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Jain NK, Chandrasekaran B, Khazaleh N, Jain HK, Lal M, Joshi G, Jha V. Computational Network Pharmacology, Molecular Docking, and Molecular Dynamics to Decipher Natural Compounds of Alchornea laxiflora for Liver Cancer Chemotherapy. Pharmaceuticals (Basel) 2025; 18:508. [PMID: 40283942 PMCID: PMC12030508 DOI: 10.3390/ph18040508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2025] [Revised: 03/20/2025] [Accepted: 03/28/2025] [Indexed: 04/29/2025] Open
Abstract
Background:Alchornea laxiflora (Benth.) Pax & K. Hoffm. (A. laxiflora) is utilized as a traditional herb for treating several diseases. Objective: Our study aims to identify the active phytochemical candidates from A. laxiflora and analyses to predict their anticancer activity mechanism by employing network pharmacology, molecular docking, and molecular dynamics (MD). Methods: The phytoconstituents of A. laxiflora were retrieved from the literature, and phytoconstituent-related targets implicated in hepatocellular carcinoma (HCC) were collected from respective databases. Computational methods were employed to recognize essential compounds, hub gene targets, and signaling pathways. Results: Our study has identified 12 potentially bioactive compounds, 150 potential anti-HCC targets, and 15 hub gene targets for A. laxiflora. Molecular docking results recognized the better binding energy values of below -5.6 kcal/mol. Further, MD simulations of the three of the top-scoring protein-ligand complexes (MAPK-3-acetylursolic acid, AKT1-quercetin, and AKT1-3-acetylursolic acid) allowed us to validate the docking results, evaluate the stability of the complexes, and associated conformational changes. Conclusions: Our research claims that phytoconstituents of A. laxiflora are crucial for treating liver cancer, and the recognized protein targets can serve as biomarkers, respectively.
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Affiliation(s)
- Nem Kumar Jain
- School of Pharmacy, ITM University, Gwalior 474001, Madhya Pradesh, India;
| | | | - Nasha’t Khazaleh
- Faculty of Pharmacy, Philadelphia University, P.O. Box 1, Amman 19392, Jordan;
| | - Hemant Kumar Jain
- Department of General Medicine, Government Medical College, Datia 475661, Madhya Pradesh, India
| | - Moti Lal
- School of Sciences, ITM University, Gwalior 474001, Madhya Pradesh, India;
| | - Gaurav Joshi
- Department of Pharmaceutical Science, Hemvati Nandan Bahuguna Garhwal University, Srinagar 246174, Uttarakhand, India;
- Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
| | - Vibhu Jha
- Institute of Cancer Therapeutics, School of Pharmacy and Medical Sciences, Faculty of Life Sciences, University of Bradford, Bradford BD7 1DP, UK
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Teuter M, Hu Y, Ross TL, Lolatte K, Ott M, Bengel FM, Balakrishnan A, Bankstahl JP. Longitudinal multi-tracer imaging of hepatocellular carcinoma identifies novel stage- and oncogene-specific changes. Nucl Med Biol 2025; 144-145:109000. [PMID: 39970776 DOI: 10.1016/j.nucmedbio.2025.109000] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Revised: 02/12/2025] [Accepted: 02/13/2025] [Indexed: 02/21/2025]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths, globally. There is a need for novel biomarkers for early detection and novel, effective targeted therapies. Molecular imaging can faithfully visualize, characterize and quantify specific relevant biological processes. BASIC PROCEDURE We performed longitudinal dedicated small-animal positron emission tomography-computed tomography (PET/CT) imaging to analyze changes in glucose metabolism using [18F]fluorodeoxyglucose ([18F]FDG), amino acid turnover with [18F]fluoroethyltyrosine ([18F]FET), and chemokine receptor expression using [68Ga]pentixafor targeting CXCR4, during stages of early tumor development, overt HCC and regression. We used two conditional transgenic mouse models of HCC, driven by clinically relevant oncogenes c-MYC (LT2/MYC) or HRASV12 (LT2/RAS). Conditional doxycycline-regulated mouse models, enable liver-specific oncogene activation or inhibition, leading to liver tumor development and regression, respectively. Correlation of our PET/CT findings with our gene expression and metabolomics data and with histological analyses followed. MAIN FINDINGS We show PET/CT identifies HCC stage-specific and oncogene-specific molecular changes that may serve as potential novel biomarkers and therapeutic targets. Glucose metabolism and CXCR4 chemokine expression are differentially deregulated during HCC development in an oncogene-specific manner. Our [18F]FDG results correlated with glucose transporter GLUT1 gene expression and with our metabolomics data. Increased expression of CXCR4 and CD68 inflammatory markers mirrored [68Ga]pentixafor results in LT2/MYC mice. FET-based measurement of amino acid turnover are insensitive to stages of HCC-development, in our studies. Concurrently, no significant changes in expression of tyrosine metabolism genes were observed. PRINCIPAL CONCLUSIONS Our study highlights that identified changes in targeted molecular imaging can facilitate a better understanding of underlying biological processes and may help guide novel oncogene-specific targeted anti-tumor therapies in HCC, with promising translational potential.
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Affiliation(s)
- Mari Teuter
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Yuhai Hu
- Department of Gastroenterology, Hepatology Infectious Diseases and Endocrinology, Hannover Medical School, Germany
| | - Tobias L Ross
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Kelsey Lolatte
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Michael Ott
- Department of Gastroenterology, Hepatology Infectious Diseases and Endocrinology, Hannover Medical School, Germany
| | - Frank M Bengel
- Department of Nuclear Medicine, Hannover Medical School, Germany
| | - Asha Balakrishnan
- Department of Gastroenterology, Hepatology Infectious Diseases and Endocrinology, Hannover Medical School, Germany.
| | - Jens P Bankstahl
- Department of Nuclear Medicine, Hannover Medical School, Germany.
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Ling C, Liu SS, Wang YY, Huo GT, Yang YW, Xu N, Wang H, Wu Y, Miao YF, Fu R, Zhao YW, Fan CF. Overexpression of wild-type HRAS drives non-alcoholic steatohepatitis to hepatocellular carcinoma in mice. Zool Res 2024; 45:551-566. [PMID: 38757223 PMCID: PMC11188599 DOI: 10.24272/j.issn.2095-8137.2024.002] [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: 03/21/2024] [Accepted: 04/07/2024] [Indexed: 05/18/2024] Open
Abstract
Hepatocellular carcinoma (HCC), a prevalent solid carcinoma of significant concern, is an aggressive and often fatal disease with increasing global incidence rates and poor therapeutic outcomes. The etiology and pathological progression of non-alcoholic steatohepatitis (NASH)-related HCC is multifactorial and multistage. However, no single animal model can accurately mimic the full NASH-related HCC pathological progression, posing considerable challenges to transition and mechanistic studies. Herein, a novel conditional inducible wild-type human HRAS overexpressed mouse model (HRAS-HCC) was established, demonstrating 100% morbidity and mortality within approximately one month under normal dietary and lifestyle conditions. Advanced symptoms of HCC such as ascites, thrombus, internal hemorrhage, jaundice, and lung metastasis were successfully replicated in mice. In-depth pathological features of NASH- related HCC were demonstrated by pathological staining, biochemical analyses, and typical marker gene detections. Combined murine anti-PD-1 and sorafenib treatment effectively prolonged mouse survival, further confirming the accuracy and reliability of the model. Based on protein-protein interaction (PPI) network and RNA sequencing analyses, we speculated that overexpression of HRAS may initiate the THBS1-COL4A3 axis to induce NASH with severe fibrosis, with subsequent progression to HCC. Collectively, our study successfully duplicated natural sequential progression in a single murine model over a very short period, providing an accurate and reliable preclinical tool for therapeutic evaluations targeting the NASH to HCC continuum.
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Affiliation(s)
- Chen Ling
- College of Life Sciences, Northwest University, Provincial Key Laboratory of Biotechnology of Shaanxi Province, Xi'an, Shaanxi 710069, China
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
| | - Su-Su Liu
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
| | - Yu-Ya Wang
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
| | - Gui-Tao Huo
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control (NIFDC), Beijing 100176, China
| | - Yan-Wei Yang
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control (NIFDC), Beijing 100176, China
| | - Nan Xu
- Division of HIV/AIDS and Sexually Transmitted Virus Vaccines, Institute for Biological Products Control, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
| | - Hong Wang
- Division of Laboratory Animal Monitoring, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
| | - Yong Wu
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
| | - Yu-Fa Miao
- National Center for Safety Evaluation of Drugs, National Institutes for Food and Drug Control (NIFDC), Beijing 100176, China
| | - Rui Fu
- Division of Laboratory Animal Monitoring, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China
| | - Yu-Wei Zhao
- College of Life Sciences, Northwest University, Provincial Key Laboratory of Biotechnology of Shaanxi Province, Xi'an, Shaanxi 710069, China. E-mail:
| | - Chang-Fa Fan
- Division of Animal Model Research, Institute for Laboratory Animal Resources, National Institutes for Food and Drug Control (NIFDC), Beijing 102629, China. E-mail:
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Chen L, Li Y, Chen Y. KLHL7 promotes hepatocellular carcinoma progression and molecular therapy resistance by degrading RASA2. iScience 2023; 26:106914. [PMID: 37378318 PMCID: PMC10291331 DOI: 10.1016/j.isci.2023.106914] [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: 09/25/2022] [Revised: 12/27/2022] [Accepted: 05/14/2023] [Indexed: 06/29/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is a common aggressive tumor with a poor prognosis, and patients often seem to be refractory to the use of therapeutic drugs. In this study, we found that the KLHL7 expression was upregulated in HCC that was associated with poor patient prognosis. KLHL7 has been found to promote HCC development in both in vitro and in vivo experiments. Mechanistically, RASA2, a RAS GAP, was identified as a substrate of KLHL7. Upregulation of KLHL7 by growth factors promotes K48-linked polyubiquitination of RASA2 for degradation via the proteasomal pathway. Our in vivo experiments revealed that inhibition of KLHL7 in combination with lenvatinib treatment resulted in efficient killing of HCC cells. Together, these findings demonstrate a role for KLHL7 in HCC and reveal a mechanism by which growth factors regulate the RAS-MAPK pathway. It represents a potential therapeutic target for HCC.
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Affiliation(s)
- Lin Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yun Li
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
| | - Yongheng Chen
- Department of Oncology, NHC Key Laboratory of Cancer Proteomics, State Local Joint Engineering Laboratory for Anticancer Drugs, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan 410008, China
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Hernandez JC, Chen CL, Machida T, Uthaya Kumar DB, Tahara SM, Montana J, Sher L, Liang J, Jung JU, Tsukamoto H, Machida K. LIN28 and histone H3K4 methylase induce TLR4 to generate tumor-initiating stem-like cells. iScience 2023; 26:106254. [PMID: 36949755 PMCID: PMC10025994 DOI: 10.1016/j.isci.2023.106254] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 01/09/2022] [Accepted: 02/16/2023] [Indexed: 02/24/2023] Open
Abstract
Chemoresistance and plasticity of tumor-initiating stem-like cells (TICs) promote tumor recurrence and metastasis. The gut-originating endotoxin-TLR4-NANOG oncogenic axis is responsible for the genesis of TICs. This study investigated mechanisms as to how TICs arise through transcriptional, epigenetic, and post-transcriptional activation of oncogenic TLR4 pathways. Here, we expressed constitutively active TLR4 (caTLR4) in mice carrying pLAP-tTA or pAlb-tTA, under a tetracycline withdrawal-inducible system. Liver progenitor cell induction accelerated liver tumor development in caTLR4-expressing mice. Lentiviral shRNA library screening identified histone H3K4 methylase SETD7 as central to activation of TLR4. SETD7 combined with hypoxia induced TLR4 through HIF2 and NOTCH. LIN28 post-transcriptionally stabilized TLR4 mRNA via de-repression of let-7 microRNA. These results supported a LIN28-TLR4 pathway for the development of HCCs in a hypoxic microenvironment. These findings not only advance our understanding of molecular mechanisms responsible for TIC generation in HCC, but also represent new therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Juan Carlos Hernandez
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- MS Biotechnology Program, California State University Channel Islands, Camarillo, CA 93012, USA
| | - Chia-Lin Chen
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Department of Life Sciences & Institute of Genome Sciences, National Yang Ming Chiao Tung University, Taipei 110, Taiwan
| | - Tatsuya Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Dinesh Babu Uthaya Kumar
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Stanley M. Tahara
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Jared Montana
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Linda Sher
- Department of Surgery, University of Southern California, Los Angeles, CA 90033, USA
| | | | - Jae U. Jung
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
| | - Hidekazu Tsukamoto
- Department of Pathology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
- Department of Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA, USA
| | - Keigo Machida
- Departments of Molecular Microbiology and Immunology, University of Southern California, Los Angeles, CA 90033, USA
- Southern California Research Center for ALPD and Cirrhosis, Los Angeles, CA, USA
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Wu Y, Tan HWS, Lin JY, Shen HM, Wang H, Lu G. Molecular mechanisms of autophagy and implications in liver diseases. LIVER RESEARCH 2023; 7:56-70. [PMID: 39959698 PMCID: PMC11792062 DOI: 10.1016/j.livres.2023.02.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 11/03/2022] [Accepted: 02/15/2023] [Indexed: 02/22/2023]
Abstract
Autophagy is a highly conserved process in which cytosolic contents are degraded by the lysosome, which plays an important role in energy and nutrient balance, and protein or organelle quality control. The liver is the most important organ for metabolism. Studies to date have revealed a significant role of autophagy in the maintenance of liver homeostasis under basal and stressed conditions, and the impairment of autophagy has been closely linked to various liver diseases. Therefore, a comprehensive understanding of the roles of autophagy in liver diseases may help in the development of therapeutic strategies via targeting autophagy. In this review, we will summarize the latest understanding of the molecular mechanisms of autophagy and systematically discuss its implications in various liver diseases, including alcohol-related liver disease, non-alcoholic fatty liver disease, viral hepatitis, hepatocellular carcinoma, and acetaminophen-induced liver injury.
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Affiliation(s)
- Yuankai Wu
- Department of Infectious Diseases, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Hayden Weng Siong Tan
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Jin-Yi Lin
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Han-Ming Shen
- Department of Biomedical Sciences, Faculty of Health Sciences, Ministry of Education Frontiers Science Center for Precision Oncology, University of Macau, Macau, China
| | - Haihe Wang
- Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Guang Lu
- Department of Physiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
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Abu-Shahba N, Hegazy E, Khan FM, Elhefnawi M. In Silico Analysis of MicroRNA Expression Data in Liver Cancer. Cancer Inform 2023; 22:11769351231171743. [PMID: 37200943 PMCID: PMC10185868 DOI: 10.1177/11769351231171743] [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: 11/30/2022] [Accepted: 04/04/2023] [Indexed: 05/20/2023] Open
Abstract
Abnormal miRNA expression has been evidenced to be directly linked to HCC initiation and progression. This study was designed to detect possible prognostic, diagnostic, and/or therapeutic miRNAs for HCC using computational analysis of miRNAs expression. Methods: miRNA expression datasets meta-analysis was performed using the YM500v2 server to compare miRNA expression in normal and cancerous liver tissues. The most significant differentially regulated miRNAs in our study undergone target gene analysis using the mirWalk tool to obtain their validated and predicted targets. The combinatorial target prediction tool; miRror Suite was used to obtain the commonly regulated target genes. Functional enrichment analysis was performed on the resulting targets using the DAVID tool. A network was constructed based on interactions among microRNAs, their targets, and transcription factors. Hub nodes and gatekeepers were identified using network topological analysis. Further, we performed patient data survival analysis based on low and high expression of identified hubs and gatekeeper nodes, patients were stratified into low and high survival probability groups. Results: Using the meta-analysis option in the YM500v2 server, 34 miRNAs were found to be significantly differentially regulated (P-value ⩽ .05); 5 miRNAs were down-regulated while 29 were up-regulated. The validated and predicted target genes for each miRNA, as well as the combinatorially predicted targets, were obtained. DAVID enrichment analysis resulted in several important cellular functions that are directly related to the main cancer hallmarks. Among these functions are focal adhesion, cell cycle, PI3K-Akt signaling, insulin signaling, Ras and MAPK signaling pathways. Several hub genes and gatekeepers were found that could serve as potential drug targets for hepatocellular carcinoma. POU2F1 and PPARA showed a significant difference between low and high survival probabilities (P-value ⩽ .05) in HCC patients. Our study sheds light on important biomarker miRNAs for hepatocellular carcinoma along with their target genes and their regulated functions.
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Affiliation(s)
- Nourhan Abu-Shahba
- Department of Medical Molecular Genetics, Human Genetics and Genome Research Institute, National Research Centre, Cairo, Egypt
- Stem Cell Research Group, Medical Research Center of Excellence, National Research Centre, Cairo, Egypt
| | - Elsayed Hegazy
- School of Information Technology and Computer Science, Nile University, Giza, Egypt
| | - Faiz M. Khan
- Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
| | - Mahmoud Elhefnawi
- Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, Cairo, Egypt
- Mahmoud Elhefnawi, Biomedical Informatics and Chemoinformatics Group, Informatics and Systems Department, National Research Centre, 33, elbohouth street, Cairo 11211, Egypt.
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Zhou Q, Chen L, Yang L, Zhou H, Chen Y, Guo Y. Integrated systemic analysis of FAM72A to identify its clinical relevance, biological function, and relationship to drug sensitivity in hepatocellular carcinoma. Front Oncol 2022; 12:1046473. [DOI: 10.3389/fonc.2022.1046473] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Accepted: 11/07/2022] [Indexed: 11/24/2022] Open
Abstract
BackgroundThe family with sequence similarity 72 member A (FAM72A) protein has been identified as an effector of multiple pathological processes in many cancers. The value of FAM72A in HCC remains largely unknown.MethodsData from TCGA-LIHC, ICGC-LIRI-JP, IMvigor210, cBioPortal, GeneMANIA, and TIMER were processed and visualized to explore the association between FAM72A and the prognosis, stemness phenotype, mutational burden, immune cell infiltration, and drug sensitivity in HCC patients. Potential pathways were also revealed. Furthermore, we experimentally verified the results in vivo and in vitro using immunohistochemistry, western blotting, and CCK-8 assays.ResultsFirst, FAM72A mRNA expression was significantly upregulated in HCC. High FAM72A expression was independently associated with a poor prognosis. Experimental validation confirmed that FAM72A was remarkably overexpressed in HCC patients and mice. Moreover, FAM72A knockdown suppressed HCC cell proliferation. In addition, the frequency of TP53 mutations was significantly higher in the high FAM72A expression group. Subsequently, the enrichment analysis revealed that FAM72A was closely related to immune processes and mTOR pathways. Silencing FAM72A increased the expression levels of mTOR in HCC cell lines. The FAM72A-mTOR pathway was strongly associated with a poor prognosis for patients with HCC. Patients with high FAM72A expression levels might be more resistant to sorafenib. Furthermore, the expression of FAM72A and mTOR was significantly associated with the abundance of some tumor-infiltrating immune cells, especially CD4+ T cells. Finally, patients with high levels of FAM72A and mTOR were more sensitive to immunotherapy.ConclusionsFAM72A, a member of the FAM72 family, might be a prognostic and immunotherapeutic target for HCC patients.
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Yoon JS, Lee CW. Protein phosphatases regulate the liver microenvironment in the development of hepatocellular carcinoma. Exp Mol Med 2022; 54:1799-1813. [PMID: 36380016 PMCID: PMC9722691 DOI: 10.1038/s12276-022-00883-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 08/31/2022] [Accepted: 09/01/2022] [Indexed: 11/16/2022] Open
Abstract
The liver is a complicated heterogeneous organ composed of different cells. Parenchymal cells called hepatocytes and various nonparenchymal cells, including immune cells and stromal cells, are distributed in liver lobules with hepatic architecture. They interact with each other to compose the liver microenvironment and determine its characteristics. Although the liver microenvironment maintains liver homeostasis and function under healthy conditions, it also shows proinflammatory and profibrogenic characteristics that can induce the progression of hepatitis and hepatic fibrosis, eventually changing to a protumoral microenvironment that contributes to the development of hepatocellular carcinoma (HCC). According to recent studies, phosphatases are involved in liver diseases and HCC development by regulating protein phosphorylation in intracellular signaling pathways and changing the activities and characteristics of liver cells. Therefore, this review aims to highlight the importance of protein phosphatases in HCC development and in the regulation of the cellular components in the liver microenvironment and to show their significance as therapeutic targets.
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Affiliation(s)
- Joon-Sup Yoon
- grid.264381.a0000 0001 2181 989XDepartment of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419 Republic of Korea
| | - Chang-Woo Lee
- grid.264381.a0000 0001 2181 989XDepartment of Molecular Cell Biology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Suwon, 16419 Republic of Korea ,grid.264381.a0000 0001 2181 989XDepartment of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, 06351 Republic of Korea
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Machida K. HCV and tumor-initiating stem-like cells. Front Physiol 2022; 13:903302. [PMID: 36187761 PMCID: PMC9520593 DOI: 10.3389/fphys.2022.903302] [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: 03/24/2022] [Accepted: 07/11/2022] [Indexed: 12/24/2022] Open
Abstract
Neoplasms contain tumor-initiating stem-like cells (TICs) that are characterized by increased drug resistance. The incidence of many cancer types have trended downward except for few cancer types, including hepatocellular carcinoma (HCC). Therefore mechanism of HCC development and therapy resistance needs to be understood. These multiple hits by hepatitis C virus (HCV) eventually promotes transformation and TIC genesis, leading to HCC development. This review article describes links between HCV-associated HCC and TICs. This review discusses 1) how HCV promotes genesis of TICs and HCC development; 2) how this process avails itself as a novel therapeutic target for HCC treatment; and 3) ten hall marks of TIC oncogenesis and HCC development as targets for novel therapeutic modalities.
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Mohamed EE, Abdel-Moneim A, Ahmed OM, Zoheir KM, Eldin ZE, El-Shahawy AA. Anticancer activity of a novel naringin‒dextrin nanoformula: Preparation, characterization, and in vitro induction of apoptosis in human hepatocellular carcinoma cells by inducing ROS generation, DNA fragmentation, and cell cycle arrest. J Drug Deliv Sci Technol 2022; 75:103677. [DOI: 10.1016/j.jddst.2022.103677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Kim H, Jeong M, Na DH, Ryu SH, Jeong EI, Jung K, Kang J, Lee HJ, Sim T, Yu DY, Yu HC, Cho BH, Jung YK. AK2 is an AMP-sensing negative regulator of BRAF in tumorigenesis. Cell Death Dis 2022; 13:469. [PMID: 35585049 PMCID: PMC9117275 DOI: 10.1038/s41419-022-04921-7] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/01/2022] [Revised: 05/03/2022] [Accepted: 05/05/2022] [Indexed: 12/14/2022]
Abstract
The RAS-BRAF signaling is a major pathway of cell proliferation and their mutations are frequently found in human cancers. Adenylate kinase 2 (AK2), which modulates balance of adenine nucleotide pool, has been implicated in cell death and cell proliferation independently of its enzyme activity. Recently, the role of AK2 in tumorigenesis was in part elucidated in some cancer types including lung adenocarcinoma and breast cancer, but the underlying mechanism is not clear. Here, we show that AK2 is a BRAF-suppressor. In in vitro assays and cell model, AK2 interacted with BRAF and inhibited BRAF activity and downstream ERK phosphorylation. Energy-deprived conditions in cell model and the addition of AMP to cell lysates strengthened the AK2-BRAF interaction, suggesting that AK2 is involved in the regulation of BRAF activity in response to cell metabolic state. AMP facilitated the AK2-BRAF complex formation through binding to AK2. In a panel of HCC cell lines, AK2 expression was inversely correlated with ERK/MAPK activation, and AK2-knockdown or -knockout increased BRAF activity and promoted cell proliferation. Tumors from HCC patients showed low-AK2 protein expression and increased ERK activation compared to non-tumor tissues and the downregulation of AK2 was also verified by two microarray datasets (TCGA-LIHC and GSE14520). Moreover, AK2/BRAF interaction was abrogated by RAS activation in in vitro assay and cell model and in a mouse model of HRASG12V-driven HCC, and AK2 ablation promoted tumor growth and BRAF activity. AK2 also bound to BRAF inhibitor-insensitive BRAF mutants and attenuated their activities. These findings indicate that AK2 monitoring cellular AMP levels is indeed a negative regulator of BRAF, linking the metabolic status to tumor growth.
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Affiliation(s)
- Hyunjoo Kim
- grid.31501.360000 0004 0470 5905School of Biological Science, Seoul National University, Gwanak-gu, Seoul, 08826 Korea
| | - Muhah Jeong
- grid.31501.360000 0004 0470 5905School of Biological Science, Seoul National University, Gwanak-gu, Seoul, 08826 Korea
| | - Do-Hyeong Na
- grid.31501.360000 0004 0470 5905School of Biological Science, Seoul National University, Gwanak-gu, Seoul, 08826 Korea
| | - Shin-Hyeon Ryu
- grid.31501.360000 0004 0470 5905School of Biological Science, Seoul National University, Gwanak-gu, Seoul, 08826 Korea
| | - Eun Il Jeong
- grid.31501.360000 0004 0470 5905School of Biological Science, Seoul National University, Gwanak-gu, Seoul, 08826 Korea
| | - Kwangmin Jung
- grid.31501.360000 0004 0470 5905School of Biological Science, Seoul National University, Gwanak-gu, Seoul, 08826 Korea
| | - Jaemin Kang
- grid.31501.360000 0004 0470 5905School of Biological Science, Seoul National University, Gwanak-gu, Seoul, 08826 Korea
| | - Ho-June Lee
- grid.418158.10000 0004 0534 4718Departments of Discovery Oncology, Genentech, Inc., South San Francisco, CA 94080 USA
| | - Taebo Sim
- grid.35541.360000000121053345Chemical Kinomics Research Center, Korea Institute of Science and Technology, Seoul, 02792 Korea
| | - Dae-Yeul Yu
- grid.249967.70000 0004 0636 3099Aging Intervention Research Center, Korea Research Institute of Bioscience and Biotechnology, Daejeon, Korea
| | - Hee Chul Yu
- grid.411545.00000 0004 0470 4320Department of Surgery, Chonbuk National University Medical School, Jeonju, 561-180 Korea
| | - Baik-Hwan Cho
- grid.411545.00000 0004 0470 4320Department of Surgery, Chonbuk National University Medical School, Jeonju, 561-180 Korea
| | - Yong-Keun Jung
- grid.31501.360000 0004 0470 5905School of Biological Science, Seoul National University, Gwanak-gu, Seoul, 08826 Korea
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13
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Garcia PP, Albuquerque RM, Osório FMF, Couto CA, Lima AS, Vidigal PVT. B-RAF PROTEIN IMMUNOEXPRESSION IN HEPATOCELLULAR CARCINOMA DUE TO HEPATITIS C VIRUS RELATED CIRRHOSIS. ARQUIVOS DE GASTROENTEROLOGIA 2021; 58:419-423. [PMID: 34909843 DOI: 10.1590/s0004-2803.202100000-76] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 06/15/2021] [Indexed: 11/21/2022]
Abstract
BACKGROUND Hepatocarcinogenesis is a multistep process that lead to genetic changes in hepatocytes resulting in neoplasia. However, the mechanisms of malignant transformation seem to differ widely. To know carcinogenesis mechanisms is essential to develop new treatment and prevention methods. OBJECTIVE The aim of this study is to analyze B-Raf protein immunoexpression in explants with hepatocellular carcinoma (HCC) related to hepatitis C (HCV), in adjacent cirrhotic tissue and in normal livers. We also associated the immunoexpression with known HCC related histopathogical prognostic features. METHODS Livers from 35 patients with HCV related cirrhosis and HCC that underwent liver transplantation or hepatectomy at Clinical Hospital – UFMG and 25 normal livers from necropsy archives were studied. Tumors were classified according to: tumor size, vascular invasion and differentiation grade. B-Raf protein expression was determined by immunohistochemistry. RESULTS B-Raf was strongly expressed in the HCV cirrhotic parenchyma cytoplasm of 17.1% cases and in 62.9% of HCC samples. Strong B-Raf protein staining was associated with tumor tissue (P<0.0001; OR=8.18 (2.62–26.63)). All normal livers showed weak or negative expression for B-Raf. There was no significant association among B-Raf scores and tumor differentiation grade (P=0.9485), tumor size (P=0.4427) or with vascular invasion (P=0.2666). CONCLUSION We found B-Raf protein immunostaining difference in normal livers, in the areas of HCV cirrhosis and in the hepatocarcinoma. We did not find association between B-Raf expression and histopathological markers of tumor progression. Our data suggests that B-Raf may play an important role in initial HCC carcinogenesis. Larger studies are needed to validate these observations.
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Affiliation(s)
- Paula Piedade Garcia
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Anatomia patológica e Medicina Legal, Belo Horizonte, MG, Brasil
| | - Ronniel Morais Albuquerque
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Anatomia patológica e Medicina Legal, Belo Horizonte, MG, Brasil
| | - Fernanda Maria Farage Osório
- Universidade Federal de Minas Gerais, Hospital das Clínicas - EBSERH, Instituto Alfa de Gastroenterologia, Belo Horizonte, MG, Brasil
| | - Cláudia Alves Couto
- Universidade Federal de Minas Gerais, Hospital das Clínicas - EBSERH, Instituto Alfa de Gastroenterologia, Belo Horizonte, MG, Brasil
| | - Agnaldo Soares Lima
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Cirurgia, Belo Horizonte, MG, Brasil
| | - Paula Vieira Teixeira Vidigal
- Universidade Federal de Minas Gerais, Faculdade de Medicina, Departamento de Anatomia patológica e Medicina Legal, Belo Horizonte, MG, Brasil
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14
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Scheiter A, Evert K, Reibenspies L, Cigliano A, Annweiler K, Müller K, Pöhmerer LMG, Xu H, Cui G, Itzel T, Materna-Reichelt S, Coluccio A, Honarnejad K, Teufel A, Brochhausen C, Dombrowski F, Chen X, Evert M, Calvisi DF, Utpatel K. RASSF1A independence and early galectin-1 upregulation in PIK3CA-induced hepatocarcinogenesis: new therapeutic venues. Mol Oncol 2021; 16:1091-1118. [PMID: 34748271 PMCID: PMC8895452 DOI: 10.1002/1878-0261.13135] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2021] [Revised: 09/19/2021] [Accepted: 11/04/2021] [Indexed: 02/05/2023] Open
Abstract
Aberrant activation of the phosphoinositide 3‐kinase (PI3K)/AKT/mTOR and Ras/mitogen‐activated protein kinase (MAPK) pathways is a hallmark of hepatocarcinogenesis. In a subset of hepatocellular carcinomas (HCCs), PI3K/AKT/mTOR signaling dysregulation depends on phosphatidylinositol‐4,5‐bisphosphate 3‐kinase, catalytic subunit alpha (PIK3CA) mutations, while RAS/MAPK activation is partly attributed to promoter methylation of the tumor suppressor Ras association domain‐containing protein 1 (RASSF1A). To evaluate a possible cocarcinogenic effect of PIK3CA activation and RASSF1A knockout, plasmids expressing oncogenic forms of PIK3CA (E545K or H1047R mutants) were delivered to the liver of RASSF1A knockout and wild‐type mice by hydrodynamic tail vein injection combined with sleeping beauty‐mediated somatic integration. Transfection of either PIK3CA E545K or H1047R mutants sufficed to induce HCCs in mice irrespective of RASSF1A mutational background. The related tumors displayed a lipogenic phenotype with upregulation of fatty acid synthase and stearoyl‐CoA desaturase‐1 (SCD1). Galectin‐1, which was commonly upregulated in preneoplastic lesions and tumors, emerged as a regulator of SCD1. Co‐inhibitory treatment with PIK3CA inhibitors and the galectin‐1 inhibitor OTX008 resulted in synergistic cytotoxicity in human HCC cell lines, suggesting novel therapeutic venues.
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Affiliation(s)
| | - Katja Evert
- Institute of Pathology, University of Regensburg, Germany
| | | | | | | | - Karolina Müller
- Center for Clinical Studies, University Hospital Regensburg, Germany
| | | | - Hongwei Xu
- Department of Liver Surgery, Center of Liver Transplantation, West China Hospital of Sichuan University, Chengdu, China.,Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Guofei Cui
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Timo Itzel
- Division of Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Silvia Materna-Reichelt
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany
| | - Andrea Coluccio
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany
| | - Kamran Honarnejad
- Division of Personalized Tumor Therapy, Fraunhofer Institute for Toxicology and Experimental Medicine, Regensburg, Germany
| | - Andreas Teufel
- Division of Hepatology, Department of Medicine II, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | | | - Frank Dombrowski
- Institute of Pathology, University Medicine of Greifswald, Germany
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA, USA
| | - Matthias Evert
- Institute of Pathology, University of Regensburg, Germany
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15
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Takeda T, Tsubaki M, Kato N, Genno S, Ichimura E, Enomoto A, Imano M, Satou T, Nishida S. Sorafenib treatment of metastatic melanoma with c-Kit aberration reduces tumor growth and promotes survival. Oncol Lett 2021; 22:827. [PMID: 34691254 DOI: 10.3892/ol.2021.13089] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/29/2021] [Indexed: 12/12/2022] Open
Abstract
Melanomas are highly malignant tumors that readily metastasize and have poor prognosis. Targeted therapy is a cornerstone of treatment for patients with melanoma. Although c-Kit gene aberration has found in 5-10% of melanoma cases, research on c-Kit inhibitors for melanoma with c-Kit aberration have been disappointing. Sorafenib is a tyrosine kinase inhibitor, whose targets include c-Kit, platelet derived growth factor receptor (PDGFR), VEGFR and RAF. The present study aimed to examine the effect of sorafenib on metastatic melanoma with c-Kit aberration. Cell viability was assessed via trypan blue assay. Migration and invasion were analyzed using cell culture inserts. The anti-metastatic effects and antitumour activity of sorafenib were determined in an in vivo model. Protein expression was detected via western blotting, and the expression of MMP and very late antigen (VLA) was detected via reverse transcription-quantitative PCR. It was identified that sorafenib decreased cell viability, migration and invasion in vitro. Furthermore, sorafenib inhibited metastasis and tumor growth in vivo. Mechanistically, sorafenib inhibited c-Kit, PDGFR, VEGFR, B-Raf and c-Raf phosphorylation both in vitro and in vivo. In addition, sorafenib reduced the expression levels of MMPs and VLA. Importantly, there was a significant effect of sorafenib treatment on overall survival in mice. Collectively, this study suggests that sorafenib may serve as a novel therapeutic option for melanoma with c-Kit dysregulation.
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Affiliation(s)
- Tomoya Takeda
- Department of Pharmacotherapy, Kindai University School of Pharmacy, Higashi-Osaka, Osaka 577-8502, Japan
| | - Masanobu Tsubaki
- Department of Pharmacotherapy, Kindai University School of Pharmacy, Higashi-Osaka, Osaka 577-8502, Japan
| | - Natsuki Kato
- Department of Pharmacotherapy, Kindai University School of Pharmacy, Higashi-Osaka, Osaka 577-8502, Japan
| | - Shuji Genno
- Department of Pharmacotherapy, Kindai University School of Pharmacy, Higashi-Osaka, Osaka 577-8502, Japan
| | - Eri Ichimura
- Department of Pharmacotherapy, Kindai University School of Pharmacy, Higashi-Osaka, Osaka 577-8502, Japan
| | - Aya Enomoto
- Department of Pharmacotherapy, Kindai University School of Pharmacy, Higashi-Osaka, Osaka 577-8502, Japan
| | - Motohiro Imano
- Department of Surgery, Kindai University School of Medicine, Osakasayama, Osaka 589-0014, Japan
| | - Takao Satou
- Department of Pathology, Kindai University School of Medicine, Osakasayama, Osaka 589-0014, Japan
| | - Shozo Nishida
- Department of Pharmacotherapy, Kindai University School of Pharmacy, Higashi-Osaka, Osaka 577-8502, Japan
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16
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Epigenetic Changes Affecting the Development of Hepatocellular Carcinoma. Cancers (Basel) 2021; 13:cancers13164237. [PMID: 34439391 PMCID: PMC8392268 DOI: 10.3390/cancers13164237] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Revised: 08/15/2021] [Accepted: 08/19/2021] [Indexed: 02/07/2023] Open
Abstract
Simple Summary Hepatocellular carcinoma is a life-threatening disease. Despite many efforts to understand the exact pathogenesis and the signaling pathways involved in its formation, treatment remains unsatisfactory. Currently, an important function in the development of neoplastic diseases and treatment effects is attributed to changes taking place at the epigenetic level. Epigenetic studies revealed modified methylation patterns in HCC, dysfunction of enzymes engaged in the DNA methylation process, the aberrant function of non-coding RNAs, and a set of histone modifications that influence gene expression. The aim of this review is to summarize the current knowledge on the role of epigenetics in the formation of hepatocellular carcinoma. Abstract Hepatocellular carcinoma (HCC) remains a serious oncologic issue with still a dismal prognosis. So far, no key molecular mechanism that underlies its pathogenesis has been identified. Recently, by specific molecular approaches, many genetic and epigenetic changes arising during HCC pathogenesis were detected. Epigenetic studies revealed modified methylation patterns in HCC tumors, dysfunction of enzymes engaged in the DNA methylation process, and a set of histone modifications that influence gene expression. HCC cells are also influenced by the disrupted function of non-coding RNAs, such as micro RNAs and long non-coding RNAs. Moreover, a role of liver cancer stem cells in HCC development is becoming evident. The reversibility of epigenetic changes offers the possibility of influencing them and regulating their undesirable effects. All these data can be used not only to identify new therapeutic targets but also to predict treatment response. This review focuses on epigenetic changes in hepatocellular carcinoma and their possible implications in HCC therapy.
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17
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Banerjee I, Fisher PB, Sarkar D. Astrocyte elevated gene-1 (AEG-1): A key driver of hepatocellular carcinoma (HCC). Adv Cancer Res 2021; 152:329-381. [PMID: 34353442 DOI: 10.1016/bs.acr.2021.05.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
An array of human cancers, including hepatocellular carcinoma (HCC), overexpress the oncogene Astrocyte elevated gene-1 (AEG-1). It is now firmly established that AEG-1 is a key driver of carcinogenesis, and enhanced expression of AEG-1 is a marker of poor prognosis in cancer patients. In-depth studies have revealed that AEG-1 positively regulates different hallmarks of HCC progression including growth and proliferation, angiogenesis, invasion, migration, metastasis and resistance to therapeutic intervention. By interacting with a plethora of proteins as well as mRNAs, AEG-1 regulates gene expression at transcriptional, post-transcriptional, and translational levels, and modulates numerous pro-tumorigenic and tumor-suppressive signal transduction pathways. Even though extensive research over the last two decades using various in vitro and in vivo models has established the pivotal role of AEG-1 in HCC, effective targeting of AEG-1 as a therapeutic intervention for HCC is yet to be achieved in the clinic. Targeted delivery of AEG-1 small interfering ribonucleic acid (siRNA) has demonstrated desired therapeutic effects in mouse models of HCC. Peptidomimetic inhibitors based on protein-protein interaction studies has also been developed recently. Continuous unraveling of novel mechanisms in the regulation of HCC by AEG-1 will generate valuable knowledge facilitating development of specific AEG-1 inhibitory strategies. The present review describes the current status of AEG-1 in HCC gleaned from patient-focused and bench-top studies as well as transgenic and knockout mouse models. We also address the challenges that need to be overcome and discuss future perspectives on this exciting molecule to transform it from bench to bedside.
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Affiliation(s)
- Indranil Banerjee
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Paul B Fisher
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States
| | - Devanand Sarkar
- Department of Human and Molecular Genetics, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Institute of Molecular Medicine, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States; VCU Massey Cancer Center, Virginia Commonwealth University, School of Medicine, Richmond, VA, United States.
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18
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Zhang J, Li H, Dong J, Zhang N, Liu Y, Luo X, Chen J, Wang J, Wang A. Omics-Based Identification of Shared and Gender Disparity Routes in Hras12V-Induced Hepatocarcinogenesis: An Important Role for Dlk1-Dio3 Genomic Imprinting Region. Front Genet 2021; 12:620594. [PMID: 34135934 PMCID: PMC8202007 DOI: 10.3389/fgene.2021.620594] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2020] [Accepted: 03/02/2021] [Indexed: 12/13/2022] Open
Abstract
The phenomenon of gender disparity is very profound in hepatocellular carcinoma (HCC). Although previous research has revealed important roles of microRNA (miRNA) in HCC, there are no studies investigating the role of miRNAs in gender disparity observed hepatocarcinogenesis. In the present study, we investigated the global miRNAomics changes related to Ras-induced male-prevalent hepatocarcinogenesis in a Hras12V-transgenic mouse model (Ras-Tg) by next-generation sequencing (NGS). We identified shared by also unique changes in miRNA expression profiles in gender-dependent hepatocarcinogenesis. Two hundred sixty-four differentially expressed miRNAs (DEMIRs) with q value ≤0.05 and fold change ≥2 were identified. A vertical comparison revealed that the lower numbers of DEMIRs in the hepatic tumor (T) compared with the peri-tumor precancerous tissue (P) of Ras-Tg and normal liver tissue of wild-type C57BL/6J mice (W) in males indicated that males are more susceptible to develop HCC. The expression pattern analysis revealed 43 common HCC-related miRNAs and 4 Ras-positive-related miRNAs between males and females. By integrating the mRNA transcriptomic data and using 3-node FFL analysis, a group of significant components commonly contributing to HCC between sexes were filtered out. A horizontal comparison showed that the majority of DEMIRs are located in the Dlk1-Dio3 genomic imprinting region (GIR) and that they are closely related to not only hepatic tumorigenesis but also to gender disparity in hepatocarcinogenesis. This is achieved by regulating multiple metabolic pathways, including retinol, bile acid, and steroid hormones. In conclusion, the identification of shared and gender-dependent DEMIRs in hepatocarcinogenesis provides valuable insights into the mechanisms that contribute to male-biased Ras-induced hepatic carcinogenesis.
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Affiliation(s)
- Jing Zhang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Huiling Li
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Jianyi Dong
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Nan Zhang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Yang Liu
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Xiaoqin Luo
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Jun Chen
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Jingyu Wang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
| | - Aiguo Wang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China
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19
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Barcena-Varela M, Lujambio A. The Endless Sources of Hepatocellular Carcinoma Heterogeneity. Cancers (Basel) 2021; 13:2621. [PMID: 34073538 PMCID: PMC8198457 DOI: 10.3390/cancers13112621] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2021] [Revised: 05/20/2021] [Accepted: 05/21/2021] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) represents a global health problem. The incidence keeps increasing and current therapeutic options confer limited benefits to the patients. Tumor heterogeneity plays a central role in this context, limiting the availability of predictive biomarkers and complicating the criteria used to choose the most suitable therapeutic option. HCC heterogeneity occurs at different levels: within the population (inter-patient heterogeneity) and within tumors from the same patient (intra-patient and intra-tumor heterogeneity). Experts in the field have made many efforts to classify the patients based on clinicopathological characteristics and molecular signatures; however, there is still much work ahead to be able to integrate the extra-tumor heterogeneity that emerges from the complexity of the tumor microenvironment, which plays a critical role in the pathogenesis of the disease and therapy responses. In this review, we summarize tumor intrinsic and extrinsic sources of heterogeneity of the most common etiologies of HCC and summarize the most recent discoveries regarding the evolutionary trajectory of liver cancer cells and the influence of tumor-extrinsic factors such as the microbiome and the host immune system. We further highlight the potential of novel high-throughput methodologies to contribute to a better understanding of this devastating disease and to the improvement of the clinical management of patients.
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Affiliation(s)
- Marina Barcena-Varela
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Amaia Lujambio
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA;
- Liver Cancer Program, Division of Liver Diseases, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- The Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
- Graduate School of Biomedical Sciences at Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
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20
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McBrearty N, Arzumanyan A, Bichenkov E, Merali S, Merali C, Feitelson M. Short chain fatty acids delay the development of hepatocellular carcinoma in HBx transgenic mice. Neoplasia 2021; 23:529-538. [PMID: 33945993 PMCID: PMC8111251 DOI: 10.1016/j.neo.2021.04.004] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2021] [Revised: 04/12/2021] [Accepted: 04/12/2021] [Indexed: 12/17/2022] Open
Abstract
Chronic infection with hepatitis B virus (HBV) is a major risk factor for the development of hepatocellular carcinoma (HCC). The HBV encoded oncoprotein, HBx, alters the expression of host genes and the activity of multiple signal transduction pathways that contribute to the pathogenesis of HCC by multiple mechanisms independent of HBV replication. However, it is not clear which pathways are the most relevant therapeutic targets in hepatocarcinogenesis. Short chain fatty acids (SCFAs) have strong anti-inflammatory and anti-neoplastic properties, suggesting that they may block the progression of chronic liver disease (CLD) to HCC, thereby identifying the mechanisms relevant to HCC development. This hypothesis was tested in HBx transgenic (HBxTg) mice fed SCFAs. Groups of HBxTg mice were fed with SCFAs or vehicle from 6 to 9 months of age and then assessed for dysplasia, and from 9 to 12 months of age and then assessed for HCC. Livers from 12 month old mice were then analyzed for changes in gene expression by mass spectrometry-based proteomics. SCFA-fed mice had significantly fewer dysplastic and HCC nodules compared to controls at 9 and 12 months, respectively. Pathway analysis of SCFA-fed mice showed down-regulation of signaling pathways altered by HBx in human CLD and HCC, including those involved in inflammation, phosphatidylinositol 3-kinase, epidermal growth factor, and Ras. SCFA treatment promoted increased expression of the tumor suppressor, disabled homolog 2 (DAB2). DAB2 depresses Ras pathway activity, which is constitutively activated by HBx. SCFAs also reduced cell viability in HBx-transfected cell lines in a dose-dependent manner while the viability of primary human hepatocytes was unaffected. These unique findings demonstrate that SCFAs delay the pathogenesis of CLD and development of HCC, and provide insight into some of the underlying mechanisms that are relevant to pathogenesis in that they are responsive to treatment.
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Affiliation(s)
- Noreen McBrearty
- Department of Biology, College of Science and Technology, Philadelphia, PA, USA
| | - Alla Arzumanyan
- Department of Biology, College of Science and Technology, Philadelphia, PA, USA
| | - Eugene Bichenkov
- Department of Biology, College of Science and Technology, Philadelphia, PA, USA
| | - Salim Merali
- Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, USA
| | - Carmen Merali
- Department of Pharmaceutical Sciences, School of Pharmacy, Temple University, Philadelphia, PA, USA
| | - Mark Feitelson
- Department of Biology, College of Science and Technology, Philadelphia, PA, USA.
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21
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Artesunate synergizes with sorafenib to induce ferroptosis in hepatocellular carcinoma. Acta Pharmacol Sin 2021; 42:301-310. [PMID: 32699265 DOI: 10.1038/s41401-020-0478-3] [Citation(s) in RCA: 197] [Impact Index Per Article: 49.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Accepted: 07/06/2020] [Indexed: 02/07/2023]
Abstract
Sorafenib is the first-line medication for advanced hepatocellular carcinoma (HCC), but it can only extend limited survival. It is imperative to find a combination strategy to increase sorafenib efficacy. Artesunate is such a preferred candidate, because artesunate is clinically well-tolerated and more importantly both drugs can induce ferroptosis through different mechanisms. In this study we investigated the combined effect of sorafenib and artesunate in inducing ferroptosis of HCC and elucidated the involved molecular mechanisms. We showed that artesunate greatly enhanced the anticancer effects of low dose of sorafenib against Huh7, SNU-449, and SNU-182 HCC cell lines in vitro and against Huh7 cell xenograft model in Balb/c nude mice. The combination index method confirmed that the combined effect of sorafenib and artesunate was synergistic. Compared with the treatment with artesunate or sorafenib alone, combined treatment induced significantly exacerbated lipid peroxidation and ferroptosis, which was blocked by N-acetyl cysteine and ferroptosis inhibitors liproxstatin-1 and deferoxamine mesylate, but not by inhibitors of other types of cell death (z-VAD, necrostatin-1 and belnacasan). In Huh7 cells, we demonstrated that the combined treatment induced oxidative stress and lysosome-mediated ferritinophagy, two essential aspects of ferroptosis. Sorafenib at low dose mainly caused oxidative stress through mitochondrial impairments and SLC7A11-invovled glutathione depletion. Artesunate-induced lysosome activation synergized with sorafenib-mediated pro-oxidative effects by promoting sequential reactions including lysosomal cathepsin B/L activation, ferritin degradation, lipid peroxidation, and consequent ferroptosis. Taken together, artesunate could be repurposed to sensitize sorafenib in HCC treatment. The combined treatment can be easily translated into clinical applications.
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22
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Garcia-Lezana T, Lopez-Canovas JL, Villanueva A. Signaling pathways in hepatocellular carcinoma. Adv Cancer Res 2020; 149:63-101. [PMID: 33579428 DOI: 10.1016/bs.acr.2020.10.002] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Despite the recent introduction of new effective systemic agents, the survival of patients with hepatocellular carcinoma (HCC) at advanced stages remains dismal. This underscores the need for new therapies, which has spurred extensive research on the identification of the main drivers of pathway de-regulation as a source of novel therapeutic targets. Frequently altered pathways in HCC involve growth factor receptors (e.g., VEGFR, FGFR, TGFA, EGFR, IGFR) and/or its cytoplasmic intermediates (e.g., PI3K-AKT-mTOR, RAF/ERK/MAPK) as well as key pathways in cell differentiation (e.g., Wnt/β-catenin, JAK/STAT, Hippo, Hedgehog, Notch). Somatic mutations, chromosomal aberrations and epigenetic changes are common mechanisms for pathway deregulation in HCC. Aberrant pathway activation has also been explored as a biomarker to predict response to specific therapies, but currently, these strategies are not implemented when deciding systemic therapies in HCC patients. Beyond the well-established molecular cascades, there are numerous emerging signaling pathways also deregulated in HCC (e.g., tumor microenvironment, non-coding RNA, intestinal microbiota), which have opened new avenues for therapeutic exploration.
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Affiliation(s)
- Teresa Garcia-Lezana
- Division of Liver Diseases, Liver Cancer Program, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Juan Luis Lopez-Canovas
- Department of Cell Biology, Physiology and Immunology, Maimonides Institute of Biomedical Research of Córdoba (IMIBIC), University of Córdoba, Córdoba, Spain
| | - Augusto Villanueva
- Division of Liver Diseases, Liver Cancer Program, Department of Medicine, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States; Division of Hematology and Medical Oncology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States.
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23
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Kaneya Y, Takata H, Wada R, Kure S, Ishino K, Kudo M, Kondo R, Taniai N, Ohashi R, Yoshida H, Naito Z. Inhibitor for protein disulfide-isomerase family A member 3 enhances the antiproliferative effect of inhibitor for mechanistic target of rapamycin in liver cancer: An in vitro study on combination treatment with everolimus and 16F16. Oncol Lett 2020; 21:28. [PMID: 33240434 PMCID: PMC7681208 DOI: 10.3892/ol.2020.12289] [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: 04/16/2020] [Accepted: 10/28/2020] [Indexed: 12/13/2022] Open
Abstract
mTOR is involved in the proliferation of liver cancer. However, the clinical benefit of treatment with mTOR inhibitors for liver cancer is controversial. Protein disulfide isomerase A member 3 (PDIA3) is a chaperone protein, and it supports the assembly of mTOR complex 1 (mTORC1) and stabilizes signaling. Inhibition of PDIA3 function by a small molecule known as 16F16 may destabilize mTORC1 and enhance the effect of the mTOR inhibitor everolimus (Ev). The aim of the present study was to elucidate the usefulness of combination treatment with Ev and 16F16 in liver cancer using cultured Li-7 and HuH-6 cells. The proliferation of cultured cells was examined following treatment with 0.01 µM Ev, 2 µM 16F16 or both. The expression levels and phosphorylation of S6 kinase (S6K) and 4E-binding protein 1 (4E-BP1) were examined by western blotting. Li-7 was susceptible to Ev, and proliferation was reduced to 69.5±7.2% by Ev compared with that of untreated cells. Proliferation was reduced to 90.2±10.8% by 16F16 but to 62.3±12.2% by combination treatment with Ev and 16F16. HuH-6 cells were resistant to Ev, and proliferation was reduced to 86.7±6.1% by Ev and 86.6±4.8% by 16F16. However, combination treatment suppressed proliferation to 57.7±4.0%. Phosphorylation of S6K was reduced by Ev in both Li-7 and HuH-6 cells. Phosphorylation of 4E-BP1 was reduced by combination treatment in both Li-7 and HuH-6 cells. Immunoprecipitation assays demonstrated that PDIA3 formed a complex with 4E-BP1 but not with S6K. The small molecule 16F16 increased susceptibility to Ev in cultured liver cancer cells, which are resistant to Ev. The inhibition was associated with reduction of 4E-BP1 phosphorylation, which formed a complex with PDIA3. Combination treatment with Ev and 16F16 could be a novel therapeutic strategy for liver cancer.
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Affiliation(s)
- Yohei Kaneya
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo 113-8602, Japan.,Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo 113-8602, Japan
| | - Hideyuki Takata
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo 113-8602, Japan
| | - Ryuichi Wada
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo 113-8602, Japan.,Department of Diagnostic Pathology, Nippon Medical School Hospital, Tokyo 113-8602, Japan
| | - Shoko Kure
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo 113-8602, Japan.,Department of Diagnostic Pathology, Nippon Medical School Hospital, Tokyo 113-8602, Japan
| | - Kousuke Ishino
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo 113-8602, Japan
| | - Mitsuhiro Kudo
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo 113-8602, Japan
| | - Ryota Kondo
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo 113-8602, Japan
| | - Nobuhiko Taniai
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School Musashi Kosugi Hospital, Tokyo 211-8533, Japan
| | - Ryuji Ohashi
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo 113-8602, Japan.,Department of Diagnostic Pathology, Nippon Medical School Hospital, Tokyo 113-8602, Japan
| | - Hiroshi Yoshida
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Nippon Medical School, Tokyo 113-8602, Japan
| | - Zenya Naito
- Department of Integrated Diagnostic Pathology, Nippon Medical School, Tokyo 113-8602, Japan.,Department of Diagnostic Pathology, Nippon Medical School Hospital, Tokyo 113-8602, Japan
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24
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Yamazoe T, Mori T, Yoshio S, Kanto T. Hepatocyte ploidy and pathological mutations in hepatocellular carcinoma: impact on oncogenesis and therapeutics. Glob Health Med 2020; 2:273-281. [PMID: 33330821 DOI: 10.35772/ghm.2020.01089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 10/21/2020] [Accepted: 10/23/2020] [Indexed: 12/23/2022]
Abstract
Hepatocellular carcinoma (HCC) occurs in the chronic liver inflammation such as viral hepatitis, alcoholic and non-alcoholic steatohepatitis. While anti-viral treatment has been significantly improved, the prevalence of HCC remains high and treatment is still challenging. The continuation of hepatocyte death, inflammation, and fibrosis leads to the accumulation of gene alterations, which may trigger carcinogenesis. Hepatocytes are a unique cell type having more than one complete set of 23 chromosomes, termed polyploidy. Due to gene redundancy, hepatocytes may tolerate lethal mutations. Next generation sequencing technology has revealed gene alterations in HCC related to telomere maintenance, Wnt/β-catenin pathway, p53 cell-cycle pathway, epigenetic modifiers, oxidative stress pathway, PI3K/AKT/mTOR, and RAS/RAF/MAPK pathway with or without a chromosomal instability. Some type of driver gene mutations accumulates in hepatocytes and breaks the orchestration of excessive copies of chromosomes, which may lead to unfavorable gene expressions and fuel tumorigenesis. Recently, molecular targeted drugs, developed with the aim of interfering with these signaling pathways, are being used for HCC patients in the clinics. Therefore, a deeper understanding of hepatocyte ploidy and genetic or epigenetic alterations is indispensable for the establishment of novel therapeutic strategies against HCC.
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Affiliation(s)
- Taiji Yamazoe
- Department of Liver Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Taizo Mori
- Department of Liver Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Sachiyo Yoshio
- Department of Liver Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
| | - Tatsuya Kanto
- Department of Liver Disease, Research Center for Hepatitis and Immunology, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan
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25
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Zhang Z, Zhou L, Xie N, Nice EC, Zhang T, Cui Y, Huang C. Overcoming cancer therapeutic bottleneck by drug repurposing. Signal Transduct Target Ther 2020; 5:113. [PMID: 32616710 PMCID: PMC7331117 DOI: 10.1038/s41392-020-00213-8] [Citation(s) in RCA: 310] [Impact Index Per Article: 62.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 06/03/2020] [Accepted: 06/04/2020] [Indexed: 02/06/2023] Open
Abstract
Ever present hurdles for the discovery of new drugs for cancer therapy have necessitated the development of the alternative strategy of drug repurposing, the development of old drugs for new therapeutic purposes. This strategy with a cost-effective way offers a rare opportunity for the treatment of human neoplastic disease, facilitating rapid clinical translation. With an increased understanding of the hallmarks of cancer and the development of various data-driven approaches, drug repurposing further promotes the holistic productivity of drug discovery and reasonably focuses on target-defined antineoplastic compounds. The "treasure trove" of non-oncology drugs should not be ignored since they could target not only known but also hitherto unknown vulnerabilities of cancer. Indeed, different from targeted drugs, these old generic drugs, usually used in a multi-target strategy may bring benefit to patients. In this review, aiming to demonstrate the full potential of drug repurposing, we present various promising repurposed non-oncology drugs for clinical cancer management and classify these candidates into their proposed administration for either mono- or drug combination therapy. We also summarize approaches used for drug repurposing and discuss the main barriers to its uptake.
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Affiliation(s)
- Zhe Zhang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Li Zhou
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Na Xie
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China
| | - Edouard C Nice
- Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC, Australia
| | - Tao Zhang
- The School of Biological Science and Technology, Chengdu Medical College, 610083, Chengdu, China.
- Department of Oncology, The Second Affiliated Hospital of Chengdu Medical College, China National Nuclear Corporation 416 Hospital, Chengdu, 610051, Sichuan, China.
| | - Yongping Cui
- Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, and Cancer Institute, Shenzhen Bay Laboratory Shenzhen, 518035, Shenzhen, China.
- Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, 030001, Shanxi, China.
| | - Canhua Huang
- State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, and West China School of Basic Medical Sciences & Forensic Medicine, Sichuan University, and Collaborative Innovation Center for Biotherapy, 610041, Chengdu, China.
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, Sichuan, China.
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26
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Mossenta M, Busato D, Dal Bo M, Toffoli G. Glucose Metabolism and Oxidative Stress in Hepatocellular Carcinoma: Role and Possible Implications in Novel Therapeutic Strategies. Cancers (Basel) 2020; 12:E1668. [PMID: 32585931 PMCID: PMC7352479 DOI: 10.3390/cancers12061668] [Citation(s) in RCA: 62] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 06/12/2020] [Accepted: 06/20/2020] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) metabolism is redirected to glycolysis to enhance the production of metabolic compounds employed by cancer cells to produce proteins, lipids, and nucleotides in order to maintain a high proliferative rate. This mechanism drives towards uncontrolled growth and causes a further increase in reactive oxygen species (ROS), which could lead to cell death. HCC overcomes the problem generated by ROS increase by increasing the antioxidant machinery, in which key mechanisms involve glutathione, nuclear factor erythroid 2-related factor 2 (Nrf2), and hypoxia-inducible transcription factor (HIF-1α). These mechanisms could represent optimal targets for innovative therapies. The tumor microenvironment (TME) exerts a key role in HCC pathogenesis and progression. Various metabolic machineries modulate the activity of immune cells in the TME. The deregulated metabolic activity of tumor cells could impair antitumor response. Lactic acid-lactate, derived from the anaerobic glycolytic rate of tumor cells, as well as adenosine, derived from the catabolism of ATP, have an immunosuppressive activity. Metabolic reprogramming of the TME via targeted therapies could enhance the treatment efficacy of anti-cancer immunotherapy. This review describes the metabolic pathways mainly involved in the HCC pathogenesis and progression. The potential targets for HCC treatment involved in these pathways are also discussed.
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Affiliation(s)
- Monica Mossenta
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Davide Busato
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
- Department of Life Sciences, University of Trieste, 34127 Trieste, Italy
| | - Michele Dal Bo
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
| | - Giuseppe Toffoli
- Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, 33081 Aviano (PN), Italy; (M.M.); (D.B.); (G.T.)
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27
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Li CX, Yang XX, Wang HW, Li XC, Ng KTP, Lo CM, Man K. FTY720 Suppresses Liver Tumor Growth and Metastasis by Reducing Circulating Regulating T Cells and Enhancing the Anti-Tumor Effect of Rapamycin. Onco Targets Ther 2020; 13:4743-4754. [PMID: 32547103 PMCID: PMC7262652 DOI: 10.2147/ott.s234394] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2019] [Accepted: 02/25/2020] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND In this study, we aimed to study the effect of FTY720 treatment in reducing circulating Tregs level and then suppressing liver tumor metastasis after hepatectomy and I/R injury in animal models. Furthermore, we also investigated the synergistic anti-tumor effect of FTY720 combined with rapamycin on hepatocellular carcinoma. METHODS The effect of FTY720 on suppressing Tregs mobilization and tumor metastasis after hepatectomy was investigated in an orthotopic liver tumor rat model with hepatectomy and hepatic ischemia/reperfusion (I/R) injury. The synergistic anti-tumor effect of FTY720 combined with rapamycin was further explored both in in vitro functional study and in orthotopic liver tumor mouse model. RESULTS In rat model, hepatic I/R promoted tumor metastasis and increased circulating Tregs after hepatectomy. The treatment of FTY720 reduced liver tumor metastasis and the number of circulating Tregs. Furthermore, FTY720 enhanced the anti-tumor capacity of rapamycin by inhibiting tumor cell proliferation and migration in vitro and reducing tumor growth in vivo through suppressing hepatic stellate cell activation and tumor angiogenesis. CONCLUSION FTY720 suppressed liver tumor growth and metastasis by reducing the population of circulating Tregs and enhancing the anti-tumor effect of rapamycin. It was suggested that FTY720 single or combined with rapamycin might provide novel insight for suppressing tumor growth and metastasis for HCC patients.
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Affiliation(s)
- Chang Xian Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, People’s Republic of China
| | - Xin Xiang Yang
- Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of China
| | - Hong Wei Wang
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, People’s Republic of China
| | - Xiang Cheng Li
- Hepatobiliary Center, The First Affiliated Hospital of Nanjing Medical University, Key Laboratory of Living Donor Liver Transplantation, Nanjing, Jiangsu Province, People’s Republic of China
| | - Kevin Tak-Pan Ng
- Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of China
| | - Chung Mau Lo
- Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of China
| | - Kwan Man
- Department of Surgery, The University of Hong Kong, Hong Kong, People’s Republic of China
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28
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Lei C, Chen J, Li H, Fan T, Zheng X, Wang H, Zhang N, Liu Y, Luo X, Wang J, Wang A. Role of the Mitochondrial Citrate-malate Shuttle in Hras12V-Induced Hepatocarcinogenesis: A Metabolomics-Based Analysis. Metabolites 2020; 10:metabo10050193. [PMID: 32414018 PMCID: PMC7281175 DOI: 10.3390/metabo10050193] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2020] [Accepted: 05/07/2020] [Indexed: 12/15/2022] Open
Abstract
The activation of the Ras signaling pathway is a crucial process in hepatocarcinogenesis. Till now, no reports have scrutinized the role of dynamic metabolic changes in Ras oncogene-induced transition of the normal and precancerous liver cells to hepatocellular carcinoma in vivo. In the current study, we attempted a comprehensive investigation of Hras12V transgenic mice (Ras-Tg) by concatenating nontargeted metabolomics, transcriptomics analysis, and targeted-metabolomics incorporating [U-13C] glucose. A total of 631 peaks were detected, out of which 555 metabolites were screened. Besides, a total of 122 differently expressed metabolites (DEMs) were identified, and they were categorized and subtyped with the help of variation tendency analysis of the normal (W), precancerous (P), and hepatocellular carcinoma (T) liver tissues. Thus, the positive or negative association between metabolites and the hepatocellular carcinoma and Ras oncogene were identified. The bioinformatics analysis elucidated the hepatocarcinogenesis-associated significant metabolic pathways: glycolysis, mitochondrial citrate-malate shuttle, lipid biosynthesis, pentose phosphate pathway (PPP), cholesterol and bile acid biosynthesis, and glutathione metabolism. The key metabolites and enzymes identified in this analysis were further validated. Moreover, we confirmed the PPP, glycolysis, and conversion of pyruvate to cytosol acetyl-CoA by mitochondrial citrate-malate shuttle, in vivo, by incorporating [U-13C] glucose. In summary, the current study presented the comprehensive bioinformatics analysis, depicting the Ras oncogene-induced dynamic metabolite variations in hepatocarcinogenesis. A significant finding of our study was that the mitochondrial citrate-malate shuttle plays a crucial role in detoxification of lactic acid, maintenance of mitochondrial integrity, and enhancement of lipid biosynthesis, which, in turn, promotes hepatocarcinogenesis.
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Affiliation(s)
- Chuanyi Lei
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Jun Chen
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Huiling Li
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Tingting Fan
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Xu Zheng
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Hong Wang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Nan Zhang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Yang Liu
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Xiaoqin Luo
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Jingyu Wang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
| | - Aiguo Wang
- Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian 116044, Liaoning, China
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Pinto Marques H, Gomes da Silva S, De Martin E, Agopian VG, Martins PN. Emerging biomarkers in HCC patients: Current status. Int J Surg 2020; 82S:70-76. [PMID: 32344023 DOI: 10.1016/j.ijsu.2020.04.043] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2020] [Revised: 04/10/2020] [Accepted: 04/16/2020] [Indexed: 12/12/2022]
Abstract
Hepatocellular carcinoma (HCC) is the liver's most common primary malignancy, with over half a million new cases diagnosed each year and being the fourth leading cause of cancer death, worldwide. The poor prognosis of HCC is largely related to late diagnosis. Historically, serum alpha-fetoprotein and diagnostic imaging have been primary diagnostic modalities. However, the poor prognosis due to late diagnosis of HCC has proven unacceptable and, recently, significant efforts have been devoted to identifying patients with early stage HCC. Molecular biomarkers can provide additional and relevant information about the biological behavior of these tumors. Research in biomarker combinations may provide more accurate and valuable information for the future individualized HCC diagnosis and/or prognosis. Several biomarkers with prognostic significance have been identified, however all of them have been studied retrospectively. Furthermore, of all different molecular signatures that have been published, very few have been externally validated. The aim of this review is to analyze the most relevant emerging biomarkers of HCC.
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Affiliation(s)
- Hugo Pinto Marques
- Hepato-Biliary-Pancreatic and Transplantation Center, Curry Cabral Hospital, Lisbon's Central Hospitals and University Center, NOVA Medical School, Lisboa, Portugal
| | - Sílvia Gomes da Silva
- Hepato-Biliary-Pancreatic and Transplantation Center, Curry Cabral Hospital, Lisbon's Central Hospitals and University Center, NOVA Medical School, Lisboa, Portugal.
| | - Eleonora De Martin
- Department of Hepatology, AP-HP Hôpital Paul-Brousse, Centre Hépato- Biliaire, INSERM 1193, Villejuif, France
| | - Vatche G Agopian
- Department of Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
| | - Paulo N Martins
- Department of Surgery, Transplant Division, University of Massachusetts, Worcester, MA, USA
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30
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Murdande SS. Role of rat sarcoma virus mutations in cancer and potential target for cancer therapy. Future Sci OA 2020; 6:FSO455. [PMID: 32257368 PMCID: PMC7117548 DOI: 10.2144/fsoa-2019-0045] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
The prevalence of oncogenic rat sarcoma virus (RAS) mutations has made RAS a popular target for cancer therapies. Significant discoveries have been reported regarding cancer molecular biology following the study of RAS mutations. These discoveries are integral in shaping the era of targeted cancer therapy, with direct targeting of RAS or downstream RAS effectors, such as Grb2 and MAPK a possibility. Novel agents such as farnesyltransferase directly bind and sequester RAS. While these new agents and approaches have shown promise in preclinical and clinical studies, the complexity of RAS signaling and the potential for robust adaptive feedback continue to present substantial challenges. Therefore, the development of targeted therapies will require a detailed understanding of the properties and dependencies of specific cancers to a RAS mutation. This review provides an overview of RAS mutations and their relationship with cancer and discusses their potential as therapeutic targets. The widespread prevalence of cancer has focused research attention on the discovery and development of newer therapies. Significant discoveries regarding genetic mutations have provided new opportunities for development of targeted cancer therapies. In this review, mutations in the rat sarcoma virus protein are discussed along with their potential as targets for drug development.
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Affiliation(s)
- Sanjana S Murdande
- ROSS University School of Medicine, Lloyd Erskine Sandiford Center, St Michael BB11039, Barbados
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31
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Liu H, Zhang L, Wang P. Complement factor H‑related 3 overexpression affects hepatocellular carcinoma proliferation and apoptosis. Mol Med Rep 2019; 20:2694-2702. [PMID: 31524260 PMCID: PMC6691229 DOI: 10.3892/mmr.2019.10514] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2018] [Accepted: 12/07/2018] [Indexed: 12/14/2022] Open
Abstract
Complement factor H‑related 3 (CFHR3) belongs to the human factor H protein family and is associated with various human diseases, including nephropathy, age‑related macular degeneration and atypical hemolytic uremic syndrome. However, to the best of our knowledge, the role of CFHR3 in hepatocellular carcinoma (HCC) remains largely unknown. In the present study, reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis were performed to determine mRNA and protein expression levels of CFHR3 in HCC and normal adjacent tissue. In addition, CFHR3 was overexpressed in Huh‑7 cells and cell counting kit‑8 assay was used to determine cell viability. Cell proliferation and apoptosis were assessed using flow cytometry, RT‑qPCR and western blotting. The results demonstrated that mRNA (2‑ΔΔCq) and protein expression levels of CFHR3 were significantly lower in tumor tissue compared with in adjacent tissue. Additionally, CFHR3 overexpression decreased cell viability, inhibited cell proliferation and significantly increased apoptosis. It was also identified that CFHR3 could downregulate the expression of Ki67. The results suggested that CFHR3 induced apoptosis by downregulating the expression of survivin and B cell lymphoma 2, upregulating the expression of Bcl‑2‑associated X and promoting caspase‑3 activity. Western blotting revealed that CFHR3 significantly inhibited the protein expression levels of phosphorylated (p)‑phosphoinositide 3‑kinase (PI3K), p‑protein kinase B (Akt) and p‑mammalian target of rapamycin (mTOR). Overexpression of CFHR3 suppressed proliferation and promoted apoptosis of HCC cells by inhibiting the PI3K/Akt/mTOR signaling pathway.
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Affiliation(s)
- Hong Liu
- Department of Hepatology, Yantai Infectious Disease Hospital, Yantai, Shandong 264001, P.R. China
| | - Ligang Zhang
- Department of Hepatology, Yantai Infectious Disease Hospital, Yantai, Shandong 264001, P.R. China
| | - Pengyan Wang
- Department of Research and Education, Yantai Infectious Disease Hospital, Yantai, Shandong 264001, P.R. China
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32
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Wang D, Jia W, Wang Z, Wen T, Ding W, Xia F, Zhang L, Wu F, Peng T, Liu B, Zhou C, Zheng Q, Miao X, Peng J, Huang Z, Dou K. Retrospective analysis of sorafenib efficacy and safety in Chinese patients with high recurrence rate of post-hepatic carcinectomy. Onco Targets Ther 2019; 12:5779-5791. [PMID: 31410023 PMCID: PMC6643495 DOI: 10.2147/ott.s168447] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2018] [Accepted: 01/17/2019] [Indexed: 02/05/2023] Open
Abstract
Background: There is no guideline recommendation for preventing hepatocellular carcinoma (HCC) recurrence after hepatic resection. Moreover, an unmet need exists on the effectiveness of sorafenib therapy in recurrent HCC. Purpose: We therefore assessed the efficacy and safety of sorafenib in Chinese HCC patients with high risk of recurrence. Patients and methods: Data were collected retrospectively from 15 Chinese research centers from January 1, 2012 to November 15, 2013, by chart reviews of patients with moderate-advanced HCC who received hepatic carcinectomy. The primary end point was recurrence-free survival rate at 1 year in patients with a high recurrence risk. Secondary end points included 1-year survival rate, time to recurrence and safety assessment. Results: A total of 209 high-risk patients (sorafenib, n=98; control, n=111) who underwent carcinectomy were analyzed. There was no significant difference in the proportion of patients with recurrence-free survival at 1 year between the sorafenib and control (70.43% vs 68.90%: χ2=0.007, P=0.934). One-year survival rate was significantly higher with sorafenib than observed with control (95.5% vs 83.35%; χ2=7.441, P=0.006). Time to recurrence between sorafenib and control groups was similar. Incidences of all the adverse events (AEs) were similar in both the groups and transaminase elevation was most common in both groups (20.37% vs 24.79%). Thrombocytopenia incidence was significantly lower with the sorafenib group than with control (1.85% vs 9.40%; P=0.015). Conclusion: Sorafenib may be considered as a feasible option in the treatment of HCC recurrence.
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Affiliation(s)
- Desheng Wang
- Department of Hepatobiliary Surgery, Xijing Hospital, Shaanxi, China
| | - Weridong Jia
- Department of Hepatobiliary Surgery, Anhui Provincial Hospital, Hefei, China
| | - Zhiming Wang
- Department of Hepatobiliary Surgery, Xiangya Hospital, Changsha, China
| | - Tianfu Wen
- Department of Hepatobiliary Surgery, West China Hospital, Chengdu, China
| | - Wei Ding
- Department of Hepatobiliary Surgery, Cancer Hospital of Xinjiang, Urumqi, China
| | - Feng Xia
- Department of Hepatobiliary Surgery, Southwest Hospital, Chongqing, China
| | - Ling Zhang
- Department of Hepatobiliary Surgery, Cancer Hospital of Henan, Zhengzhou, China
| | - Feixiang Wu
- Department of Hepatobiliary Surgery, Cancer Hospital of Guangxi Medical University, Nanning, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangxi Medical University, Nanning, China
| | - Bin Liu
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Kunming Medical University, Kunming, China
| | - Cuncai Zhou
- Department of Hepatobiliary Surgery, Cancer Hospital of Jiangxi, Nanchang, China
| | - Qichang Zheng
- Department of Hepatobiliary Surgery, Wuhan Union Hospital, Wuhan, China
| | - Xiongying Miao
- Department of Hepatobiliary Surgery, The Second Affiliated Hospital of Xiangya, Changsha, China
| | - Junping Peng
- Department of Hepatopancreatobiliary Surgery, Cancer Hospital of Sichuan, Chengdu, China
| | - Zhiyong Huang
- Department of Hepatobiliary Surgery, Wuhan Tongji Hospital, Wuhan, China
| | - Kefeng Dou
- Department of Hepatobiliary Surgery, Xijing Hospital, Shaanxi, China
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Babiker HM, Karass M, Recio-Boiles A, Chandana SR, McBride A, Mahadevan D. Everolimus for the treatment of advanced pancreatic ductal adenocarcinoma (PDAC). Expert Opin Investig Drugs 2019; 28:583-592. [PMID: 31215251 PMCID: PMC6681663 DOI: 10.1080/13543784.2019.1632289] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2019] [Accepted: 06/12/2019] [Indexed: 02/08/2023]
Abstract
Introduction: PDAC is a lethal malignancy with a clear unmet need; almost all patients fail 1st, 2nd, and 3rd line multi-agent cytotoxic chemotherapy. The mammalian target of rapamycin (mTOR) has been identified as a key signaling node enhancing tumor survival and drug resistance in PDAC; hence, it is considered a promising therapeutic target. Areas covered: We comprehensively reviewed the evidence from preclinical and phase I and II clinical trials, based on the authors'clinical experience and a PubMed, Cochrane library, Embase, and Google Scholar search everolimus + pancreatic cancer. Expert opinion: Everolimus has not demonstrated efficacy in PDAC; however, an mTOR inhibitor in combination with stroma-targeted therapies may be a promising area to explore in clinical trials.
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Affiliation(s)
- Hani M Babiker
- University of Arizona Cancer Center, Early Phase Clinical Trials Program, 1515 N Campbell Ave, Tucson, AZ 85724, USA
| | - Michael Karass
- Westchester Medical Center, New York Medical College, 100 Woods Road, Valhalla, NY 10595, USA
| | - Alejandro Recio-Boiles
- University of Arizona Cancer Center, Early Phase Clinical Trials Program, 1515 N Campbell Ave, Tucson, AZ 85724, USA
| | - Sreenivasa R Chandana
- Phase I Program, START Midwest, 5800 Foremost Drive, SE, Grand Rapids, MI 49546, USA
| | - Ali McBride
- University of Arizona Cancer Center, Department of Pharmacy, 1295 N Martin Ave, Tucson, AZ 85721, USA
| | - Daruka Mahadevan
- University of Arizona Cancer Center, Early Phase Clinical Trials Program, 1515 N Campbell Ave, Tucson, AZ 85724, USA
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Pinyol R, Montal R, Bassaganyas L, Sia D, Takayama T, Chau GY, Mazzaferro V, Roayaie S, Lee HC, Kokudo N, Zhang Z, Torrecilla S, Moeini A, Rodriguez-Carunchio L, Gane E, Verslype C, Croitoru AE, Cillo U, de la Mata M, Lupo L, Strasser S, Park JW, Camps J, Solé M, Thung SN, Villanueva A, Pena C, Meinhardt G, Bruix J, Llovet JM. Molecular predictors of prevention of recurrence in HCC with sorafenib as adjuvant treatment and prognostic factors in the phase 3 STORM trial. Gut 2019; 68:1065-1075. [PMID: 30108162 PMCID: PMC6580745 DOI: 10.1136/gutjnl-2018-316408] [Citation(s) in RCA: 238] [Impact Index Per Article: 39.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Revised: 07/16/2018] [Accepted: 07/16/2018] [Indexed: 12/12/2022]
Abstract
OBJECTIVE Sorafenib is the standard systemic therapy for advanced hepatocellular carcinoma (HCC). Survival benefits of resection/local ablation for early HCC are compromised by 70% 5-year recurrence rates. The phase 3 STORM trial comparing sorafenib with placebo as adjuvant treatment did not achieve its primary endpoint of improving recurrence-free survival (RFS). The biomarker companion study BIOSTORM aims to define (A) predictors of recurrence prevention with sorafenib and (B) prognostic factors with B level of evidence. DESIGN Tumour tissue from 188 patients randomised to receive sorafenib (83) or placebo (105) in the STORM trial was collected. Analyses included gene expression profiling, targeted exome sequencing (19 known oncodrivers), immunohistochemistry (pERK, pVEGFR2, Ki67), fluorescence in situ hybridisation (VEGFA) and immunome. A gene signature capturing improved RFS in sorafenib-treated patients was generated. All 70 RFS events were recurrences, thus time to recurrence equalled RFS. Predictive and prognostic value was assessed using Cox regression models and interaction test. RESULTS BIOSTORM recapitulates clinicopathological characteristics of STORM. None of the biomarkers tested (related to angiogenesis and proliferation) or previously proposed gene signatures, or mutations predicted sorafenib benefit or recurrence. A newly generated 146-gene signature identifying 30% of patients captured benefit to sorafenib in terms of RFS (p of interaction=0.04). These sorafenib RFS responders were significantly enriched in CD4+ T, B and cytolytic natural killer cells, and lacked activated adaptive immune components. Hepatocytic pERK (HR=2.41; p=0.012) and microvascular invasion (HR=2.09; p=0.017) were independent prognostic factors. CONCLUSION In BIOSTORM, only hepatocytic pERK and microvascular invasion predicted poor RFS. No mutation, gene amplification or previously proposed gene signatures predicted sorafenib benefit. A newly generated multigene signature associated with improved RFS on sorafenib warrants further validation. TRIAL REGISTRATION NUMBER NCT00692770.
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MESH Headings
- Adult
- Aged
- Aged, 80 and over
- Angiogenesis Inhibitors/therapeutic use
- Biopsy, Needle
- Carcinoma, Hepatocellular/drug therapy
- Carcinoma, Hepatocellular/mortality
- Carcinoma, Hepatocellular/pathology
- Carcinoma, Hepatocellular/surgery
- Chemotherapy, Adjuvant
- Disease-Free Survival
- Female
- Humans
- Immunohistochemistry
- Liver Neoplasms/drug therapy
- Liver Neoplasms/mortality
- Liver Neoplasms/pathology
- Liver Neoplasms/surgery
- Male
- Middle Aged
- Molecular Targeted Therapy/methods
- Neoplasm Invasiveness/pathology
- Neoplasm Recurrence, Local/mortality
- Neoplasm Recurrence, Local/pathology
- Neoplasm Recurrence, Local/therapy
- Neoplasm Staging
- Predictive Value of Tests
- Prognosis
- Sorafenib/therapeutic use
- Survival Analysis
- Tissue Embedding
- Treatment Outcome
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Affiliation(s)
- Roser Pinyol
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Robert Montal
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Laia Bassaganyas
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Daniela Sia
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Tadatoshi Takayama
- Department of Digestive Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Gar-Yang Chau
- Department of surgery, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Vincenzo Mazzaferro
- Hepatology and Liver Transplantation Unit, Department of Surgery, University of Milan and Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Sasan Roayaie
- Liver Cancer Program, White Plains Hospital, Montefiore Health, New York City, New York, USA
| | - Han Chu Lee
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | | | - Zhongyang Zhang
- Department of Genetics and Genomic Sciences, Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Sara Torrecilla
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Agrin Moeini
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Leonardo Rodriguez-Carunchio
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Edward Gane
- New Zealand Liver Transplant Unit, Auckland City Hospital, Auckland, New Zealand
| | - Chris Verslype
- Department of Hepatology, University Hospital Leuven, Leuven, Belgium
| | | | - Umberto Cillo
- Unità Operativa di Chirurgia Epatobiliare e Trapianto Epatico, Azienda Ospedaliera Università di Padova, Padova, Italy
| | - Manuel de la Mata
- Unit of Hepatology and Liver Transplantation, CIBERehd, IMIBIC, University Hospital Reina Sofia, Cordoba, Spain
| | - Luigi Lupo
- Sezione Chirurgia Generale e Trapianti di Fegato, Policlinico di Bari, Bari, Italy
| | - Simone Strasser
- AW Morrow Gastroenterology and Liver Centre, Royal Prince Alfred Hospital-University of Sydney, Sydney, New South Wales, Australia
| | - Joong-Won Park
- Department of Cancer Control and Population Health, National Cancer Center, Goyang, South Korea
| | - Jordi Camps
- Gastrointestinal and Pancreatic Oncology Group, IDIBAPS-Hospital Clínic, CIBERehd, Barcelona, Spain
| | - Manel Solé
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Swan N Thung
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Augusto Villanueva
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
| | - Carol Pena
- Bayer HealthCare Pharmaceuticals, Whippany, New Jersey, USA
| | | | - Jordi Bruix
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
| | - Josep M Llovet
- BCLC Group, Liver Unit, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS)-Hospital Clínic, CIBERehd, Universitat de Barcelona, Barcelona, Spain
- Mount Sinai Liver Cancer Program (Divisions of Liver Diseases, Department of Hematology/Oncology, Department of Medicine, Department of Pathology, Recanati Miller Transplantation Institute), Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York City, New York, USA
- Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
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Wrighton PJ, Oderberg IM, Goessling W. There Is Something Fishy About Liver Cancer: Zebrafish Models of Hepatocellular Carcinoma. Cell Mol Gastroenterol Hepatol 2019; 8:347-363. [PMID: 31108233 PMCID: PMC6713889 DOI: 10.1016/j.jcmgh.2019.05.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/11/2019] [Revised: 05/03/2019] [Accepted: 05/03/2019] [Indexed: 12/16/2022]
Abstract
The incidence of hepatocellular carcinoma (HCC) and the mortality resulting from HCC are both increasing. Most patients with HCC are diagnosed at advanced stages when curative treatments are impossible. Current drug therapy extends mean overall survival by only a short period of time. Genetic mutations associated with HCC vary widely. Therefore, transgenic and mutant animal models are needed to investigate the molecular effects of specific mutations, classify them as drivers or passengers, and develop targeted treatments. Cirrhosis, however, is the premalignant state common to 90% of HCC patients. Currently, no specific therapies are available to halt or reverse the progression of cirrhosis to HCC. Understanding the genetic drivers of HCC as well as the biochemical, mechanical, hormonal, and metabolic changes associated with cirrhosis could lead to novel treatments and cancer prevention strategies. Although additional therapies recently received Food and Drug Administration approval, significant clinical breakthroughs have not emerged since the introduction of the multikinase inhibitor sorafenib, necessitating alternate research strategies. Zebrafish (Danio rerio) are effective for disease modeling because of their high degree of gene and organ architecture conservation with human beings, ease of transgenesis and mutagenesis, high fecundity, and low housing cost. Here, we review zebrafish models of HCC and identify areas on which to focus future research efforts to maximize the advantages of the zebrafish model system.
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Affiliation(s)
- Paul J Wrighton
- Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Isaac M Oderberg
- Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts
| | - Wolfram Goessling
- Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts; Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts; Broad Institute, Massachusetts Institute of Technology and Harvard, Cambridge, Massachusetts; Division of Health Sciences and Technology, Harvard and Massachusetts Institute of Technology, Boston, Massachusetts; Division of Gastroenterology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
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Yu XN, Chen H, Liu TT, Wu J, Zhu JM, Shen XZ. Targeting the mTOR regulatory network in hepatocellular carcinoma: Are we making headway? Biochim Biophys Acta Rev Cancer 2019; 1871:379-391. [PMID: 30951815 DOI: 10.1016/j.bbcan.2019.03.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2018] [Revised: 03/20/2019] [Accepted: 03/20/2019] [Indexed: 12/24/2022]
Abstract
The mechanistic target of rapamycin (mTOR) pathway coordinates organismal growth and homeostasis in response to growth factors, nutrients, and cellular energy stage. The pathway regulates several major cellular processes and is implicated in various pathological conditions, including hepatocellular carcinoma (HCC). This review summarizes recent advances of the mTOR pathway, highlights the potential of the mTOR pathway as a therapeutic target, and explores clinical trials targeting the mTOR pathway in HCC. Although the review focuses on the mTOR pathway involved in HCC, more comprehensive discussions (eg, developing a rational design for future trials targeting the mTOR pathway) are also applicable to other tumors.
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Affiliation(s)
- Xiang-Nan Yu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Hong Chen
- Department of Endocrinology, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Tao-Tao Liu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China
| | - Jian Wu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China; Department of Medical Microbiology, Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ji-Min Zhu
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China.
| | - Xi-Zhong Shen
- Department of Gastroenterology and Hepatology, Zhongshan Hospital of Fudan University, Shanghai, China; Shanghai Institute of Liver Diseases, Zhongshan Hospital of Fudan University, Shanghai, China; Department of Medical Microbiology, Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Fudan University, Shanghai, China.
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Shen Z, Zhang C, Qu L, Lu C, Xiao M, Ni R, Liu J. MKP-4 suppresses hepatocarcinogenesis by targeting ERK1/2 pathway. Cancer Cell Int 2019; 19:61. [PMID: 30923463 PMCID: PMC6423746 DOI: 10.1186/s12935-019-0776-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 03/08/2019] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND Mitogen-activated protein kinase phosphatases-4 (MKP-4) is reported to exert a prognostic merit in hepatocarcinogenesis. However, the underlying molecular mechanisms have not been clearly defined. METHODS Immunoprecipitation-mass spectrometry (IP-MS) approach was used to identify interactive proteins with MKP-4. Western blot and immunohistochemistry were employed to detect proteins in HCC tissues. Cell counting kit-8, colony formation, Edu incorporation and sphere formation assays were performed to investigate functions of MKP-4/ERK1/2 interaction. Tumor xenografts in nude mice were used to determine effects in vivo. RESULTS Extracellular signal-regulated kinase 1 and 2 (ERK1/2) were identified as binding partners of MKP-4. Knockdown of MKP-4 increased cell proliferation and cancer stem cell (CSC) traits while upregulation of MKP-4 or pre-incubation with ERK1/2 inhibition reversed these effects. Mechanistically MKP-4 negatively regulated phosphorylation of ERK1/2 and reduced expressions of CyclinD1 and c-Myc. Both xenograft tumor models and clinical analysis of HCC patients indicated that lower expression of MKP-4 and higher expressions of ERK1/2 were associated with worse prognosis. CONCLUSIONS MKP-4-mediated dephosphorylation of ERK1/2 might serve as a novel tumor-suppressive mechanism and provide a potential therapy for HCC.
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Affiliation(s)
- Zhongyi Shen
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
- Clinical Medicine Medical College, Nantong University, Nantong, Jiangsu People’s Republic of China
| | - Chengliang Zhang
- Clinical Medicine Medical College, Nantong University, Nantong, Jiangsu People’s Republic of China
| | - Lishuai Qu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
| | - Cuihua Lu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
| | - Mingbing Xiao
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
| | - Runzhou Ni
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
| | - Jinxia Liu
- Department of Gastroenterology, Affiliated Hospital of Nantong University, 20 Xisi Road, Nantong, 226001 Jiangsu People’s Republic of China
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Weeda VB, Aronson DC, Verheij J, Lamers WH. Is hepatocellular carcinoma the same disease in children and adults? Comparison of histology, molecular background, and treatment in pediatric and adult patients. Pediatr Blood Cancer 2019; 66:e27475. [PMID: 30259629 DOI: 10.1002/pbc.27475] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Revised: 08/10/2018] [Accepted: 09/05/2018] [Indexed: 12/11/2022]
Abstract
Pediatric hepatocellular carcinoma (HCC) is rare, resulting in scattered knowledge of tumor biology and molecular background. Thus far, the variant in children has been treated as a different entity from adult HCC. We weigh the hypothesis that HCC in the pediatric and adult groups may be the same entity and may benefit from the same treatment. Although certain differences between adult and pediatric HCC are obvious and certain types of HCC may ask for a customized approach, in conventional HCC, similarities predominate, warranting treatment aiming at common molecular targets in adult and pediatric HCC patients.
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Affiliation(s)
- V B Weeda
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
| | - D C Aronson
- Department of Paediatric Surgery, University Children's Hospital Zürich, Zürich, Switzerland
| | - J Verheij
- Department of Pathology, Academic Medical Center, Amsterdam, The Netherlands
| | - W H Lamers
- Tytgat Institute for Liver and Intestinal Research, Amsterdam, The Netherlands
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Shi JJ, Dang SS. Recent advances in molecular targeted therapy of hepatocellular carcinoma. Shijie Huaren Xiaohua Zazhi 2018; 26:2008-2017. [DOI: 10.11569/wcjd.v26.i34.2008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Juan-Juan Shi
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
| | - Shuang-Suo Dang
- Department of Infectious Diseases, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710004, Shaanxi Province, China
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Au KP, Chok KSH. Multidisciplinary approach for post-liver transplant recurrence of hepatocellular carcinoma: A proposed management algorithm. World J Gastroenterol 2018; 24:5081-5094. [PMID: 30568386 PMCID: PMC6288653 DOI: 10.3748/wjg.v24.i45.5081] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 10/21/2018] [Accepted: 11/07/2018] [Indexed: 02/06/2023] Open
Abstract
A large number of liver transplants have been performed for hepatocellular carcinoma (HCC), and recurrence is increasingly encountered. The recurrence of HCC after liver transplantation is notoriously difficult to manage. We hereby propose multi-disciplinary management with a systematic approach. The patient is jointly managed by the transplant surgeon, physician, oncologist and radiologist. Immunosuppressants should be tapered to the lowest effective dose to protect against rejection. The combination of a mammalian target of rapamycin inhibitor with a reduced calcineurin inhibitor could be considered with close monitoring of graft function and toxicity. Comprehensive staging can be performed by dual-tracer positron emission tomography-computed tomography or the combination of contrast computed tomography and a bone scan. In patients with disseminated recurrence, sorafenib confers survival benefits but is associated with significant drug toxicity. Oligo-recurrence encompasses recurrent disease that is limited in number and location so that loco-regional treatments convey disease control and survival benefits. Intra-hepatic recurrence can be managed with graft resection, but significant operative morbidity is expected. Radiofrequency ablation and stereotactic body radiation therapy (SBRT) are effective alternative strategies. In patients with more advanced hepatic disease, regional treatment with trans-arterial chemoembolization or intra-arterial Yttrium-90 can be considered. For patients with extra-hepatic oligo-recurrence, loco-regional treatment can be considered if practical. Patients with more than one site of recurrence are not always contraindicated for curative treatments. Surgical resection is effective for patients with pulmonary oligo-recurrence, but adequate lung function is a pre-requisite. SBRT is a non-invasive and effective modality that conveys local control to pulmonary and skeletal oligo-recurrences.
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Affiliation(s)
- Kin Pan Au
- Department of Surgery, Queen Mary Hospital, Hong Kong, China
| | - Kenneth Siu Ho Chok
- Department of Surgery and State Key Laboratory for Liver Research, The University of Hong Kong, Hong Kong, China
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The novel PI3K inhibitor S1 synergizes with sorafenib in non-small cell lung cancer cells involving the Akt-S6 signaling. Invest New Drugs 2018; 37:828-836. [PMID: 30456603 DOI: 10.1007/s10637-018-0698-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2018] [Accepted: 11/12/2018] [Indexed: 12/19/2022]
Abstract
Non-small cell lung cancer (NSCLC) has been the major cause of cancer-related deaths worldwide. Targeted therapy has been available as an additive strategy for NSCLC patients, but the inevitable resistance to mono-targeted agents has largely hampered its usage in the clinic. We have previously designed and synthesized a novel small molecule compound S1, 2-methoxy-3-phenylsulfonamino-5-(quinazolin-6-yl) benzamides and demonstrated its inhibition of PI3K and mTOR as well as the anti-tumor potential. In the present study, we have identified that S1 alone or combined with the multi-kinase inhibitor sorafenib can inhibit the in vitro cell proliferation of NSCLC cells (A549, NCI-H157 and 95D cells) and tumor growth in the A549 xenograft model. S1 alone produced inhibitory effects on the colony formation, cell migration and invasion and angiogenesis, with more pronounced inhibition when used with sorafenib. We further revealed that S1 mainly inhibited the Akt/S6 phosphorylation while sorafenib mostly decreased the phosphorylation of ERK. Together, the novel PI3K/mTOR inhibitor S1 per se exhibits strong anti-tumor effects in NSCLC cells and A549 xenograft, effects possibly via its inhibition of cell proliferation, invasion and migration and angiogenesis. The combination of S1 and sorafenib exerts potentiated anti-tumor effects, in which the underlying mechanisms may involve their differential modulation of the phosphorylation of Akt and S6 in the PI3K/Akt/mTOR cascades and ERK phosphorylation in the Raf/MEK/ERK pathways. The combination of S1 and sorafenib could be used as an additive approach in treating NSCLC in the clinic.
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Phospho-ERK is a biomarker of response to a synthetic lethal drug combination of sorafenib and MEK inhibition in liver cancer. J Hepatol 2018; 69:1057-1065. [PMID: 30030148 DOI: 10.1016/j.jhep.2018.07.004] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2018] [Revised: 06/01/2018] [Accepted: 07/05/2018] [Indexed: 12/24/2022]
Abstract
BACKGROUND & AIMS Treatment of liver cancer remains challenging because of a paucity of drugs that target critical dependencies. Sorafenib is a multikinase inhibitor that is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but it only provides limited survival benefit. In this study we aimed to identify potential combination therapies to improve the clinical response to sorafenib. METHODS To investigate the cause of the limited therapeutic effect of sorafenib, we performed a CRISPR-Cas9 based synthetic lethality screen to search for kinases whose knockout synergizes with sorafenib. Synergistic effects of sorafenib and selumetinib on cell apoptosis and phospho-ERK (p-ERK) were analyzed by caspase-3/7 apoptosis assay and western blot, respectively. p-ERK was measured by immunochemical analysis using a tissue microarray containing 78 liver cancer specimens. The in vivo effects of the combination were also measured in two xenograft models. RESULT We found that suppression of ERK2 (MAPK1) sensitizes several liver cancer cell lines to sorafenib. Drugs inhibiting the MEK (MEK1/2 [MAP2K1/2]) or ERK (ERK1/2 [MAPK1/3]) kinases reverse unresponsiveness to sorafenib in vitro and in vivo in a subset of liver cancer cell lines characterized by high levels of active p-ERK, through synergistic inhibition of ERK kinase activity. CONCLUSION Our data provide a combination strategy for treating liver cancer and suggest that tumors with high basal p-ERK levels, which are seen in approximately 30% of liver cancers, are most likely to benefit from such combinatorial treatment. LAY SUMMARY Sorafenib is approved as the standard therapy for patients with advanced hepatocellular carcinoma, but only provides limited survival benefit. Herein, we found that inhibition of the kinase ERK2 increases the response to sorafenib in liver cancer. Our data indicate that a combination of sorafenib and a MEK inhibitor is most likely to be effective in tumors with high basal phospho-ERK levels.
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Xu A, Wang B, Fu J, Qin W, Yu T, Yang Z, Lu Q, Chen J, Chen Y, Wang H. Diet-induced hepatic steatosis activates Ras to promote hepatocarcinogenesis via CPT1α. Cancer Lett 2018; 442:40-52. [PMID: 30401637 DOI: 10.1016/j.canlet.2018.10.024] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2018] [Revised: 10/06/2018] [Accepted: 10/17/2018] [Indexed: 01/22/2023]
Abstract
Aberrant activation of the RAS cascade ubiquitously occurs in human hepatocellular carcinomas (HCC), regardless of rare mutations of RAS. However, the association between the Ras cascade and hepatic steatosis during hepatocarcinogenesis remains under-investigated. Here, the variation in the constitutive activity of Ras signaling and HCC incidence was found in a nonalcoholic fatty liver disease (NAFLD)-HCC mouse model, and Ras activity was induced by hepatic steatosis. Even in hepatocyte-specific expression of KrasG12D (Alb-Cre/KrasG12D, Krashep) mice, mutagenic activation of Ras signaling was still significantly enhanced by NAFLD, with downregulation of negative regulators. Interestingly, hepatic steatosis could be alleviated by persistent activation of Ras, whereas Ras accelerated DNA damage and HCC progression through Carnitine palmitoyltransferase 1A (CPT1α). A close correlation between active Ras and CPT1α was also shown in clinical steatosis peri-tumor tissues of HCC samples and experimental models. CPT1α inhibitor etomoxir (ETO) largely ameliorated active Ras-drived HCC. These findings can provide a novel link between steatosis and Ras activity in liver cancer.
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Affiliation(s)
- An Xu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
| | - Bibo Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Jinling Hospital, School of Medicine, Nanjing University, Nanjing, China
| | - Jing Fu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
| | - Wenhao Qin
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Ting Yu
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; Fuling Central Hospital of Chongqing City, Chongqing, China
| | - Zhishi Yang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
| | - Qingjun Lu
- State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jingyi Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China
| | - Yao Chen
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China.
| | - Hongyang Wang
- International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China; National Center for Liver Cancer, Shanghai, China; Fuling Central Hospital of Chongqing City, Chongqing, China.
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mTOR and ERK regulate VKORC1 expression in both hepatoma cells and hepatocytes which influence blood coagulation. Clin Exp Med 2018; 19:121-132. [PMID: 30306378 DOI: 10.1007/s10238-018-0528-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 09/22/2018] [Indexed: 02/08/2023]
Abstract
Deficiency of γ-glutamyl carboxylation of coagulation factors, as evidenced by the elevated level of Des-γ-carboxyl prothrombin (DCP), is a common feature in hepatocellular carcinoma patients. Additionally, treatment of cancer patients with mTOR inhibitors significantly increases hemorrhagic events. However, the underlying mechanisms remain unknown. In the present study, Vitamin K epoxide reductase complex subunit 1 (VKORC1) was found to be significantly down-regulated in clinical hepatoma tissues and most tested hepatoma cell lines. In vitro investigations showed that VKORC1 expression was promoted by p-mTOR at the translational level and repressed by p-ERK at the transcriptional level. By exploring Hras12V transgenic mice, a hepatic tumor model, VKROC1 was significantly down-regulated in hepatic tumors and showed prolonged activated partial prothrombin time (APTT). In vivo investigations further showed that VKORC1 expression was promoted by p-mTOR and repressed by p-ERK in both hepatoma and hepatocytes. Consistently, APTT and prothrombin time were significantly prolonged under the mTOR inhibitor treatment and significantly shortened under the ERK inhibitor treatment. Conclusively, these findings indicate that mTOR and ERK play crucial roles in controlling VKORC1 expression in both hepatoma and hepatocytes, which provides a valuable molecular basis for preventing hemorrhage in clinical therapies.
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45
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Extracellular matrix collagen I promotes the tumor progression of residual hepatocellular carcinoma after heat treatment. BMC Cancer 2018; 18:901. [PMID: 30227844 PMCID: PMC6145107 DOI: 10.1186/s12885-018-4820-9] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2018] [Accepted: 09/13/2018] [Indexed: 12/29/2022] Open
Abstract
Background Accelerated malignant behaviors induced by insufficient thermal ablation have been increasingly reported, however, the exact mechanisms are still unclear. Here, we investigated the importance of the extracellular matrix (ECM) in modulating the progression of residual hepatocellular carcinoma (HCC) after heat treatment. Methods Heat-exposed residual HCC cells were cultured in different ECM gels. We used basement membrane gel (Matrigel) to simulate the normal microenvironment and collagen I to model the pathological stromal ECM. The alterations of morphology and parameters of proliferation, epithelial-mesenchymal transition (EMT) and stemness were analyzed in vitro and in vivo. Results Increased collagen I deposition was observed at the periablational zone after incomplete RFA of HCC in a xenograft model. The markers of cell proliferation, EMT, motility and progenitor-like traits of heat-exposed residual HCC cells were significantly induced by collagen I as compared to Matrigel (p values all < 0.05). Importantly, collagen I induced the activation of ERK phosphorylation in heat-exposed residual HCC cells. ERK1/2 inhibitor reversed the collagen I-promoted ERK phosphorylation, cell proliferative, protrusive and spindle-like appearance of heat-treated residual HCC cells in vitro. Moreover, collagen I promoted the in vivo tumor progression of heat-exposed residual HCC cells, and sorafenib markedly reversed the collagen I-mediated protumor effects. Conclusions Our findings demonstrate that collagen I could enhance the aggressive progression of residual HCC cells after suboptimal heat treatment and sorafenib may be a treatment approach to thwart this process. Electronic supplementary material The online version of this article (10.1186/s12885-018-4820-9) contains supplementary material, which is available to authorized users.
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Jung DH, Tak E, Hwang S, Song GW, Ahn CS, Kim KH, Moon DB, Ha TY, Park GC, Ryoo BY, Lee KJ, Kim N, Kwon JH, Jwa EK, Lee SG. Antitumor effect of sorafenib and mammalian target of rapamycin inhibitor in liver transplantation recipients with hepatocellular carcinoma recurrence. Liver Transpl 2018; 24:932-945. [PMID: 29710388 DOI: 10.1002/lt.25191] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/31/2017] [Revised: 12/23/2017] [Accepted: 04/13/2018] [Indexed: 12/12/2022]
Abstract
Both sorafenib and mammalian target of rapamycin inhibitor (mTORi) have antitumor effects. This study aimed to evaluate their antitumor effects in liver transplantation (LT) recipients with hepatocellular carcinoma (HCC) recurrence. We performed a laboratory study using sorafenib and mTORi and subsequently validated their survival benefit in a clinical LT setting. In the laboratory study, the HepG2.2.15 liver tumor cell line and 5 patient-derived graft HCC cell lines were used for in vitro cytotoxic studies. After treatment with everolimus and sorafenib, cell viability and apoptosis assays revealed noticeable cytotoxic effects with individual agents and augmented effects by combination therapy. An in vivo mouse study also demonstrated similar cytotoxic outcomes. In the clinical study including 232 LT recipients with HCC recurrence, the 3-month medication drop-out rate was 35.6% for sorafenib administration and 23.5% for mTORi administration. Postrecurrence survival rates were not different according to sorafenib administration (P = 0.17) but were significantly improved following mTORi administration (P < 0.001). In mTORi subgroups with and without sorafenib, there was no difference in the overall postrecurrence patient survival period (P = 0.26), indicating an absence of synergistic or additional antitumor effect from sorafenib. The median progression-free and overall survival period was 6.4 and 11.8 months, respectively, after sorafenib administration. Time of tumor recurrence and use of mTORi were independent risk factors. In conclusion, our laboratory study demonstrated synergistic antitumor effects of sorafenib and mTORi, but this was not reproduced in our clinical LT study. Our clinical result of mTORi administration showed improved postrecurrence survival, thus administering mTORi in LT recipients with HCC recurrence appears worthwhile. However, the antitumor effect of sorafenib on posttransplant recurrence was not determined in this retrospective study, thus requiring further studies with early start of sorafenib administration. Liver Transplantation 24 932-945 2018. © 2018 AASLD.
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Affiliation(s)
- Dong-Hwan Jung
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | - Eunyoung Tak
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Shin Hwang
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | - Gi-Won Song
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | - Chul-Soo Ahn
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | - Ki-Hun Kim
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | - Deok-Bog Moon
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | - Tae-Yong Ha
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | - Gil-Chun Park
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | | | - Kyung Jin Lee
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Nayoung Kim
- Asan Institute of Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jae-Hyeon Kwon
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | - Eun-Kyoung Jwa
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
| | - Sung-Gyu Lee
- Division of Hepatobiliary Surgery and Liver Transplantation, Departments of Surgery
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Treatment with mTOR inhibitors after liver transplantation enables a sustained increase in regulatory T-cells while preserving their suppressive capacity. Clin Res Hepatol Gastroenterol 2018; 42:237-244. [PMID: 29175009 DOI: 10.1016/j.clinre.2017.10.001] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2017] [Revised: 09/26/2017] [Accepted: 10/02/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND The mammalian targets of rapamycin (mTOR) inhibitors (sirolimus [SRL] and everolimus [EVR]) are used after transplantation for their immunosuppressive activity. Regulatory T-cells (Tregs) play a crucial role in immune tolerance. mTOR inhibitors appear to preserve Tregs, unlike Tacrolimus (Tac). AIM The aim of this study was to evaluate the number and function of Tregs in liver transplant recipients before and after conversion from Tac to mTOR inhibitors. METHODS Fifteen patients with stable graft function where converted to SRL (n=5) or EVR (n=10). Tregs (CD4+ CD25+ FoxP3+ CD127low) number and activity were analysed prospectively in blood cells using flow cytometry, and functional assay. RESULTS Patients of both groups displayed a sustained rise in Treg levels after introduction of mTOR inhibitors (Treg levels at 3 months: 6.45±0.38% of CD4 T-cells, vs. baseline level of 3.61±0.37%, P<0.001; mean fold increase 2.04±0.73). In SRL group, 3-month Treg levels were 6.01±0.53 vs. 3.79±0.39; P=0.037, while in EVR group they were 6.63±0.67 vs. 3.54±0.51; P=0.001. By contrast, no statistical change was observed in an unconverted Tac control group. Tregs also preserved their functional ability to suppress activated T-cells. CONCLUSION These results suggest that mTOR inhibitors induce a significant increase in Tregs while maintaining suppressive activity after LT.
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48
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Predicting hepatocellular carcinoma through cross-talk genes identified by risk pathways. Oncotarget 2018; 9:21259-21267. [PMID: 29765536 PMCID: PMC5940387 DOI: 10.18632/oncotarget.24915] [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: 01/19/2017] [Accepted: 11/16/2017] [Indexed: 11/25/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is the most frequent type of liver cancer with poor survival rate and high mortality. Despite efforts on the mechanism of HCC, new molecular markers are needed for exact diagnosis, evaluation and treatment. Here, we combined transcriptome of HCC with networks and pathways to identify reliable molecular markers. Through integrating 249 differentially expressed genes with syncretic protein interaction networks, we constructed a HCC-specific network, from which we further extracted 480 pivotal genes. Based on the cross-talk between the enriched pathways of the pivotal genes, we finally identified a HCC signature of 45 genes, which could accurately distinguish HCC patients with normal individuals and reveal the prognosis of HCC patients. Among these 45 genes, 15 showed dysregulated expression patterns and a part have been reported to be associated with HCC and/or other cancers. These findings suggested that our identified 45 gene signature could be potential and valuable molecular markers for diagnosis and evaluation of HCC.
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Hepatitis C Virus core+1/ARF Protein Modulates the Cyclin D1/pRb Pathway and Promotes Carcinogenesis. J Virol 2018; 92:JVI.02036-17. [PMID: 29444947 DOI: 10.1128/jvi.02036-17] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2017] [Accepted: 02/06/2018] [Indexed: 02/06/2023] Open
Abstract
Viruses often encompass overlapping reading frames and unconventional translation mechanisms in order to maximize the output from a minimum genome and to orchestrate their timely gene expression. Hepatitis C virus (HCV) possesses such an unconventional open reading frame (ORF) within the core-coding region, encoding an additional protein, initially designated ARFP, F, or core+1. Two predominant isoforms of core+1/ARFP have been reported, core+1/L, initiating from codon 26, and core+1/S, initiating from codons 85/87 of the polyprotein coding region. The biological significance of core+1/ARFP expression remains elusive. The aim of the present study was to gain insight into the functional and pathological properties of core+1/ARFP through its interaction with the host cell, combining in vitro and in vivo approaches. Our data provide strong evidence that the core+1/ARFP of HCV-1a stimulates cell proliferation in Huh7-based cell lines expressing either core+1/S or core+1/L isoforms and in transgenic liver disease mouse models expressing core+1/S protein in a liver-specific manner. Both isoforms of core+1/ARFP increase the levels of cyclin D1 and phosphorylated Rb, thus promoting the cell cycle. In addition, core+1/S was found to enhance liver regeneration and oncogenesis in transgenic mice. The induction of the cell cycle together with increased mRNA levels of cell proliferation-related oncogenes in cells expressing the core+1/ARFP proteins argue for an oncogenic potential of these proteins and an important role in HCV-associated pathogenesis.IMPORTANCE This study sheds light on the biological importance of a unique HCV protein. We show here that core+1/ARFP of HCV-1a interacts with the host machinery, leading to acceleration of the cell cycle and enhancement of liver carcinogenesis. This pathological mechanism(s) may complement the action of other viral proteins with oncogenic properties, leading to the development of hepatocellular carcinoma. In addition, given that immunological responses to core+1/ARFP have been correlated with liver disease severity in chronic HCV patients, we expect that the present work will assist in clarifying the pathophysiological relevance of this protein as a biomarker of disease progression.
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50
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Okajima W, Komatsu S, Ichikawa D, Miyamae M, Kawaguchi T, Hirajima S, Ohashi T, Imamura T, Kiuchi J, Arita T, Konishi H, Shiozaki A, Moriumura R, Ikoma H, Okamoto K, Taniguchi H, Itoh Y, Otsuji E. Circulating microRNA profiles in plasma: identification of miR-224 as a novel diagnostic biomarker in hepatocellular carcinoma independent of hepatic function. Oncotarget 2018; 7:53820-53836. [PMID: 27462777 PMCID: PMC5288224 DOI: 10.18632/oncotarget.10781] [Citation(s) in RCA: 49] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2016] [Accepted: 07/09/2016] [Indexed: 12/21/2022] Open
Abstract
Aims This study was designed to identify novel microRNAs (miRNAs) in plasma for detecting and monitoring hepatocellular carcinoma (HCC), independent of hepatic function and background liver diseases with different etiologies. Results (1) Four oncogenic miRNAs (miR-151, 155, 191 and 224) with high expression in HCC tissues were selected as candidates. (2) Quantitative RT-PCR using plasma samples from 107 HCC patients and 75 healthy volunteers revealed a significantly higher level of plasma miR-224 in HCC patients than in healthy volunteers according to a small-scale analysis (P < 0.0001), two independent large-scale cohort analysis (P < 0.0001, AUC 0.908). (3) miR-224 expression was significantly higher in HCC tissues and HCC cell lines than in normal hepatic tissues and fibroblasts, respectively. (P = 0.0011, 0.0150) (4) Plasma miR-224 reflected tumor dynamics; preoperative plasma levels of miR-224 were significantly reduced in postoperative samples (P = 0.0058), and plasma miR-224 levels were significantly correlated with paired miR-224 levels in HCC tissues (P = 0.0005). (5) Furthermore, plasma miR-224 levels significantly discriminated HCC patients from patients with chronic liver disease (P = 0.0008). A high plasma miR-224 level was significantly correlated with larger tumor size (P = 0.0005) and recurrences (P = 0.0027). The plasma miR-224 level could accurately detect small tumors less than 18 mm preoperatively. Methods We performed a systematic review of the NCBI database and selected candidate miRNAs reported as highly expressed in HCC tissue. Conclusions Plasma miR-224 may be a sensitive biomarker for screening HCC and monitoring tumor dynamics.
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Affiliation(s)
- Wataru Okajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shuhei Komatsu
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Daisuke Ichikawa
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Mahito Miyamae
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tsutomu Kawaguchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Shoji Hirajima
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Takuma Ohashi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Taisuke Imamura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Jun Kiuchi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Tomohiro Arita
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hirotaka Konishi
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Atsushi Shiozaki
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Ryo Moriumura
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hisashi Ikoma
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Kazuma Okamoto
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Hiroki Taniguchi
- Department of Surgery, Kyoto Second Red Cross Hospital, Haruobicho, Kamigyo-ku, 602-8026, Kyoto, Japan
| | - Yoshito Itoh
- Department of Molecular Gastroenterology and Hepatology, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
| | - Eigo Otsuji
- Division of Digestive Surgery, Department of Surgery, Kyoto Prefectural University of Medicine, Kawaramachihirokoji, Kamigyo-ku, Kyoto, 602-8566, Japan
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