriptional level. Gene-specific catalytic DNA molecules, or DNAzymes, have shown promise as a therapeutic intervention against cancer in various in vitro and in vivo models, expediting towards clinical applications. DNAzymes are single-stranded catalytic DNA that has not been observed in nature, and they are synthesized through in vitro selection processes from a large pool of random DNA libraries. The intrinsic properties of DNAzymes like small molecular weight, higher stability, excellent programmability, diversity, and low cost have brought them to the forefront of the nucleic acid-based therapeutic arsenal available for cancers. In recent years, considerable efforts have been undertaken to assess a variety of DNAzymes against different cancers. However, their therapeutic application is constrained by the low delivery efficiency, cellular uptake, and target detection within the tumour microenvironment. Thus, there is a pursuit to identify efficient delivery methods in vivo before the full potential of DNAzymes in cancer therapy is realized. In this light, a review of the recent advances in the use of DNAzymes against cancers in preclinical and clinical settings is valuable to understand its potential as effective cancer therapy. We have thus sought to firstly provide a brief overview of construction and recent improvements in the design of DNAzymes. Secondly, this review stipulates the efficacy, safety, and tolerability of DNAzymes developed against major hallmarks of cancers tested in preclinical and clinical settings. Lastly, the recent advances in DNAzyme delivery systems along with the challenges and prospects for the clinical application of DNAzymes as cancer therapy are also discussed.
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Kim M, Reinhard C, Niehrs C. A MET-PTPRK kinase-phosphatase rheostat controls ZNRF3 and Wnt signaling. eLife 2021; 10:70885. [PMID: 34590584 PMCID: PMC8516413 DOI: 10.7554/elife.70885] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Accepted: 09/29/2021] [Indexed: 12/11/2022] Open
Abstract
Zinc and ring finger 3 (ZNRF3) is a transmembrane E3 ubiquitin ligase that targets Wnt receptors for ubiquitination and lysosomal degradation. Previously, we showed that dephosphorylation of an endocytic tyrosine motif (4Y motif) in ZNRF3 by protein tyrosine phosphatase receptor-type kappa (PTPRK) promotes ZNRF3 internalization and Wnt receptor degradation (Chang et al 2020). However, a responsible protein tyrosine kinase(s) (PTK) phosphorylating the 4Y motif remained elusive. Here we identify the proto-oncogene MET (mesenchymal-epithelial transition factor) as a 4Y kinase. MET binds to ZNRF3 and induces 4Y phosphorylation, stimulated by the MET ligand HGF (hepatocyte growth factor, scatter factor). HGF-MET signaling reduces ZNRF3-dependent Wnt receptor degradation thereby enhancing Wnt/β-catenin signaling. Conversely, depletion or pharmacological inhibition of MET promotes the internalization of ZNRF3 and Wnt receptor degradation. We conclude that HGF-MET signaling phosphorylates- and PTPRK dephosphorylates ZNRF3 to regulate ZNRF3 internalization, functioning as a rheostat for Wnt signaling that may offer novel opportunities for therapeutic intervention.
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Affiliation(s)
- Minseong Kim
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Carmen Reinhard
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany
| | - Christof Niehrs
- Division of Molecular Embryology, DKFZ-ZMBH Alliance, Deutsches Krebsforschungszentrum (DKFZ), Heidelberg, Germany.,Institute of Molecular Biology (IMB), Mainz, Germany
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25
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Álvarez-Mercado AI, Caballeria-Casals A, Rojano-Alfonso C, Chávez-Reyes J, Micó-Carnero M, Sanchez-Gonzalez A, Casillas-Ramírez A, Gracia-Sancho J, Peralta C. Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection. Biomedicines 2021; 9:1158. [PMID: 34572344 PMCID: PMC8470173 DOI: 10.3390/biomedicines9091158] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2021] [Revised: 08/29/2021] [Accepted: 09/01/2021] [Indexed: 01/18/2023] Open
Abstract
Hepatocellular carcinoma has become a leading cause of cancer-associated mortality throughout the world, and is of great concern. Currently used chemotherapeutic drugs in the treatment of hepatocellular carcinoma lead to severe side effects, thus underscoring the need for further research to develop novel and safer therapies. Liver resection in cancer patients is routinely performed. After partial resection, liver regeneration is a perfectly calibrated response apparently sensed by the body's required liver function. This process hinges on the effect of several growth factors, among other molecules. However, dysregulation of growth factor signals also leads to growth signaling autonomy and tumor progression, so control of growth factor expression may prevent tumor progression. This review describes the role of some of the main growth factors whose dysregulation promotes liver tumor progression, and are also key in regenerating the remaining liver following resection. We herein summarize and discuss studies focused on partial hepatectomy and liver carcinogenesis, referring to hepatocyte growth factor, insulin-like growth factor, and epidermal growth factor, as well as their suitability as targets in the treatment of hepatocellular carcinoma. Finally, and given that drugs remain one of the mainstay treatment options in liver carcinogenesis, we have reviewed the current pharmacological approaches approved for clinical use or research targeting these factors.
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Affiliation(s)
- Ana I. Álvarez-Mercado
- Department of Biochemistry and Molecular Biology II, Faculty of Pharmacy, University of Granada, 18071 Granada, Spain
- Institute of Nutrition and Food Technology, Biomedical Research Center, University of Granada, 18016 Armilla, Spain
- Instituto de Investigación Biosanitaria ibs.GRANADA, Complejo Hospitalario Universitario de Granada, 18014 Granada, Spain
| | - Albert Caballeria-Casals
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Carlos Rojano-Alfonso
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Jesús Chávez-Reyes
- Facultad de Medicina e Ingeniería en Sistemas Computacionales Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico; (J.C.-R.); (A.C.-R.)
| | - Marc Micó-Carnero
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
| | - Alfredo Sanchez-Gonzalez
- Teaching and Research Department, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico;
| | - Araní Casillas-Ramírez
- Facultad de Medicina e Ingeniería en Sistemas Computacionales Matamoros, Universidad Autónoma de Tamaulipas, Matamoros 87300, Mexico; (J.C.-R.); (A.C.-R.)
- Teaching and Research Department, Hospital Regional de Alta Especialidad de Ciudad Victoria “Bicentenario 2010”, Ciudad Victoria 87087, Mexico;
| | - Jordi Gracia-Sancho
- Liver Vascular Biology Research Group, Barcelona Hepatic Hemodynamic Laboratory, IDIBAPS Biomedical Research Institute, CIBEREHD, 03036 Barcelona, Spain;
- Barcelona Hepatic Hemodynamic Laboratory, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), 08036 Barcelona, Spain
| | - Carmen Peralta
- Hepatic Ischemia-Reperfusion Injury Department, Institut de Recerca Biomèdica August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain; (A.C.-C.); (C.R.-A.); (M.M.-C.)
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26
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Abdelmeguid NE, Khalil MI, Badr NS, Alkhuriji AF, El-Gerbed MS, Sultan AS. Ameliorative effects of colostrum against DMBA hepatotoxicity in rats. Saudi J Biol Sci 2021; 28:2254-2266. [PMID: 33911940 PMCID: PMC8071819 DOI: 10.1016/j.sjbs.2021.01.016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2020] [Revised: 12/09/2020] [Accepted: 01/07/2021] [Indexed: 02/07/2023] Open
Abstract
Colostrum, the sole diet for newborns, is an emerging nutraceutical. To date, the chemopreventive effect of Bovine Colostrum against liver injury induced by the potent carcinogen, 7,12-dimethyl-Benz[a]anthracene (DMBA) is unexplored. Humans are daily exposed to DMBA which is a highly lipophilic environmental organic pollutant. The study aimed to investigate the hepatoprotective role of Bovine Colostrum against DMBA-induced hepatotoxicity using a rat model. Fifty male rats were divided into five groups; GI (control), GII (olive oil, vehicle for DMBA), GIII (DMBA), GIV (DMBA + Bovine Colostrum), GV (Bovine Colostrum). After 12 weeks, body weight changes and mortality were calculated. Histological and ultrastructural examinations of liver tissue were performed. Expressions of p53, TGFβ2, TNF-α, S6K2, and c20orf20 were assessed by RT-PCR. Post-treatment with Bovine Colostrum increased both the body weight and the survival rate of rats treated with DMBA. In addition, remarkable protection against the pathological effect of DMBA was noted. Ultrastructurally, Bovine Colostrum ameliorated/prevented most of the toxic effects of DMBA on hepatocytes, including irregularities of nuclear envelope, clumping, and margination of heterochromatin aggregates, segregated nucleoli, and mitochondrial pleomorphism. Bovine Colostrum administration down-regulated p53, C20orf20, and S6K2 mRNA levels, and up-regulated TNF-α and TGFβ2. In conclusion, Bovine Colostrum have a protective effect against DMBA-induced toxicity on the liver of albino rats. Consequently, Bovine Colostrum may prevent polycyclic aromatic hydrocarbons-induced hepatotoxicity and may be useful in promoting human health if supplemented in the diet.
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Key Words
- BC, Bovine Colostrum
- CAM, Complementary and Alternative Medicine
- Colostrum
- DMBA
- DMBA, 7,12-dimethyl-Benz[a]anthracene
- Hepatoprotective
- IGF, insulin-like growth factor
- IL-1β, cytokines including interleukin-1 beta
- IL-6, interleukin-6
- INF-γ, interferon-gamma
- Nutraceutical
- PAHs, polycyclic aromatic hydrocarbons
- ROS, reactive oxygen species
- S6K, 40S ribosomal protein S6 kinase
- S6K2
- TGFβ, transforming growth factor-beta
- TNFα, tumor necrosis factor-alpha
- p53
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Affiliation(s)
| | - Mahmoud I. Khalil
- Department of Biological Sciences, Faculty of Science, Beirut Arab University, Lebanon
- Molecular Biology Unit, Zoology Department, Faculty of Science, Alexandria University, Alexandria, Egypt
| | - Nada S. Badr
- Zoology Department, Faculty of Science, Damanhur University, Damanhur, Egypt
| | - Afrah F. Alkhuriji
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
| | | | - Ahmed S. Sultan
- Biochemistry Department, Faculty of Science, Alexandria University, Alexandria, Egypt
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Yamada N, Matsushima-Nishiwaki R, Kobayashi K, Tachi J, Kozawa O. GLP-1 reduces the migration of hepatocellular carcinoma cells via suppression of the stress-activated protein kinase/c-Jun N-terminal kinase pathway. Arch Biochem Biophys 2021; 703:108851. [PMID: 33771507 DOI: 10.1016/j.abb.2021.108851] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 03/11/2021] [Accepted: 03/17/2021] [Indexed: 12/25/2022]
Abstract
Incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), are hormones secreted from small intestine accompanied with oral intake. We previously showed that transforming growth factor (TGF)-α stimulates the migration of hepatocellular carcinoma (HCC) cells via mitogen-activated protein (MAP) kinases, AKT and Rho-kinase. However, it remains to be elucidated whether incretins affect HCC cell functions. In the present study, therefore, we investigated whether incretins affect the migration of HCC cells using human HCC-derived HuH7 cells. GLP-1, but not GIP, reduced both TGF-α- and hepatocyte growth factor (HGF)-induced cell migration. IBMX, an inhibitor of cyclic nucleotide phosphodiesterase, enhanced the suppressive effect of GLP-1. GLP-1 attenuated the phosphorylation of stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) by TGF-α and HGF. Our results strongly suggest that GLP-1 suppresses TGF-α- and HGF-induced migration of HCC cells through inhibiting the SAPK/JNK signaling pathway, and that the inhibition by GLP-1 is due to cAMP production.
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Affiliation(s)
- Noriko Yamada
- Department of Pharmacology, Gifu University Graduate School of Medicine, 501-1194, Gifu, Japan
| | | | - Kaido Kobayashi
- Department of Pharmacology, Gifu University Graduate School of Medicine, 501-1194, Gifu, Japan
| | - Junko Tachi
- Department of Pharmacology, Gifu University Graduate School of Medicine, 501-1194, Gifu, Japan
| | - Osamu Kozawa
- Department of Pharmacology, Gifu University Graduate School of Medicine, 501-1194, Gifu, Japan.
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Arancillo M, Taechalertpaisarn J, Liang X, Burgess K. Piptides: New, Easily Accessible Chemotypes For Interactions With Biomolecules. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202015203] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- Maritess Arancillo
- Department of Chemistry Texas A & M University Box 30012 College Station TX 77842 USA
| | | | - Xiaowen Liang
- Center for Infectious and Inflammatory Diseases Institute of Biosciences and Technology Texas A&M Health Science Center Houston TX 77030 USA
| | - Kevin Burgess
- Department of Chemistry Texas A & M University Box 30012 College Station TX 77842 USA
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29
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Arancillo M, Taechalertpaisarn J, Liang X, Burgess K. Piptides: New, Easily Accessible Chemotypes For Interactions With Biomolecules. Angew Chem Int Ed Engl 2021; 60:6653-6659. [PMID: 33319463 PMCID: PMC7940574 DOI: 10.1002/anie.202015203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2020] [Revised: 12/07/2020] [Indexed: 12/22/2022]
Abstract
Small molecule probe development is pivotal in biomolecular science. Research described here was undertaken to develop a non-peptidic chemotype, piptides, that is amenable to convenient, iterative solid-phase syntheses, and useful in biomolecular probe discovery. Piptides can be made from readily accessible pip acid building blocks and have good proteolytic and pH stabilities. An illustrative application of piptides against a protein-protein interaction (PPI) target was explored. The Exploring Key Orientations (EKO) strategy was used to evaluate piptide candidates for this. A library of only 14 piptides contained five members that disrupted epidermal growth factor (EGF) and its receptor, EGFR, at low micromolar concentrations. These piptides also caused apoptotic cell death, and antagonized EGF-induced phosphorylation of intracellular tyrosine residues in EGFR.
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Affiliation(s)
- Maritess Arancillo
- Department of Chemistry, Texas A & M University, Box 30012, College Station, TX, 77842, USA
| | - Jaru Taechalertpaisarn
- Department of Chemistry, Texas A & M University, Box 30012, College Station, TX, 77842, USA
| | - Xiaowen Liang
- Center for Infectious and Inflammatory Diseases, Institute of Biosciences and Technology, Texas A&M Health Science Center, Houston, TX, 77030, USA
| | - Kevin Burgess
- Department of Chemistry, Texas A & M University, Box 30012, College Station, TX, 77842, USA
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Ning J, Ye Y, Bu D, Zhao G, Song T, Liu P, Yu W, Wang H, Li H, Ren X, Ying G, Zhao Y, Yu J. Imbalance of TGF-β1/BMP-7 pathways induced by M2-polarized macrophages promotes hepatocellular carcinoma aggressiveness. Mol Ther 2021; 29:2067-2087. [PMID: 33601054 DOI: 10.1016/j.ymthe.2021.02.016] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 01/27/2021] [Accepted: 02/10/2021] [Indexed: 12/27/2022] Open
Abstract
The transforming growth factor-beta (TGF-β) signaling pathway is the predominant cytokine signaling pathway in the development and progression of hepatocellular carcinoma (HCC). Bone morphogenetic protein (BMP), another member of the TGF-β superfamily, has been frequently found to participate in crosstalk with the TGF-β pathway. However, the complex interaction between the TGF-β and BMP pathways has not been fully elucidated in HCC. We found that the imbalance of TGF-β1/BMP-7 pathways was associated with aggressive pathological features and poor clinical outcomes in HCC. The induction of the imbalance of TGF-β1/BMP-7 pathways in HCC cells could significantly promote HCC cell invasion and stemness by increasing inhibitor of differentiation 1 (ID1) expression. We also found that the microRNA (miR)-17-92 cluster, originating from the extracellular vesicles (EVs) of M2-polarized tumor-associated macrophages (M2-TAMs), stimulated the imbalance of TGF-β1/BMP-7 pathways in HCC cells by inducing TGF-β type II receptor (TGFBR2) post-transcriptional silencing and inhibiting activin A receptor type 1 (ACVR1) post-translational ubiquitylation by targeting Smad ubiquitylation regulatory factor 1 (Smurf1). In vivo, short hairpin (sh)-MIR17HG and ACVR1 inhibitors profoundly attenuated HCC cell growth and metastasis by rectifying the imbalance of TGF-β1/BMP-7 pathways. Therefore, we proposed that the imbalance of TGF-β1/BMP-7 pathways is a feasible prognostic biomarker and recovering the imbalance of TGF-β1/BMP-7 pathways might be a potential therapeutic strategy for HCC.
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Affiliation(s)
- Junya Ning
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yingnan Ye
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Dechao Bu
- Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China
| | - Gang Zhao
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Tianqiang Song
- Department of Liver Cancer, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Pengpeng Liu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Wenwen Yu
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Hailong Wang
- Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Hui Li
- Department of Gastrointestinal Cancer Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Xiubao Ren
- Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Guoguang Ying
- Laboratory of Cancer Cell Biology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China
| | - Yi Zhao
- Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China; Ningbo Institute of Life and Health Industry, University of China Academy of Sciences, Zhejiang 315000, China.
| | - Jinpu Yu
- Cancer Molecular Diagnostics Core, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Prevention and Therapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China; Department of Immunology, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Caner, Key Laboratory of Cancer Immunology and Biotherapy, Tianjin's Clinical Research Center for Cancer, Tianjin 300060, China.
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31
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The Role of Autophagy in Liver Cancer: Crosstalk in Signaling Pathways and Potential Therapeutic Targets. Pharmaceuticals (Basel) 2020; 13:ph13120432. [PMID: 33260729 PMCID: PMC7760785 DOI: 10.3390/ph13120432] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 11/26/2020] [Accepted: 11/26/2020] [Indexed: 02/06/2023] Open
Abstract
Autophagy is an evolutionarily conserved lysosomal-dependent pathway for degrading cytoplasmic proteins, macromolecules, and organelles. Autophagy-related genes (Atgs) are the core molecular machinery in the control of autophagy, and several major functional groups of Atgs coordinate the entire autophagic process. Autophagy plays a dual role in liver cancer development via several critical signaling pathways, including the PI3K-AKT-mTOR, AMPK-mTOR, EGF, MAPK, Wnt/β-catenin, p53, and NF-κB pathways. Here, we review the signaling pathways involved in the cross-talk between autophagy and hepatocellular carcinoma (HCC) and analyze the status of the development of novel HCC therapy by targeting the core molecular machinery of autophagy as well as the key signaling pathways. The induction or the inhibition of autophagy by the modulation of signaling pathways can confer therapeutic benefits to patients. Understanding the molecular mechanisms underlying the cross-link of autophagy and HCC may extend to translational studies that may ultimately lead to novel therapy and regimen formation in HCC treatment.
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32
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Ogawa E, Nomura H, Nakamuta M, Furusyo N, Kajiwara E, Dohmen K, Kawano A, Ooho A, Azuma K, Takahashi K, Satoh T, Koyanagi T, Ichiki Y, Kuniyoshi M, Yanagita K, Amagase H, Morita C, Sugimoto R, Kato M, Shimoda S, Hayashi J. Incidence of Hepatocellular Carcinoma after Treatment with Sofosbuvir-Based or Sofosbuvir-Free Regimens in Patients with Chronic Hepatitis C. Cancers (Basel) 2020; 12:cancers12092602. [PMID: 32933027 PMCID: PMC7563479 DOI: 10.3390/cancers12092602] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2020] [Revised: 09/03/2020] [Accepted: 09/09/2020] [Indexed: 01/17/2023] Open
Abstract
Simple Summary The development of hepatocellular carcinoma (HCC) has not been well-controlled, even after the elimination of hepatitis C virus (HCV), especially for those with cirrhosis or of high-age. Fibrosis-related biomarkers have been recognized as useful predictors for the development of HCC; however, there are few analyses of the HCC incidence for the various regimens with direct-acting antivirals (DAA). We found that DAA treatment with sofosbuvir, an oral nucleotide analogue inhibitor of HCV NS5B polymerase, was not associated with the development of de novo HCC within five years by propensity score matched analysis. Moreover, the distribution of the early stage of HCC (the Barcelona Clinic Liver Cancer stage 0/A) was similar for all treatment regimens, irrespective of the use of sofosbuvir. Abstract Advanced fibrosis/cirrhosis and related biomarkers have been recognized as useful predictors of the development of hepatocellular carcinoma (HCC) by patients with chronic hepatitis C (CHC) following hepatitis C virus (HCV) cure by direct-acting antivirals (DAAs). However, it remains unclear if DAAs themselves have an influence on or facilitate the development of HCC. This multicenter cohort study included CHC patients without a history of HCC who achieved HCV elimination by DAAs. Cohorts of 835 patients treated with a sofosbuvir (SOF)-based regimen and 835 treated with a SOF-free regimen were matched 1:1 by propensity scoring with nine variables to evaluate differences in HCC incidence. The median observation period was 3.5 years. Sixty-nine cases of HCC were found during 5483.9 person-years (PY) over the entire follow-up period. The annual incidence was similar for both groups (SOF-based 1.25 and SOF-free 1.27 per 100 PY, respectively: adjusted hazard ratio (HR) 1.26, 95% confidence interval (CI) 0.75–2.12, p = 0.39). However, the annual incidence within the first two years was higher for patients treated with SOF than for those without, but did not reach significance (1.50 and 0.97 per 100 PY incidence rates, respectively: adjusted HR 2.05, 95% CI 0.98–4.25, p = 0.06). In summary, DAA treatment with SOF was not associated with an increase in the development of de novo HCC.
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Affiliation(s)
- Eiichi Ogawa
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka 8128582, Japan;
- Correspondence:
| | - Hideyuki Nomura
- The Center for Liver Disease, Shin-Kokura Hospital, Kitakyushu 8038505, Japan;
- Department of Internal Medicine, Haradoi Hospital, Fukuoka 8138588, Japan
| | - Makoto Nakamuta
- Department of Gastroenterology, National Hospital Organization Kyushu Medical Center, Fukuoka 8108563, Japan;
| | - Norihiro Furusyo
- Department of General Internal Medicine, Kyushu University Hospital, Fukuoka 8128582, Japan;
- General Internal Medicine, Taihaku Avenue Clinic, Fukuoka 8120039, Japan
| | | | - Kazufumi Dohmen
- Department of Internal Medicine, Chihaya Hospital, Fukuoka 8138501, Japan;
| | - Akira Kawano
- Department of Medicine, Kitakyushu Municipal Medical Center, Kitakyushu 8028561, Japan;
| | - Aritsune Ooho
- Department of Hepatology, Steel Memorial Yawata Hospital, Kitakyushu 8058508, Japan;
| | - Koichi Azuma
- Department of Medicine, Kyushu Central Hospital, Fukuoka 8158588, Japan;
| | | | - Takeaki Satoh
- Center for Liver Disease, National Hospital Organization Kokura Medical Center, Kitakyushu 8028533, Japan;
| | - Toshimasa Koyanagi
- Department of Medicine, Fukuoka City Hospital, Higashi-ku, Fukuoka 8120046, Japan;
| | - Yasunori Ichiki
- Department of Internal Medicine, JCHO Kyushu Hospital, Kitakyushu 8068501, Japan;
| | - Masami Kuniyoshi
- Department of Gastroenterology, Kyushu Rosai Hospital, Kitakyushu 8000296, Japan;
| | - Kimihiko Yanagita
- Department of Internal Medicine, Saiseikai Karatsu Hospital, Karatsu 8470852, Japan;
| | | | - Chie Morita
- Department of Internal Medicine, Kyushu Railway Memorial Hospital, Kitakyushu 8000031, Japan;
| | - Rie Sugimoto
- Department of Gastroenterology, Kyushu Cancer Center, Fukuoka 8111395, Japan;
| | - Masaki Kato
- Department of Medicine and Bioregulatory Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan;
| | - Shinji Shimoda
- Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka 8128582, Japan;
| | - Jun Hayashi
- Kyushu General Internal Medicine Center, Haradoi Hospital, Fukuoka 8138588, Japan;
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Kobayashi K, Matsushima-Nishiwaki R, Yamada N, Migita S, Hioki T, Mizutani D, Kozawa O. Heat shock protein 70 positively regulates transforming growth factor-α-induced hepatocellular carcinoma cell migration via the AKT signaling pathway. Heliyon 2020; 6:e05002. [PMID: 33005803 PMCID: PMC7519371 DOI: 10.1016/j.heliyon.2020.e05002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2020] [Revised: 08/25/2020] [Accepted: 09/17/2020] [Indexed: 12/20/2022] Open
Abstract
Heat shock proteins (HSPs) are induced in response to extracellular stress and manage the quality of proteins as molecular chaperones. HSP70, a highly conserved HSP, has been reported to correlate with the proliferation and migration of human cancer cells, such as oral, prostate, lung and liver cancer. Regarding hepatocellular carcinoma (HCC), the HSP70 levels in the tumor tissues from patients are significantly higher than those in the normal liver tissues. HSP70 reportedly upregulates the migration and invasion of HCC. The AKT, p38 mitogen-activated protein kinase (MAPK), c-jun N-terminal kinase (JNK) and Rho-kinase signaling pathways regulate the transforming growth factor (TGF)-α-induced migration of human HCC-derived HuH7 cells. However, the exact mechanism underlying the role of HSP70 in growth factor-induced HCC migration remains unclear. Therefore, in the present study, the mechanism underlying the involvement of HSP70 in TGF-α-induced HCC cell migration was investigated. Treatment with the HSP70 inhibitors VER155008 and YM-08 and the downregulation of HSP70 protein were confirmed to significantly suppress the TGF-α-induced cell migration of HuH7 cells. Both VER155008 and YM-08 reduced the TGF-α-induced phosphorylation of AKT without affecting the phosphorylation of p38 MAPK, JNK or Rho-kinase. These results strongly suggest that HSP70 positively regulates the TGF-α-induced migration of HCC cells via the AKT signaling pathway.
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Affiliation(s)
- Kaido Kobayashi
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | | | - Noriko Yamada
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Saori Migita
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Tomoyuki Hioki
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
- Department of Dermatology, Kizawa Memorial Hospital, Minokamo, Gifu, Japan
| | - Daisuke Mizutani
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Osamu Kozawa
- Department of Pharmacology, Gifu University Graduate School of Medicine, Gifu, Japan
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34
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Jiang H, Zhu L, Xu D, Lu Z. A newly discovered role of metabolic enzyme PCK1 as a protein kinase to promote cancer lipogenesis. Cancer Commun (Lond) 2020; 40:389-394. [PMID: 32809272 PMCID: PMC7494067 DOI: 10.1002/cac2.12084] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 07/05/2020] [Accepted: 07/22/2020] [Indexed: 12/11/2022] Open
Abstract
Highly active lipogenesis is essential for rapid tumor growth. Sterol regulatory element‐binding protein (SREBP) is a key transcriptional factor for lipogenesis and activated by reduced sterol and oxysterol levels. However, the mechanism by which cancer cells activate SREBP without altering these sterol/oxysterol levels remains elusive. In one of our recent studies published in Nature entitled “The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis”, we demonstrated that activated AKT‐mediated phosphoenolpyruvate carboxykinase 1 (PCK1) S90 phosphorylation reduces the gluconeogenic activity of PCK1 and triggers its translocation to the endoplasmic reticulum (ER), where PCK1 acts as a protein kinase and uses GTP, rather than ATP, as a phosphate donor to phosphorylate Insig1/2 thereby reducing oxysterol's binding to Insig1/2 and activating SREBP‐mediated lipogenesis for tumor growth. These findings elucidate a coordinated regulation between gluconeogenesis and lipogenesis and uncover a critical role of the protein kinase activity of PCK1 in SREBP‐dependent lipid synthesis.
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Affiliation(s)
- Hongfei Jiang
- The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, Shandong, 266071, P. R. China
| | - Lei Zhu
- The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, Shandong, 266071, P. R. China
| | - Daqian Xu
- Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310029, P. R. China
| | - Zhimin Lu
- Department of Hepatobiliary and Pancreatic Surgery, Zhejiang Provincial Key Laboratory of Pancreatic Disease, Institute of Translational Medicine, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, 310029, P. R. China
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35
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Masuda A, Nakamura T, Abe M, Iwamoto H, Sakaue T, Tanaka T, Suzuki H, Koga H, Torimura T. Promotion of liver regeneration and anti‑fibrotic effects of the TGF‑β receptor kinase inhibitor galunisertib in CCl4‑treated mice. Int J Mol Med 2020; 46:427-438. [PMID: 32377696 DOI: 10.3892/ijmm.2020.4594] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 03/30/2020] [Indexed: 11/05/2022] Open
Abstract
The cytokine transforming growth factor‑β (TGF‑β) serves a key role in hepatic fibrosis and has cytostatic effects on hepatocytes. The present study investigated the anti‑fibrogenic and regenerative effects of the TGF‑β receptor type I kinase inhibitor galunisertib (LY2157299) in mice with carbon tetrachloride (CCl4)‑induced liver cirrhosis and in vitro. Mice were intraperitoneally treated with CCl4 for 8 weeks. At week 5, the mice were divided randomly into four treatment groups: Vehicle‑treated; and treated with low‑; middle‑; and high‑dose galunisertib, which was administered from weeks 5‑8. The mice were sacrificed after 8 weeks of CCl4 treatment. Liver fibrosis, as evaluated by histology and determination of hydroxyproline content, progressed during week 4‑8 of CCl4 treatment in the vehicle‑treated mice. Galunisertib treatment dose‑dependently prevented liver fibrosis, as demonstrated by the direct inhibition of α‑smooth muscle actin‑positive activated hepatic stellate cells (HSCs) after 8 weeks of CCl4 treatment. The levels of active matrix metalloproteinase (MMP)‑9 in galunisertib‑treated livers were significantly increased compared with the vehicle‑treated livers. In the high‑dose group, the number of PCNA‑positive hepatocytes and endothelial cells markedly increased compared with the vehicle group. Reverse transcription‑quantitative PCR analysis verified that interleukin‑6 and epiregulin expression levels were significantly increased in livers from the group treated with high‑dose galunisertib compared with the vehicle‑treated group. Galunisertib inhibited the proliferation of activated HSCs and collagen synthesis in addition to restoring MMP activity. Moreover, galunisertib promoted liver remodeling by proliferating hepatocytes and vascular endothelial cells, while significantly increasing liver weight. These results are consistent with the cytostatic action of TGF‑β that negatively regulates liver regeneration, and demonstrated that galunisertib inhibited TGF‑β signaling, halted liver fibrosis progression and promoted hepatic regeneration. The results of the present study suggest that galunisertib may be an effective treatment for liver cirrhosis.
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Affiliation(s)
- Atsutaka Masuda
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Toru Nakamura
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Mitsuhiko Abe
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Hideki Iwamoto
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Takahiko Sakaue
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Toshimitsu Tanaka
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Hiroyuki Suzuki
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Hironori Koga
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
| | - Takuji Torimura
- Division of Gastroenterology, Department of Medicine, School of Medicine, Kurume University, Kurume, Fukuoka 830‑0011, Japan
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36
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Xu D, Wang Z, Xia Y, Shao F, Xia W, Wei Y, Li X, Qian X, Lee JH, Du L, Zheng Y, Lv G, Leu JS, Wang H, Xing D, Liang T, Hung MC, Lu Z. The gluconeogenic enzyme PCK1 phosphorylates INSIG1/2 for lipogenesis. Nature 2020; 580:530-535. [PMID: 32322062 DOI: 10.1038/s41586-020-2183-2] [Citation(s) in RCA: 232] [Impact Index Per Article: 46.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2018] [Accepted: 02/06/2020] [Indexed: 01/04/2023]
Abstract
Cancer cells increase lipogenesis for their proliferation and the activation of sterol regulatory element-binding proteins (SREBPs) has a central role in this process. SREBPs are inhibited by a complex composed of INSIG proteins, SREBP cleavage-activating protein (SCAP) and sterols in the endoplasmic reticulum. Regulation of the interaction between INSIG proteins and SCAP by sterol levels is critical for the dissociation of the SCAP-SREBP complex from the endoplasmic reticulum and the activation of SREBPs1,2. However, whether this protein interaction is regulated by a mechanism other than the abundance of sterol-and in particular, whether oncogenic signalling has a role-is unclear. Here we show that activated AKT in human hepatocellular carcinoma (HCC) cells phosphorylates cytosolic phosphoenolpyruvate carboxykinase 1 (PCK1), the rate-limiting enzyme in gluconeogenesis, at Ser90. Phosphorylated PCK1 translocates to the endoplasmic reticulum, where it uses GTP as a phosphate donor to phosphorylate INSIG1 at Ser207 and INSIG2 at Ser151. This phosphorylation reduces the binding of sterols to INSIG1 and INSIG2 and disrupts the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, the activation of SREBP proteins (SREBP1 or SREBP2) and the transcription of downstream lipogenesis-related genes, proliferation of tumour cells, and tumorigenesis in mice. In addition, phosphorylation of PCK1 at Ser90, INSIG1 at Ser207 and INSIG2 at Ser151 is not only positively correlated with the nuclear accumulation of SREBP1 in samples from patients with HCC, but also associated with poor HCC prognosis. Our findings highlight the importance of the protein kinase activity of PCK1 in the activation of SREBPs, lipogenesis and the development of HCC.
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Affiliation(s)
- Daqian Xu
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. .,Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | - Zheng Wang
- The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Yan Xia
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.,Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Fei Shao
- The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China
| | - Weiya Xia
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Yongkun Wei
- Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Xinjian Li
- CAS Key Laboratory of Infection and Immunity, CAS Center for Excellence in Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China
| | - Xu Qian
- Jiangsu Key Laboratory of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, School of Public Health, Nanjing Medical University, Nanjing, China
| | - Jong-Ho Lee
- Department of Biological Sciences, Dong-A University, Busan, South Korea
| | - Linyong Du
- Key Laboratory of Laboratory Medicine, Ministry of Education of China, School of Laboratory Medicine and Life Science, Wenzhou Medical University, Wenzhou, China
| | - Yanhua Zheng
- Department of Neuro-Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Guishuai Lv
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Jia-Shiun Leu
- Department of Neurosurgery, Houston Methodist Research Institute, Houston, TX, USA
| | - Hongyang Wang
- International Co-operation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
| | - Dongming Xing
- The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China.,School of Life Sciences, Tsinghua University, Beijing, China
| | - Tingbo Liang
- Department of Hepatobiliary and Pancreatic Surgery and Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China
| | - Mien-Chie Hung
- Graduate Institute of Biomedical Sciences and Center for Molecular Medicine, and Office of the President, China Medical University, Taichung, Taiwan.
| | - Zhimin Lu
- The Affiliated Hospital of Qingdao University and Qingdao Cancer Institute, Qingdao, China. .,Zhejiang Provincial Key Laboratory of Pancreatic Disease of The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
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37
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Ruan Q, Wang H, Burke LJ, Bridle KR, Li X, Zhao CX, Crawford DHG, Roberts MS, Liang X. Therapeutic modulators of hepatic stellate cells for hepatocellular carcinoma. Int J Cancer 2020; 147:1519-1527. [PMID: 32010970 DOI: 10.1002/ijc.32899] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 01/14/2020] [Accepted: 01/21/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the most common type of primary tumor in the liver and is a leading cause of cancer-related death worldwide. Activated hepatic stellate cells (HSCs) are key components of the HCC microenvironment and play an important role in the onset and progression of HCC through the secretion of growth factors and cytokines. Current treatment modalities that include chemotherapy, radiotherapy and ablation are able to activate HSCs and remodel the tumor microenvironment. Growing evidence has demonstrated that the complex interaction between activated HSCs and tumor cells can facilitate cancer chemoresistance and metastasis. Therefore, therapeutic targeting of activated HSCs has emerged as a promising strategy to improve treatment outcomes for HCC. This review summarizes the molecular mechanisms of HSC activation triggered by treatment modalities, the function of activated HSCs in HCC, as well as the crosstalk between tumor cells and activated HSCs. Pathways of activated HSC reduction are discussed, including inhibition, apoptosis, and reversion to the inactivated state. Finally, we outline the progress and challenges of therapeutic approaches targeting activated HSCs in the development of HCC treatment.
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Affiliation(s)
- Qi Ruan
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Haolu Wang
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia.,Department of Biliary-Pancreatic Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Leslie J Burke
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Kim R Bridle
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Xinxing Li
- Department of General Surgery, Changzheng Hospital, The Second Military Medical University, Shanghai, China
| | - Chun-Xia Zhao
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, St Lucia, QLD, Australia
| | - Darrell H G Crawford
- Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
| | - Michael S Roberts
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia
| | - Xiaowen Liang
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, QLD, Australia.,Gallipoli Medical Research Institute, Greenslopes Private Hospital, Brisbane, QLD, Australia.,Faculty of Medicine, The University of Queensland, Brisbane, QLD, Australia
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38
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Yamada N, Matsushima-Nishiwaki R, Kozawa O. Quercetin suppresses the migration of hepatocellular carcinoma cells stimulated by hepatocyte growth factor or transforming growth factor-α: Attenuation of AKT signaling pathway. Arch Biochem Biophys 2020; 682:108296. [PMID: 32032576 DOI: 10.1016/j.abb.2020.108296] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 01/27/2020] [Accepted: 02/03/2020] [Indexed: 02/06/2023]
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39
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Genomic Perspective on Mouse Liver Cancer Models. Cancers (Basel) 2019; 11:cancers11111648. [PMID: 31731480 PMCID: PMC6895968 DOI: 10.3390/cancers11111648] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 10/22/2019] [Accepted: 10/23/2019] [Indexed: 02/07/2023] Open
Abstract
Selecting the most appropriate mouse model that best recapitulates human hepatocellular carcinoma (HCC) allows translation of preclinical mouse studies into clinical studies. In the era of cancer genomics, comprehensive and integrative analysis of the human HCC genome has allowed categorization of HCC according to molecular subtypes. Despite the variety of mouse models that are available for preclinical research, there is a lack of evidence for mouse models that closely resemble human HCC. Therefore, it is necessary to identify the accurate mouse models that represent human HCC based on molecular subtype as well as histologic aggressiveness. In this review, we summarize the mouse models integrated with human HCC genomic data to provide information regarding the models that recapitulates the distinct aspect of HCC biology and prognosis based on molecular subtypes.
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40
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Fekry B, Ribas-Latre A, Baumgartner C, Mohamed AMT, Kolonin MG, Sladek FM, Younes M, Eckel-Mahan KL. HNF4α-Deficient Fatty Liver Provides a Permissive Environment for Sex-Independent Hepatocellular Carcinoma. Cancer Res 2019; 79:5860-5873. [PMID: 31575546 DOI: 10.1158/0008-5472.can-19-1277] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 08/02/2019] [Accepted: 09/23/2019] [Indexed: 02/07/2023]
Abstract
The incidence of hepatocellular carcinoma (HCC) is on the rise worldwide. Although the incidence of HCC in males is considerably higher than in females, the projected rates of HCC incidence are increasing for both sexes. A recently appreciated risk factor for HCC is the growing problem of nonalcoholic fatty liver disease, which is usually associated with obesity and the metabolic syndrome. In this study, we showed that under conditions of fatty liver, female mice were more likely to develop HCC than expected from previous models. Using an inducible knockout model of the tumor-suppressive isoform of hepatocyte nuclear factor 4 alpha ("P1-HNF4α") in the liver in combination with prolonged high fat (HF) diet, we found that HCC developed equally in male and female mice as early as 38 weeks of age. Similar sex-independent HCC occurred in the "STAM" model of mice, in which severe hyperglycemia and HF feeding results in rapid hepatic lipid deposition, fibrosis, and ultimately HCC. In both sexes, reduced P1-HNF4α activity, which also occurs under chronic HF diet feeding, increased hepatic lipid deposition and produced a greatly augmented circadian rhythm in IL6, a factor previously linked with higher HCC incidence in males. Loss of HNF4α combined with HF feeding induced epithelial-mesenchymal transition in an IL6-dependent manner. Collectively, these data provide a mechanism-based working hypothesis that could explain the rising incidence of aggressive HCC. SIGNIFICANCE: This study provides a mechanism for the growing incidence of hepatocellular carcinoma in both men and women, which is linked to nonalcoholic fatty liver disease.
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Affiliation(s)
- Baharan Fekry
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Aleix Ribas-Latre
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Corrine Baumgartner
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Alaa M T Mohamed
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Mikhail G Kolonin
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas.,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Frances M Sladek
- Department of Molecular, Cell and Systems Biology, University of California Riverside, Riverside, California
| | - Mamoun Younes
- Department of Pathology and Laboratory Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
| | - Kristin L Eckel-Mahan
- Institute of Molecular Medicine, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas. .,Department of Integrative Biology and Pharmacology, McGovern Medical School at the University of Texas Health Science Center (UT Health), Houston, Texas
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41
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MAT2B mediates invasion and metastasis by regulating EGFR signaling pathway in hepatocellular carcinoma. Clin Exp Med 2019; 19:535-546. [PMID: 31493275 DOI: 10.1007/s10238-019-00579-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 08/30/2019] [Indexed: 01/15/2023]
Abstract
The poor prognosis of hepatocellular carcinoma (HCC) patients is mainly due to cancer metastasis. Methionine adenosyltransferase 2β (MAT2B) encodes a regulatory subunit (β) for methionine adenosyltransferase. Previous studies reveal that MAT2B provides a growth advantage for HCC, but its role in metastasis is unknown. This study showed that both in the xenograft zebra fish model and in the lung metastasis model in nude mice, the stable inhibition of MAT2B could suppress the metastasis of HCC cancer cells. Silencing of MAT2B in HCC cell lines could remarkably inhibit migration and invasion. By analysis of human phospho-kinase array membranes, we found several differentially expressed proteins, including phosphor-AKT, phospho-EGFR, phospho-Src family, phospho-FAK, phospho-STAT3 and phospho-ERK. We further confirmed the change of these EGFR pathway-related proteins was in accordance with MAT2B expression pattern through immunoblotting test. Finally, we found that MAT2B was overexpressed in HCC caner tissues and correlated with poor prognosis for HCC patients in clinical manifestation. Our study demonstrated that silencing of MAT2B could suppress liver cancer cell migration and invasion through the inhibition of EGFR signaling, which suggested that MAT2B might serve as a new prognostic marker and therapeutic target for HCC.
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42
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Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Takane K, Shinozaki M, Tsurita G, Yano H, Furukawa Y. Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells. Oncogene 2019; 38:6051-6064. [PMID: 31292489 DOI: 10.1038/s41388-019-0856-9] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2018] [Revised: 02/27/2019] [Accepted: 04/16/2019] [Indexed: 12/29/2022]
Abstract
Impaired Wnt signaling pathway plays a crucial role in the development of colorectal cancer through activation of the β-catenin/TCF7L2 complex. Although genes upregulated by Wnt/β-catenin signaling have been intensively studied, the roles of downregulated genes are poorly understood. Previously, we reported that interferon-induced proteins with tetratricopeptide repeats 2 (IFIT2) was downregulated by the Wnt/β-catenin signaling, and that the suppressed expression of IFIT2 conferred antiapoptotic property to colorectal cancer (CRC) cells. However, the mechanisms underlying how Wnt/β-catenin signaling regulates IFIT2 remain to be elucidated. In this study, we have uncovered that the expression of IFIT2 is induced by IRF1, which is negatively regulated by the Wnt/β-catenin signaling. In addition, we found that downregulation of IRF1 is mediated by its degradation through the ubiquitination-proteasome pathway, and that decreased activity of a deubiquitinase complex containing USP1 and UAF1 is involved in the degradation of IRF1 by Wnt/β-catenin signaling. These data should provide better understanding of the Wnt signaling pathway and human carcinogenesis.
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Affiliation(s)
- Tomoyuki Ohsugi
- Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan
| | - Kiyoshi Yamaguchi
- Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan
| | - Chi Zhu
- Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan
| | - Tsuneo Ikenoue
- Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan
| | - Kiyoko Takane
- Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan
| | - Masaru Shinozaki
- Department of Surgery, IMSUT Hospital, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan
| | - Giichiro Tsurita
- Department of Surgery, IMSUT Hospital, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan
| | - Hideaki Yano
- Department of Surgery, Center Hospital of the National Center for Global Health and Medicine, Tokyo, 162-8655, Japan
| | - Yoichi Furukawa
- Division of Clinical Genome Research, Advanced Clinical Research Center, Institute of Medical Science, the University of Tokyo, Tokyo, 108-8639, Japan.
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43
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Chen H, Wong CC, Liu D, Go MY, Wu B, Peng S, Kuang M, Wong N, Yu J. APLN promotes hepatocellular carcinoma through activating PI3K/Akt pathway and is a druggable target. Am J Cancer Res 2019; 9:5246-5260. [PMID: 31410213 PMCID: PMC6691573 DOI: 10.7150/thno.34713] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2019] [Accepted: 06/11/2019] [Indexed: 12/24/2022] Open
Abstract
Background: The pathogenesis of hepatocellular carcinoma (HCC) is a multistep process contributed by the accumulation of molecular alterations. We identified Apelin (APLN) as an outlier gene up-regulated in hepatocellular carcinoma (HCC) through RNA-Seq and microarray analysis. We aimed to investigate its function, mechanism of action and clinical implication in HCC. Methods: Gene expression and clinical implication of APLN were assessed in multiple human HCC cohorts. Ectopic expression and silencing of APLN were performed to determine its function. The therapeutic potential of APLN and its downstream pathway was investigated using in vitro and in vivo models. Results: APLN overexpression was commonly observed in more than 80% of HCCs and independently predicted poorer survival of patients in three independent HCC cohorts. Apelin up-regulation was mediated by active β-catenin, which binds to the APLN promoter to induce transcription. Ectopic APLN expression in HCC cells promoted cell proliferation, accelerated G1/S progression and inhibited apoptosis, whilst APLN knockdown exerted opposite effects in vitro and inhibited HCC xenograft growth in mice. Mechanistically, APLN activated phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) pathway via APLN receptor, leading to increased expression of phospho-glycogen synthase kinase 3β (p-GSK3β) and cyclin D1. Pharmacological targeting of APLN by ML221 was safe and effective in inhibiting APLN-PI3K/Akt cascade and HCC growth in vitro and in vivo. Conclusions: Our findings unraveled an oncogenic role of APLN in HCC, and that targeting of APLN might be a promising for HCC treatment. APLN may serve as an independent prognostic factor for HCC patients.
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44
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Khan MGM, Ghosh A, Variya B, Santharam MA, Kandhi R, Ramanathan S, Ilangumaran S. Hepatocyte growth control by SOCS1 and SOCS3. Cytokine 2019; 121:154733. [PMID: 31154249 DOI: 10.1016/j.cyto.2019.154733] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Revised: 05/18/2019] [Accepted: 05/21/2019] [Indexed: 02/06/2023]
Abstract
The extraordinary capacity of the liver to regenerate following injury is dependent on coordinated and regulated actions of cytokines and growth factors. Whereas hepatocyte growth factor (HGF) and epidermal growth factor (EGF) are direct mitogens to hepatocytes, inflammatory cytokines such as TNFα and IL-6 also play essential roles in the liver regeneration process. These cytokines and growth factors activate different signaling pathways in a sequential manner to elicit hepatocyte proliferation. The kinetics and magnitude of these hepatocyte-activating stimuli are tightly regulated to ensure restoration of a functional liver mass without causing uncontrolled cell proliferation. Hepatocyte proliferation can become deregulated under conditions of chronic inflammation, leading to accumulation of genetic aberrations and eventual neoplastic transformation. Among the control mechanisms that regulate hepatocyte proliferation, negative feedback inhibition by the 'suppressor of cytokine signaling (SOCS)' family proteins SOCS1 and SOCS3 play crucial roles in attenuating cytokine and growth factor signaling. Loss of SOCS1 or SOCS3 in the mouse liver increases the rate of liver regeneration and renders hepatocytes susceptible to neoplastic transformation. The frequent epigenetic repression of the SOCS1 and SOCS3 genes in hepatocellular carcinoma has stimulated research in understanding the growth regulatory mechanisms of SOCS1 and SOCS3 in hepatocytes. Whereas SOCS3 is implicated in regulating JAK-STAT signaling induced by IL-6 and attenuating EGFR signaling, SOCS1 is crucial for the regulation of HGF signaling. These two proteins also module the functions of certain key proteins that control the cell cycle. In this review, we discuss the current understanding of the functions of SOCS1 and SOCS3 in controlling hepatocyte proliferation, and its implications to liver health and disease.
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Affiliation(s)
- Md Gulam Musawwir Khan
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Amit Ghosh
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Bhavesh Variya
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Madanraj Appiya Santharam
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Rajani Kandhi
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Sheela Ramanathan
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada
| | - Subburaj Ilangumaran
- Department of Anatomy and Cell Biology, Faculty of Medicine and Health Sciences, Université de Sherbrooke, Sherbrooke J1H 5N4, Québec, Canada.
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45
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Hu X, Tang Z, Ma S, Yu Y, Chen X, Zang G. Tripartite motif-containing protein 7 regulates hepatocellular carcinoma cell proliferation via the DUSP6/p38 pathway. Biochem Biophys Res Commun 2019; 511:889-895. [DOI: 10.1016/j.bbrc.2019.02.001] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Accepted: 02/01/2019] [Indexed: 12/21/2022]
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46
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Zhou X, Wen Y, Tian Y, He M, Ke X, Huang Z, He Y, Liu L, Scharf A, Lu M, Zhang G, Deng Y, Yan Y, Mayer MP, Chen X, Zou F. Heat Shock Protein 90α-Dependent B-Cell-2-Associated Transcription Factor 1 Promotes Hepatocellular Carcinoma Proliferation by Regulating MYC Proto-Oncogene c-MYC mRNA Stability. Hepatology 2019; 69:1564-1581. [PMID: 30015413 PMCID: PMC6586158 DOI: 10.1002/hep.30172] [Citation(s) in RCA: 43] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Accepted: 05/20/2018] [Indexed: 12/14/2022]
Abstract
B-cell lymphoma 2 (Bcl-2)-associated transcription factor 1 (Bclaf1) is known to be involved in diverse biological processes, but, to date, there has been no evidence for any functional role of Bclaf1 in hepatocellular carcinoma (HCC) progression. Here, we demonstrate that Bclaf1 is frequently up-regulated in HCC and that Bclaf1 up-regulation is associated with Edmondson grade, lower overall survival rates, and poor prognosis. Overexpression of Bclaf1 in HCC cell lines HepG2 and Huh7 promoted proliferation considerably, whereas Bclaf1 knockdown had the opposite effect. Xenograft tumors grown from Bclaf1 knockdown Huh7 cells had smaller tumor volumes than tumors grown from control cells. Furthermore, our study describes MYC proto-oncogene (c-Myc) as a downstream target of Bclaf1, given that Bclaf1 regulates c-MYC expression posttranscriptionally by its RS domain. To exert this function, Bclaf1 must interact with the molecular chaperone, heat shock protein 90 alpha (Hsp90α). In HCC tissue samples, Hsp90α levels were also increased significantly and Hsp90α-Bclaf1 interaction was enhanced. Bclaf1 interacts with the C-terminal domain of Hsp90α, and this interaction is disrupted by the C-terminal domain inhibitor, novobiocin (NB), resulting in proteasome-dependent degradation of Bclaf1. Moreover, NB-induced disruption of Hsp90α-Bclaf1 interaction dampened the production of mature c-MYC mRNA and attenuated tumor cell growth in vitro and in vivo. Conclusion: Our findings suggest that Bclaf1 affects HCC progression by manipulating c-MYC mRNA stability and that the Hsp90α/Bclaf1/c-Myc axis might be a potential target for therapeutic intervention in HCC.
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Affiliation(s)
- Xueqiong Zhou
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Ying Wen
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Ye Tian
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Meiling He
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Xiangyu Ke
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Zhizhou Huang
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Yangfan He
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Lixia Liu
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Annette Scharf
- Center for Molecular Biology of Heidelberg University (ZMBH)DKFZ‐ZMBH‐AllianceHeidelbergGermany
| | - Meiting Lu
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Guowei Zhang
- Department of Hepatobiliary SurgeryNanfang Hospital, Southern Medical UniversityGuangzhouChina
| | - Yaotang Deng
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Yuxia Yan
- Department of Biostatistics, School of Public HealthSouthern Medical UniversityGuangzhouChina
| | - Matthias P. Mayer
- Center for Molecular Biology of Heidelberg University (ZMBH)DKFZ‐ZMBH‐AllianceHeidelbergGermany
| | - Xuemei Chen
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina,Center for Molecular Biology of Heidelberg University (ZMBH)DKFZ‐ZMBH‐AllianceHeidelbergGermany
| | - Fei Zou
- Department of Occupational Health and MedicineGuangdong Provincial Key Laboratory of Tropical Disease ResearchSchool of Public HealthSouthern Medical UniversityGuangzhouChina
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47
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Madduru D, Ijaq J, Dhar S, Sarkar S, Poondla N, Das PS, Vasquez S, Suravajhala P. Systems Challenges of Hepatic Carcinomas: A Review. J Clin Exp Hepatol 2019; 9:233-244. [PMID: 31024206 PMCID: PMC6477144 DOI: 10.1016/j.jceh.2018.05.002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 05/10/2018] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular Carcinoma (HCC) is ubiquitous in its prevalence in most of the developing countries. In the era of systems biology, multi-omics has evinced an extensive approach to define the underlying mechanism of disease progression. HCC is a multifactorial disease and the investigation of progression of liver cirrhosis becomes much extensive with cultivating omics approaches. We have performed a comprehensive review about such challenges in multi-omics approaches that are concerned to identify the immunological, genetics and epidemiological factors associated with HCC.
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Affiliation(s)
- Dhatri Madduru
- Department of Biochemistry, Osmania University, Hyderabad 500007, TG, India
- Bioclues.org
| | - Johny Ijaq
- Department of Genetics and Biotechnology, Osmania University, Hyderabad 500007, TG, India
- Bioclues.org
| | | | | | | | - Partha S. Das
- Bioclues.org
- Patient MD, Chicago, IL 60640-5710, United States
| | - Silvia Vasquez
- Bioclues.org
- Instituto Peruano de Energía Nuclear, Avenida Canadá 1470, Lima, Peru
| | - Prashanth Suravajhala
- Bioclues.org
- Department of Biotechnology and Bioinformatics, Birla Institute of Scientific Research, Statue Circle 302001, RJ, India
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48
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Waly AA, El-Ekiaby N, Assal RA, Abdelrahman MM, Hosny KA, El Tayebi HM, Esmat G, Breuhahn K, Abdelaziz AI. Methylation in MIRLET7A3 Gene Induces the Expression of IGF-II and Its mRNA Binding Proteins IGF2BP-2 and 3 in Hepatocellular Carcinoma. Front Physiol 2019; 9:1918. [PMID: 30733684 PMCID: PMC6353855 DOI: 10.3389/fphys.2018.01918] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2018] [Accepted: 12/20/2018] [Indexed: 01/08/2023] Open
Abstract
miR-let-7a is a tumor suppressor miRNA with reduced expression in most cancers. Methylation of MIRLET7A3 gene was reported to be the cause of this suppression in several cancers; however, it was not explicitly investigated in hepatocellular carcinoma (HCC). We aimed at investigating miR-let-7a expression and molecular mode in HCC, identifying drug-targetable networks, which might be affected by its abundance. Our results illustrated a significant repression of miR-let-7a, which correlated with hypermethylation of its gene of origin MIRLRT7A3. This was further supported by the induction of miR-let-7a expression upon treatment of HCC cells with a DNA-methyltransferase inhibitor. Using a computational approach, insulin-like growth factor (IGF)-II and IGF-2 mRNA binding proteins (IGF2BP)-2/-3 were identified as potential targets for miR-let-7a that was further confirmed experimentally. Indeed, miR-let-7a mimics diminished IGF-II as well as IGF2BP-2/-3 expression. Direct binding of miR-let-7a to each respective transcript was confirmed using a luciferase reporter assay. In conclusion, this study suggests that DNA hypermethylation leads to epigenetic repression of miR-let-7a in HCC cells, which induces the oncogenic IGF-signaling pathway.
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Affiliation(s)
- Amr A. Waly
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
| | | | - Reem A. Assal
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
| | | | - Karim A. Hosny
- Department of General Surgery, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hend M. El Tayebi
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
| | - Gamal Esmat
- Department of Endemic Medicine and Hepatology, Cairo University, Cairo, Egypt
| | - Kai Breuhahn
- Molecular Hepatopathology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Ahmed I. Abdelaziz
- The Molecular Pathology Research Group, German University in Cairo, Cairo, Egypt
- School of Medicine, Newgiza University, Cairo, Egypt
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49
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Antiviral Therapy for AECHB and Severe Hepatitis B (Liver Failure). ACUTE EXACERBATION OF CHRONIC HEPATITIS B 2019. [PMCID: PMC7498919 DOI: 10.1007/978-94-024-1603-9_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
This chapter describes the principles of antiviral therapy, treatment strategies, medications and recommendations for AECHB, HBV-ACLF, HBV-related liver cirrhosis, HBV-related HCC, and liver transplantation.
Severe exacerbation of chronic hepatitis B is closely related to continuous HBV replication. Therefore, inhibiting HBV replication to reduce viral load may block disease progression and improve the quality of life of these patients. ETV or TDF has been recommend first-line drug for the treatment of AECHB. A hyperactive immune response due to continuous HBV replication is the main mechanism for development of severe hepatitis B. In addition to comprehensive treatment, early administration of potent nucleoside analogs can rapidly reduce HBV DNA concentration, relieve immune injury induced by HBV, and reduce liver inflammation and patient mortality. Antiviral agents have become important in the treatment of severe exacerbation of chronic hepatitis B. Long-term antiviral treatment with nucleoside analogs can delay or reverse the progress of liver cirrhosis. Virologic response, viral resistance and adverse drug reactions should be closely monitored during treatment. The treatment should be optimized for maximum effect based on each patient’s responses. Effective antiviral therapy can suppress HBV replication and reduce the incidence of HBV-related HCC. Patients with HBV-related HCC should receive individualized and optimal multidisciplinary comprehensive treatment. Anti-viral drugs with high efficacy, low resistance and low adverse drug reactions should be selected to improve the patient’s quality of life and prolong survival time. Methods to prevent HBV reinfection after liver transplantation include passive immunization (HBIG), antiviral treatment (nucleoside analogs) and active immunization (hepatitis B vaccine). Clinical trials involving sequential combination therapy with NUC and Peg-IFN have shown statistically significant decline in HBsAg levels on treatment and high rates of sustained post-treatment serologic response. Combination therapy with novel DAA and immunotherapeutic approach may hold promise to overcome both cccDNA persistence and immune escape, representing a critical step towards HBV cure.
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50
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He Q, Du H, Li Y. Retracted Article: MiR-206 reduced the malignancy of hepatocellular carcinoma cells in vitro by inhibiting MET and CTNNB1 gene expressions. RSC Adv 2019; 9:1717-1725. [PMID: 35518051 PMCID: PMC9059747 DOI: 10.1039/c8ra09229j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 01/08/2019] [Indexed: 11/21/2022] Open
Abstract
The anti-cancer role of miR-206 in hepatocellular carcinoma (HCC) cells has been reported, but its mechanism of action remains poorly understood.
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Affiliation(s)
- Qiang He
- Department of Hepatobiliary Surgery
- Linyi People's Hospital
- Linyi
- China
| | - Haiyan Du
- Pediatric Intensive Care Unit
- Linyi People's Hospital
- Linyi
- China
| | - Yundong Li
- Department of Oncology
- Jining No. 1 People's Hospital
- Jining
- China
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