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Zhang J, Dong C, Chen Z, Hua R, Li Z, Lin Y, Wang Y, Feng T, Dai J. Hedgehog pathway inhibitor HhAntag suppresses virus infection via the GLI-S1PR axis. Cell Signal 2025; 132:111807. [PMID: 40239727 DOI: 10.1016/j.cellsig.2025.111807] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2024] [Revised: 03/23/2025] [Accepted: 04/11/2025] [Indexed: 04/18/2025]
Abstract
The interplay between various signaling pathways, including tumor development, immune response, and viral infection, suggests potential mutual regulation within biological systems. To explore this, we screened 85 inhibitors targeting the Notch, Hedgehog, and Wnt signaling pathways to identify the potential antiviral candidates. Using two reporter viruses (VSV-GFP and DENV-Luc), we identified novel inhibitors with antiviral properties. Notably, the Hedgehog pathway inhibitor HhAntag exhibited broad-spectrum antiviral activity, significantly reducing the replication of viruses such as VSV, DENV, ZIKV, and SFTSV. The inhibitory effects of HhAntag were consistent with the downregulation of its target protein, GLI1; while overexpression of GLI1 promoted viral infection. HhAntag did not interfere with viral attachment, entry, or early transcription but specifically inhibited viral protein translation. Additionally, RNA-seq analysis revealed reduced expression of sphingosine-1-phosphate (S1P) signaling pathway receptors, S1PR1 and S1PR5, following HhAntag treatment. HhAntag suppresses virus infection via the GLI-S1PR axis. This study revealed the interplay between tumor-associated Hedgehog (Hh) pathway and viral infection and highlights the potential of HhAntag as a broad-spectrum antiviral drug.
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Affiliation(s)
- Jinyu Zhang
- Jiangsu Key Laboratory of Infection and Immunity, Children's Hospital of Soochow University, Institute of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China; Central Laboratory, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Chunsheng Dong
- Jiangsu Key Laboratory of Infection and Immunity, Children's Hospital of Soochow University, Institute of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Zhiqiang Chen
- Department of Nuclear Medicine, The First Affiliated Hospital of Soochow University, Suzhou 215006, China
| | - Runbin Hua
- Jiangsu Key Laboratory of Infection and Immunity, Children's Hospital of Soochow University, Institute of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China
| | - Zhuozheng Li
- School of Life Science and Technology, Shandong Second Medical University, Weifang 261053, China
| | - Yuzhuo Lin
- The Second Clinical Medical School of Nanjing Medical University, Nanjing 211166, China
| | - Yuqing Wang
- Department of Respiratory Medicine, Children's Hospital of Soochow University, Suzhou 215000, China.
| | - Tingting Feng
- Central Laboratory, The Fourth Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
| | - Jianfeng Dai
- Jiangsu Key Laboratory of Infection and Immunity, Children's Hospital of Soochow University, Institute of Biology and Medical Sciences, Suzhou Medical College of Soochow University, Suzhou 215123, China; MOE Key Laboratory of Geriatric Diseases and Immunology, Suzhou Medical College of Soochow University, Suzhou 215123, China.
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Jiang D, Qian Y, Gu YJ, Wang R, Yu H, Dong H, Chen DY, Chen Y, Jiang HZ, Tan BB, Peng M, Li YR. Predicting hepatocellular carcinoma: A new non-invasive model based on shear wave elastography. World J Gastroenterol 2024; 30:3166-3178. [PMID: 39006386 PMCID: PMC11238667 DOI: 10.3748/wjg.v30.i25.3166] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 05/22/2024] [Accepted: 05/27/2024] [Indexed: 07/01/2024] Open
Abstract
BACKGROUND Integrating conventional ultrasound features with 2D shear wave elastography (2D-SWE) can potentially enhance preoperative hepatocellular carcinoma (HCC) predictions. AIM To develop a 2D-SWE-based predictive model for preoperative identification of HCC. METHODS A retrospective analysis of 884 patients who underwent liver resection and pathology evaluation from February 2021 to August 2023 was conducted at the Oriental Hepatobiliary Surgery Hospital. The patients were divided into the modeling group (n = 720) and the control group (n = 164). The study included conventional ultrasound, 2D-SWE, and preoperative laboratory tests. Multiple logistic regression was used to identify independent predictive factors for malignant liver lesions, which were then depicted as nomograms. RESULTS In the modeling group analysis, maximal elasticity (Emax) of tumors and their peripheries, platelet count, cirrhosis, and blood flow were independent risk indicators for malignancies. These factors yielded an area under the curve of 0.77 (95% confidence interval: 0.73-0.81) with 84% sensitivity and 61% specificity. The model demonstrated good calibration in both the construction and validation cohorts, as shown by the calibration graph and Hosmer-Lemeshow test (P = 0.683 and P = 0.658, respectively). Additionally, the mean elasticity (Emean) of the tumor periphery was identified as a risk factor for microvascular invasion (MVI) in malignant liver tumors (P = 0.003). Patients receiving antiviral treatment differed significantly in platelet count (P = 0.002), Emax of tumors (P = 0.033), Emean of tumors (P = 0.042), Emax at tumor periphery (P < 0.001), and Emean at tumor periphery (P = 0.003). CONCLUSION 2D-SWE's hardness value serves as a valuable marker for enhancing the preoperative diagnosis of malignant liver lesions, correlating significantly with MVI and antiviral treatment efficacy.
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Affiliation(s)
- Dong Jiang
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Yi Qian
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Yi-Jun Gu
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Ru Wang
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Hua Yu
- Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Hui Dong
- Department of Pathology, Shanghai Eastern Hepatobiliary Surgery Hospital, Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Dong-Yu Chen
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Yan Chen
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Hao-Zheng Jiang
- Department of College of Art and Science, Case Western Reserve University, Cleveland, OH 44106, United States
| | - Bi-Bo Tan
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
| | - Min Peng
- Ultrasound Diagnosis, PLA Naval Medical Center, Shanghai 200437, China
| | - Yi-Ran Li
- Department of Ultrasound, Eastern Hepatobiliary Surgery Hospital, The Third Affiliated Hospital of Naval Medical University, Shanghai 200433, China
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3
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Li J, Vranjkovic A, Read D, Delaney SP, Stanford WL, Cooper CL, Crawley AM. Lasting differential gene expression of circulating CD8 T cells in chronic HCV infection with cirrhosis identifies a role for Hedgehog signaling in cellular hyperfunction. Front Immunol 2024; 15:1375485. [PMID: 38887299 PMCID: PMC11180750 DOI: 10.3389/fimmu.2024.1375485] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2024] [Accepted: 04/19/2024] [Indexed: 06/20/2024] Open
Abstract
Background The impact of chronic hepatic infection on antigen non-specific immune cells in circulation remains poorly understood. We reported lasting global hyperfunction of peripheral CD8 T cells in HCV-infected individuals with cirrhosis. Whether gene expression patterns in bulk CD8 T cells are associated with the severity of liver fibrosis in HCV infection is not known. Methods RNA sequencing of blood CD8 T cells from treatment naïve, HCV-infected individuals with minimal (Metavir F0-1 ≤ 7.0 kPa) or advanced fibrosis or cirrhosis (F4 ≥ 12.5 kPa), before and after direct-acting antiviral therapy, was performed. CD8 T cell function was assessed by flow cytometry. Results In CD8 T cells from pre-DAA patients with advanced compared to minimal fibrosis, Gene Ontology analysis and Gene Set Enrichment Analysis identified differential gene expression related to cellular function and metabolism, including upregulated Hedgehog (Hh) signaling, IFN-α, -γ, TGF-β response genes, apoptosis, apical surface pathways, phospholipase signaling, phosphatidyl-choline/inositol activity, and second-messenger-mediated signaling. In contrast, genes in pathways associated with nuclear processes, RNA transport, cytoskeletal dynamics, cMyc/E2F regulation, oxidative phosphorylation, and mTOR signaling, were reduced. Hh signaling pathway was the top featured gene set upregulated in cirrhotics, wherein hallmark genes GLI1 and PTCH1 ranked highly. Inhibition of Smo-dependent Hh signaling ablated the expression of IFN-γ and perforin in stimulated CD8 T cells from chronic HCV-infected patients with advanced compared to minimal fibrosis. CD8 T cell gene expression profiles post-DAA remained clustered with pre-DAA profiles and disparately between advanced and minimal fibrosis, suggesting a persistent perturbation of gene expression long after viral clearance. Conclusions This analysis of bulk CD8 T cell gene expression in chronic HCV infection suggests considerable reprogramming of the CD8 T cell pool in the cirrhotic state. Increased Hh signaling in cirrhosis may contribute to generalized CD8 T cell hyperfunction observed in chronic HCV infection. Understanding the lasting nature of immune cell dysfunction may help mitigate remaining clinical challenges after HCV clearance and more generally, improve long term outcomes for individuals with severe liver disease.
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Affiliation(s)
- Jiafeng Li
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
| | - Agatha Vranjkovic
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Daniel Read
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
| | - Sean P. Delaney
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
| | - William L. Stanford
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
| | - Curtis L. Cooper
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Division of Infectious Diseases, The Ottawa Hospital, Ottawa, ON, Canada
- School of Epidemiology and Public Health, University of Ottawa, Ottawa, ON, Canada
- Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
| | - Angela M. Crawley
- Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, ON, Canada
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Centre for Infection, Immunity and Inflammation, University of Ottawa, Ottawa, ON, Canada
- Department of Biology and Institute of Biochemistry, Carleton University, Ottawa, ON, Canada
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Jeng KS, Chang CF, Tsang YM, Sheen IS, Jeng CJ. Reappraisal of the Roles of the Sonic Hedgehog Signaling Pathway in Hepatocellular Carcinoma. Cancers (Basel) 2024; 16:1739. [PMID: 38730691 PMCID: PMC11083695 DOI: 10.3390/cancers16091739] [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: 04/05/2024] [Revised: 04/24/2024] [Accepted: 04/25/2024] [Indexed: 05/13/2024] Open
Abstract
HCC remains one of the leading causes of cancer-related death globally. The main challenges in treatments of hepatocellular carcinoma (HCC) primarily arise from high rates of postoperative recurrence and the limited efficacy in treating advanced-stage patients. Various signaling pathways involved in HCC have been reported. Among them, the Sonic hedgehog (SHH) signaling pathway is crucial. The presence of SHH ligands is identified in approximately 60% of HCC tumor tissues, including tumor nests. PTCH-1 and GLI-1 are detected in more than half of HCC tissues, while GLI-2 is found in over 84% of HCC tissues. The SHH signaling pathway (including canonical and non-canonical) is involved in different aspects of HCC, including hepatocarcinogenesis, tumor growth, tumor invasiveness, progression, and migration. The SHH signaling pathway also contributes to recurrence, metastasis, modulation of the cancer microenvironment, and sustaining cancer stem cells. It also affects the resistance of HCC cells to chemotherapy, target therapy, and radiotherapy. Reappraisal of the roles of the SHH signaling pathway in HCC may trigger some novel therapies for HCC.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of Surgery, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan
| | - Chiung-Fang Chang
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan;
| | - Yuk-Ming Tsang
- Department of Imaging Medicine, Far Eastern Memorial Hospital, New Taipei City 220, Taiwan;
| | - I-Shyan Sheen
- Department of Gastroenterology & Hepatology, Linkou Chang Memorial Hospital, Chang Gung Medical Foundation, Taoyuan City 333, Taiwan;
| | - Chi-Juei Jeng
- Graduate Institude of Clinical Medicine, National Taiwan University, College of Medicine, Taipei City 10617, Taiwan;
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Ahmad A, Tiwari RK, Siddiqui S, Chadha M, Shukla R, Srivastava V. Emerging trends in gastrointestinal cancers: Targeting developmental pathways in carcinogenesis and tumor progression. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2024; 385:41-99. [PMID: 38663962 DOI: 10.1016/bs.ircmb.2023.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/25/2024]
Abstract
Gastrointestinal carcinomas are a group of cancers associated with the digestive system and its accessory organs. The most prevalent cancers related to the gastrointestinal tract are colorectal, gall bladder, gastric, hepatocellular, and esophageal cancers, respectively. Molecular aberrations in different signaling pathways, such as signal transduction systems or developmental pathways are the chief triggering mechanisms in different cancers Though a massive advancement in diagnostic and therapeutic interventions results in improved survival of patients with gastrointestinal cancer; the lower malignancy stages of these carcinomas are comparatively asymptomatic. Various gastrointestinal-related cancers are detected at advanced stages, leading to deplorable prognoses and increased rates of recurrence. Recent molecular studies have elucidated the imperative roles of several signaling pathways, namely Wnt, Hedgehog, and Notch signaling pathways, play in the progression, therapeutic responsiveness, and metastasis of gastrointestinal-related cancers. This book chapter gives an interesting update on recent findings on the involvement of developmental signaling pathways their mechanistic insight in gastrointestinalcancer. Subsequently, evidences supporting the exploration of gastrointestinal cancer related molecular mechanisms have also been discussed for developing novel therapeutic strategies against these debilitating carcinomas.
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Affiliation(s)
- Afza Ahmad
- Department of Biosciences, Integral University, Lucknow, Uttar Pradesh, India
| | - Rohit Kumar Tiwari
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Saleha Siddiqui
- Department of Biotechnology, Delhi Technological University, Delhi, India
| | - Muskan Chadha
- Department of Nutrition and Dietetics, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Ratnakar Shukla
- Department of Clinical Research, Sharda School of Allied Health Sciences, Sharda University, Greater Noida, Uttar Pradesh, India
| | - Vivek Srivastava
- Department of Chemistry & Biochemistry, Sharda School of Basic Sciences & Research, Sharda University, Greater Noida, Uttar Pradesh, India.
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6
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Salem GA, Mohamed AAR, Khater SI, Noreldin AE, Alosaimi M, Alansari WS, Shamlan G, Eskandrani AA, Awad MM, El-Shaer RAA, Nassan MA, Mostafa M, Khamis T. Enhancement of biochemical and genomic pathways through lycopene-loaded nano-liposomes: Alleviating insulin resistance, hepatic steatosis, and autophagy in obese rats with non-alcoholic fatty liver disease: Involvement of SMO, GLI-1, and PTCH-1 genes. Gene 2023; 883:147670. [PMID: 37516284 DOI: 10.1016/j.gene.2023.147670] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 07/11/2023] [Accepted: 07/25/2023] [Indexed: 07/31/2023]
Abstract
Non-alcoholic fatty liver (NAFL) is a prevalent hepatic disorder of global significance that can give rise to severe complications. This research endeavor delves into the potential of nano-liposomal formulated Lycopene (Lip-Lyco) in averting the development of obesity and insulin resistance, both of which are major underlying factors contributing to NAFL. The investigation further scrutinizes the impact of Lip-Lyco on intricate cellular pathways within the liver tissue of rats induced with NAFL, specifically focusing on the progression of steatosis and fibrosis. To establish an obesity-NAFL model, twenty rats were subjected to a high-fat diet (HFD) for a duration of twelve weeks, after which they received an oral treatment of Lip-Lyco (10mg/kg) for an additional eight weeks. Another group of sixteen non-obese rats were subjected to treatment with or without Lip-Lyco, serving as a control for comparison. Results: The rats on a hypercaloric diet had high body mass index (BMI) and insulin resistance, reflected in disturbed serum adipokines and lipid profiles. Oxidative stress, inflammation, and apoptosis were evident in hepatic tissue, and the autophagic process in hepatocytes was inhibited. Additionally, the hedgehog pathway was activated in the liver tissue of NAFL group. Lip-Lyco was found to counteract all these aspects of NAFL pathogenesis. Lip-Lyco exhibited antioxidant, anti-inflammatory, hypoglycemic, antiapoptotic, autophagy-inducing, and Hedgehog signaling inhibitory effects. This study concludes that Lip-Lyco, a natural compound, has promising therapeutic potential in combating NAFLdisease. However, more experimental and clinical studies are required to confirm the effectiveness of lycopene in treating NAFLdisease.
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Affiliation(s)
- Gamal A Salem
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44511 Zagazig, Egypt
| | - Amany Abdel-Rahman Mohamed
- Department of Forensic Medicine and Toxicology, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt.
| | - Safaa I Khater
- Department of Biochemistry, Faculty of Veterinary Medicine, Zagazig University, Zagazig 44511, Egypt
| | - Ahmed E Noreldin
- Department of Histology and Cytology, Faculty of Veterinary Medicine, Damanhour University, Damanhour 22511, Egypt
| | - Manal Alosaimi
- Department of Basic Medical Sciences, College of Medicine, Princess Nourah bint Abdulrahman University, Riyadh 11671, Saudi Arabia
| | - Wafa S Alansari
- Biochemistry Department, Faculty of Science, University of Jeddah, Jeddah 21577, Saudi Arabia
| | - Ghalia Shamlan
- Department of Food Science and Nutrition, College of Food and Agriculture Sciences, King Saud University, Riyadh 11362, Saudi Arabia
| | - Areej A Eskandrani
- Chemistry Department, College of Science, Taibah University, Medina 30002, Saudi Arabia
| | - Marwa Mahmoud Awad
- Physiology Department, Faculty of Medicine, Tanta University, Tanta 31527, Egypt
| | | | - Mohamed A Nassan
- Department of Clinical Laboratory Sciences, Turabah University College, Taif University, PO Box 11099, Taif 21944, Saudi Arabia
| | - Mahmoud Mostafa
- Department of Pharmaceutics, Faculty of Pharmacy, Minia University, Minia 61519, Egypt
| | - Tarek Khamis
- Department of Pharmacology, Faculty of Veterinary Medicine, Zagazig University, 44511 Zagazig, Egypt; Laboratory of Biotechnology, Faculty of Veterinary Medicine, Zagazig University, 44519 Zagazig, Egypt
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Cierpikowski P, Leszczyszyn A, Bar J. The Role of Hedgehog Signaling Pathway in Head and Neck Squamous Cell Carcinoma. Cells 2023; 12:2083. [PMID: 37626893 PMCID: PMC10453169 DOI: 10.3390/cells12162083] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2023] [Revised: 08/12/2023] [Accepted: 08/15/2023] [Indexed: 08/27/2023] Open
Abstract
Head and neck squamous cell carcinoma (HNSCC) is the sixth leading malignancy worldwide, with a poor prognosis and limited treatment options. Molecularly targeted therapies for HNSCC are still lacking. However, recent reports provide novel insights about many molecular alterations in HNSCC that may be useful in future therapies. Therefore, it is necessary to identify new biomarkers that may provide a better prediction of the disease and promising targets for personalized therapy. The poor response of HNSCC to therapy is attributed to a small population of tumor cells called cancer stem cells (CSCs). Growing evidence indicates that the Hedgehog (HH) signaling pathway plays a crucial role in the development and maintenance of head and neck tissues. The HH pathway is normally involved in embryogenesis, stem cell renewal, and tissue regeneration. However, abnormal activation of the HH pathway is also associated with carcinogenesis and CSC regulation. Overactivation of the HH pathway was observed in several tumors, including basal cell carcinoma, that are successfully treated with HH inhibitors. However, clinical studies about HH pathways in HNSCC are still rare. In this review, we summarize the current knowledge and recent advances regarding the HH pathway in HNSCC and discuss its possible implications for prognosis and future therapy.
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Affiliation(s)
- Piotr Cierpikowski
- Department of Maxillofacial Surgery, The Ludwik Rydygier Specialist Hospital, Osiedle Zlotej Jesieni 1, 31-826 Krakow, Poland
| | - Anna Leszczyszyn
- Dental Surgery Outpatient Clinic, 4th Military Clinical Hospital, Weigla 5, 53-114 Wroclaw, Poland;
| | - Julia Bar
- Department of Immunopathology and Molecular Biology, Wroclaw Medical University, Bujwida 44, 50-345 Wroclaw, Poland
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Chowdhary S, Deka R, Panda K, Kumar R, Solomon AD, Das J, Kanoujiya S, Gupta AK, Sinha S, Ruokolainen J, Kesari KK, Gupta PK. Recent Updates on Viral Oncogenesis: Available Preventive and Therapeutic Entities. Mol Pharm 2023; 20:3698-3740. [PMID: 37486263 PMCID: PMC10410670 DOI: 10.1021/acs.molpharmaceut.2c01080] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 06/13/2023] [Accepted: 06/14/2023] [Indexed: 07/25/2023]
Abstract
Human viral oncogenesis is a complex phenomenon and a major contributor to the global cancer burden. Several recent findings revealed cellular and molecular pathways that promote the development and initiation of malignancy when viruses cause an infection. Even, antiviral treatment has become an approach to eliminate the viral infections and prevent the activation of oncogenesis. Therefore, for a better understanding, the molecular pathogenesis of various oncogenic viruses like, hepatitis virus, human immunodeficiency viral (HIV), human papillomavirus (HPV), herpes simplex virus (HSV), and Epstein-Barr virus (EBV), could be explored, especially, to expand many potent antivirals that may escalate the apoptosis of infected malignant cells while sparing normal and healthy ones. Moreover, contemporary therapies, such as engineered antibodies antiviral agents targeting signaling pathways and cell biomarkers, could inhibit viral oncogenesis. This review elaborates the recent advancements in both natural and synthetic antivirals to control viral oncogenesis. The study also highlights the challenges and future perspectives of using antivirals in viral oncogenesis.
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Affiliation(s)
- Shivam Chowdhary
- Department
of Industrial Microbiology, Sam Higginbottom
University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh India
| | - Rahul Deka
- Department
of Bioengineering and Biotechnology, Birla
Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India
| | - Kingshuk Panda
- Department
of Applied Microbiology, Vellore Institute
of Technology, Vellore 632014, Tamil Nadu, India
| | - Rohit Kumar
- Department
of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
| | - Abhishikt David Solomon
- Department
of Molecular & Cellular Engineering, Sam Higginbottom University of Agriculture, Technology and Sciences, Prayagraj 211007, Uttar Pradesh, India
| | - Jimli Das
- Centre
for
Biotechnology and Bioinformatics, Dibrugarh
University, Assam 786004, India
| | - Supriya Kanoujiya
- School
of
Biotechnology, Jawaharlal Nehru University, New Delhi 110067, India
| | - Ashish Kumar Gupta
- Department
of Biophysics, All India Institute of Medical
Sciences, New Delhi 110029, India
| | - Somya Sinha
- Department
of Biotechnology, Graphic Era Deemed to
Be University, Dehradun 248002, Uttarakhand, India
| | - Janne Ruokolainen
- Department
of Applied Physics, School of Science, Aalto
University, 02150 Espoo, Finland
| | - Kavindra Kumar Kesari
- Department
of Applied Physics, School of Science, Aalto
University, 02150 Espoo, Finland
- Division
of Research and Development, Lovely Professional
University, Phagwara 144411, Punjab, India
| | - Piyush Kumar Gupta
- Department
of Life Sciences, Sharda School of Basic Sciences and Research, Sharda University, Greater Noida 201310, Uttar Pradesh, India
- Department
of Biotechnology, Graphic Era Deemed to
Be University, Dehradun 248002, Uttarakhand, India
- Faculty
of Health and Life Sciences, INTI International
University, Nilai 71800, Malaysia
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9
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Hu Y, He X, Zhou X, Liang Y, Fu Y, Zhang L, Fang J, Liu W, Chen G, Mu Y, Zhang H, Cai H, Liu C, Liu P, Chen J. Gypenosides ameliorate ductular reaction and liver fibrosis via inhibition of hedgehog signaling. Front Pharmacol 2022; 13:1033103. [PMID: 36483737 PMCID: PMC9722742 DOI: 10.3389/fphar.2022.1033103] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2022] [Accepted: 11/09/2022] [Indexed: 08/30/2023] Open
Abstract
Backgroud and aims: Ductular reaction (DR) is a common pathological change and thought to have a key role in the pathogenesis and progression of liver fibrosis. Our previous study reported Gypenosides (GPs) ameliorated liver fibrosis, however, the anti-fibrotic mechanisms of GPs are still unclear. Methods: Liver fibrosis was induced in rats by carbon tetrachloride combining with 2-acerylaminofluorene (CCl4/2-AAF), and Mdr2 knockout (Mdr2 -/-) mice to evaluate the anti-fibrotic role of GPs. In vitro, WB-F344 cells, a hepatic progenitor cells (HPCs) line, with or without Gli1 overexpressing lentiviral vectors, were induced by sodium butyrate (SB) to validate the mechanism of GPs and NPLC0393, the main ingredient of GPs. Results: Both in CCl4/2-AAF-treated rats and Mdr2 -/- mice, GPs obviously reduced the deposition of collagen and hydroxyproline content, inhibited the activation of hepatic stellate cells and inflammatory cell infiltration. Notably, GPs reduced the expressions of Epcam, CK19, CK7, Dhh, Smo, Ptch2, Gli1 and Gli2. Furthermore, CK19+ cells co-expressed Gli1, while the number of CK19+/Gli1+ cells was decreased by GPs. In vitro, GPs and NPLC0393 inhibited the differentiation of WB-F344 cells toward a biliary phenotype. Mechanistically, GPs and NPLC0393 protected against DR by inhibiting hedgehog signaling, which was supported by the results that DR, triggered directly by Gli1 overexpressing lentiviral vector was blocked by administration with GPs or NPLC0393. Conclusion: GPs attenuated DR and liver fibrosis by inhibiting hedgehog signaling, which provided more evidences and a novel mechanism of anti-fibrotic effect of GPs.
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Affiliation(s)
- Yonghong Hu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Xiaoli He
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Xiaoxi Zhou
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Yue Liang
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Yadong Fu
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Linzhang Zhang
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jing Fang
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Wei Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Gaofeng Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Yongping Mu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Hua Zhang
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Hong Cai
- Xiamen Hospital of Traditional Chinese Medicine, Xiamen, Fujian, China
| | - Chenghai Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
| | - Ping Liu
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiamei Chen
- Institute of Liver Diseases, Key Laboratory of Liver and Kidney Diseases (Ministry of Education), Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai, China
- Shanghai Key Laboratory of Traditional Chinese Clinical Medicine, Shanghai, China
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10
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Mao X, Cheung KS, Peng C, Mak LY, Cheng HM, Fung J, Peleg N, Leung HHW, Kumar R, Lee JH, Shlomai A, Yuen MF, Seto WK. Steatosis, HBV-related HCC, cirrhosis, and HBsAg seroclearance: A systematic review and meta-analysis. Hepatology 2022; 77:1735-1745. [PMID: 36111362 DOI: 10.1002/hep.32792] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 08/22/2022] [Accepted: 09/13/2022] [Indexed: 01/05/2023]
Abstract
BACKGROUND AND AIMS NAFLD and chronic hepatitis B (CHB) infection are common etiologies of HCC. The impact of hepatic steatosis on HCC in CHB, as well as its relationship with the development of cirrhosis, fibrosis, and HBsAg seroclearance, remains controversial. APPROACH AND RESULTS Data from observational studies were collected through PubMed, EMBASE, and the Cochrane Library from inception to February 1, 2022. Outcomes of interest included the association of hepatic steatosis with HCC, cirrhosis, advanced fibrosis, and HBsAg seroclearance, expressed in terms of pooled ORs. Additional subgroup and sensitivity analyses were performed to validate the robustness of findings. A total of 34 studies with 68,268 patients with CHB were included. Hepatic steatosis was associated with higher odds of HCC (OR, 1.59; 95% CI, 1.12-2.26; I2 = 72.5%), with the association remaining consistent in Asia (OR, 1.56; 95% CI, 1.08-2.25), studies with a median follow-up duration of ≥5 years (OR, 2.82; 95% CI, 1.57-5.08), exclusion of alcohol use (OR, 1.71; 95% CI, 1.01-2.91), and biopsy-proven steatosis (OR, 2.86; 95% CI, 1.61-5.06), although no significant association was noted among nucleos(t)ide analogue-treated patients (OR, 1.05; 95% CI, 0.62-1.77). Steatosis was associated with the development of cirrhosis (OR, 1.52; 95% CI, 1.07-2.16; I2 = 0%) and HBsAg seroclearance (OR, 2.22; 95% CI, 1.58-3.10; I2 = 49.0%). CONCLUSIONS Hepatic steatosis was associated with an increased risk of HCC and cirrhosis among patients with CHB but with a higher chance of achieving a functional cure, highlighting the importance of identifying concomitant steatosis in CHB.
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Affiliation(s)
- Xianhua Mao
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - Ka Shing Cheung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Chengzhi Peng
- Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong
| | - Lung-Yi Mak
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Ho Ming Cheng
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong
| | - James Fung
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Noam Peleg
- Division of Gastroenterology, Rabin Medical Center, Petach Tikva, Israel.,Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Howard H-W Leung
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Hong Kong
| | - Rajneesh Kumar
- Department of Gastroenterology and Hepatology, Singapore General Hospital, Singapore.,Duke-NUS Graduate Medical School, Singapore
| | - Jeong-Hoon Lee
- Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - Amir Shlomai
- Department of Medicine D and The Liver Institute, Rabin Medical Center, Beilinson Hospital, Petah-Tikva and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Man-Fung Yuen
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
| | - Wai-Kay Seto
- Department of Medicine, School of Clinical Medicine, The University of Hong Kong, Hong Kong.,Department of Medicine, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China.,State Key Laboratory of Liver Research, The University of Hong Kong, Hong Kong
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11
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Zeng LH, Barkat MQ, Syed SK, Shah S, Abbas G, Xu C, Mahdy A, Hussain N, Hussain L, Majeed A, Khan KUR, Wu X, Hussain M. Hedgehog Signaling: Linking Embryonic Lung Development and Asthmatic Airway Remodeling. Cells 2022; 11:1774. [PMID: 35681469 PMCID: PMC9179967 DOI: 10.3390/cells11111774] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Revised: 05/05/2022] [Accepted: 05/16/2022] [Indexed: 12/28/2022] Open
Abstract
The development of the embryonic lung demands complex endodermal-mesodermal interactions, which are regulated by a variety of signaling proteins. Hedgehog (Hh) signaling is vital for lung development. It plays a key regulatory role during several morphogenic mechanisms, such as cell growth, differentiation, migration, and persistence of cells. On the other hand, abnormal expression or loss of regulation of Hh signaling leads to airway asthmatic remodeling, which is characterized by cellular matrix modification in the respiratory system, goblet cell hyperplasia, deposition of collagen, epithelial cell apoptosis, proliferation, and activation of fibroblasts. Hh also targets some of the pathogens and seems to have a significant function in tissue repairment and immune-related disorders. Similarly, aberrant Hh signaling expression is critically associated with the etiology of a variety of other airway lung diseases, mainly, bronchial or tissue fibrosis, lung cancer, and pulmonary arterial hypertension, suggesting that controlled regulation of Hh signaling is crucial to retain healthy lung functioning. Moreover, shreds of evidence imply that the Hh signaling pathway links to lung organogenesis and asthmatic airway remodeling. Here, we compiled all up-to-date investigations linked with the role of Hh signaling in the development of lungs as well as the attribution of Hh signaling in impairment of lung expansion, airway remodeling, and immune response. In addition, we included all current investigational and therapeutic approaches to treat airway asthmatic remodeling and immune system pathway diseases.
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Affiliation(s)
- Ling-Hui Zeng
- Department of Pharmacology, Zhejiang University City College, 51 Huzhou Street, Hangzhou 310015, China;
| | - Muhammad Qasim Barkat
- Key Laboratory of CFDA for Respiratory Drug Research, Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China; (M.Q.B.); (C.X.)
| | - Shahzada Khurram Syed
- Department of Basic Medical Sciences, School of Health Sciences, University of Management and Technology Lahore, Lahore 54000, Pakistan;
| | - Shahid Shah
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad 38000, Pakistan; (S.S.); (G.A.); (L.H.)
| | - Ghulam Abbas
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad 38000, Pakistan; (S.S.); (G.A.); (L.H.)
| | - Chengyun Xu
- Key Laboratory of CFDA for Respiratory Drug Research, Department of Pharmacology, School of Medicine, Zhejiang University, Hangzhou 310058, China; (M.Q.B.); (C.X.)
| | - Amina Mahdy
- Medical Pharmacology Department, International School of Medicine, Istanbul Medipol University, Istanbul 34000, Turkey;
| | - Nadia Hussain
- Department of Pharmaceutical Sciences, College of Pharmacy, Al Ain University, Al Ain 64141, United Arab Emirates;
| | - Liaqat Hussain
- Faculty of Pharmaceutical Sciences, Government College University, Faisalabad 38000, Pakistan; (S.S.); (G.A.); (L.H.)
| | - Abdul Majeed
- Faculty of Pharmacy, Bahauddin Zakariya University, Mulatn 60000, Pakistan;
| | - Kashif-ur-Rehman Khan
- Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan;
| | - Ximei Wu
- Department of Pharmacology, Zhejiang University City College, 51 Huzhou Street, Hangzhou 310015, China;
| | - Musaddique Hussain
- Faculty of Pharmacy, The Islamia University of Bahawalpur, Bahawalpur 63100, Pakistan;
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12
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Byerly CD, Mitra S, Patterson LL, Pittner NA, Velayutham TS, Paessler S, Veljkovic V, McBride JW. Ehrlichia SLiM ligand mimetic activates Hedgehog signaling to engage a BCL-2 anti-apoptotic cellular program. PLoS Pathog 2022; 18:e1010345. [PMID: 35576232 PMCID: PMC9135340 DOI: 10.1371/journal.ppat.1010345] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2022] [Revised: 05/26/2022] [Accepted: 04/21/2022] [Indexed: 11/19/2022] Open
Abstract
Ehrlichia chaffeensis (E. chaffeensis) has evolved eukaryotic ligand mimicry to repurpose multiple cellular signaling pathways for immune evasion. In this investigation, we demonstrate that TRP120 has a novel repetitive short linear motif (SLiM) that activates the evolutionarily conserved Hedgehog (Hh) signaling pathway to inhibit apoptosis. In silico analysis revealed that TRP120 has sequence and functional similarity with Hh ligands and a candidate Hh ligand SLiM was identified. siRNA knockdown of Hh signaling and transcriptional components significantly reduced infection. Co-immunoprecipitation and surface plasmon resonance demonstrated that rTRP120-TR interacted directly with Hh receptor Patched-2 (PTCH2). E. chaffeensis infection resulted in early upregulation of Hh transcription factor GLI-1 and regulation of Hh target genes. Moreover, soluble recombinant TRP120 (rTRP120) activated Hh and induced gene expression consistent with the eukaryotic Hh ligand. The TRP120-Hh-SLiM (NPEVLIKD) induced nuclear translocation of GLI-1 in THP-1 cells and primary human monocytes and induced a rapid and expansive activation of Hh pathway target genes. Furthermore, Hh activation was blocked by an α-TRP120-Hh-SLiM antibody. TRP120-Hh-SLiM significantly increased levels of Hh target, anti-apoptotic protein B-cell lymphoma 2 (BCL-2), and siRNA knockdown of BCL-2 dramatically inhibited infection. Blocking Hh signaling with the inhibitor Vismodegib, induced a pro-apoptotic cellular program defined by decreased mitochondria membrane potential, significant reductions in BCL-2, activation of caspase 3 and 9, and increased apoptotic cells. This study reveals a novel E. chaffeensis SLiM ligand mimetic that activates Hh signaling to maintain E. chaffeensis infection by engaging a BCL-2 anti-apoptotic cellular program.
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Affiliation(s)
- Caitlan D. Byerly
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Shubhajit Mitra
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - LaNisha L. Patterson
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Nicholas A. Pittner
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Thangam S. Velayutham
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
| | - Slobodan Paessler
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Biomed Protection, LLC, Galveston, Texas, United States of America
| | - Veljko Veljkovic
- Biomed Protection, LLC, Galveston, Texas, United States of America
| | - Jere W. McBride
- Department of Pathology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America
- Center for Biodefense and Emerging Infectious Diseases, University of Texas Medical Branch, Galveston, Texas, United States of America
- Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, Texas, United States of America
- Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, Texas, United States of America
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13
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Zhou Y, Huang J, Jin B, He S, Dang Y, Zhao T, Jin Z. The Emerging Role of Hedgehog Signaling in Viral Infections. Front Microbiol 2022; 13:870316. [PMID: 35464958 PMCID: PMC9023792 DOI: 10.3389/fmicb.2022.870316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2022] [Accepted: 03/07/2022] [Indexed: 11/13/2022] Open
Abstract
The hedgehog (HH) signaling pathway is one of the key pathways that is indispensable for many developmental processes and postnatal tissue homeostasis. Dysregulated HH signaling could lead to developmental disorders and tumorigenesis in a variety of tissues via inherited or sporadic mutation, gene overexpression, and crosstalk with other signaling pathways. Recently, accumulating evidence has shown that HH signaling is targeted by viruses to facilitate viral transcription, immune evasion, and uncontrolled growth, leading to effective viral replication and pathogenesis. In this study, we will summarize recent advances in functional interaction between HH signaling and different types of viruses, particularly focusing on the pathological role of HH signaling in viral infections and related diseases.
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14
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Ruan T, Sun Y, Zhang J, Sun J, Liu W, Prinz RA, Peng D, Liu X, Xu X. H5N1 infection impairs the alveolar epithelial barrier through intercellular junction proteins via Itch-mediated proteasomal degradation. Commun Biol 2022; 5:186. [PMID: 35233032 PMCID: PMC8888635 DOI: 10.1038/s42003-022-03131-3] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2021] [Accepted: 02/08/2022] [Indexed: 12/16/2022] Open
Abstract
The H5N1 subtype of the avian influenza virus causes sporadic but fatal infections in humans. H5N1 virus infection leads to the disruption of the alveolar epithelial barrier, a pathologic change that often progresses into acute respiratory distress syndrome (ARDS) and pneumonia. The mechanisms underlying this remain poorly understood. Here we report that H5N1 viruses downregulate the expression of intercellular junction proteins (E-cadherin, occludin, claudin-1, and ZO-1) in several cell lines and the lungs of H5N1 virus-infected mice. H5N1 virus infection activates TGF-β-activated kinase 1 (TAK1), which then activates p38 and ERK to induce E3 ubiquitin ligase Itch expression and to promote occludin ubiquitination and degradation. Inhibition of the TAK1-Itch pathway restores the intercellular junction structure and function in vitro and in the lungs of H5N1 virus-infected mice. Our study suggests that H5N1 virus infection impairs the alveolar epithelial barrier by downregulating the expression of intercellular junction proteins at the posttranslational level.
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Affiliation(s)
- Tao Ruan
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China
| | - Yuling Sun
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China
| | - Jingting Zhang
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China
| | - Jing Sun
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.,Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China
| | - Wei Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China
| | - Richard A Prinz
- Department of Surgery, NorthShore University Health System, Evanston, IL, 60201, USA
| | - Daxin Peng
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, 225009, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China
| | - Xiufan Liu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou, Jiangsu Province, 225009, China.,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China
| | - Xiulong Xu
- College of Veterinary Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. .,Institute of Comparative Medicine, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China. .,Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou, 225009, Jiangsu Province, China.
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15
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Repurposing Antifungals for Host-Directed Antiviral Therapy? Pharmaceuticals (Basel) 2022; 15:ph15020212. [PMID: 35215323 PMCID: PMC8878022 DOI: 10.3390/ph15020212] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/04/2022] [Accepted: 02/08/2022] [Indexed: 02/04/2023] Open
Abstract
Because of their epidemic and pandemic potential, emerging viruses are a major threat to global healthcare systems. While vaccination is in general a straightforward approach to prevent viral infections, immunization can also cause escape mutants that hide from immune cell and antibody detection. Thus, other approaches than immunization are critical for the management and control of viral infections. Viruses are prone to mutations leading to the rapid emergence of resistant strains upon treatment with direct antivirals. In contrast to the direct interference with pathogen components, host-directed therapies aim to target host factors that are essential for the pathogenic replication cycle or to improve the host defense mechanisms, thus circumventing resistance. These relatively new approaches are often based on the repurposing of drugs which are already licensed for the treatment of other unrelated diseases. Here, we summarize what is known about the mechanisms and modes of action for a potential use of antifungals as repurposed host-directed anti-infectives for the therapeutic intervention to control viral infections.
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16
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Mehmood R, Sheikh N, Khawar MB, Abbasi MH, Mukhtar M. High-fat diet intake ameliorates the expression of hedgehog signaling pathway in adult rat liver. Mol Biol Rep 2022; 49:1985-1994. [PMID: 35040007 DOI: 10.1007/s11033-021-07012-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 11/24/2021] [Indexed: 10/19/2022]
Abstract
BACKGROUND Disproportionate fatty diet intake provokes hepatic lipid accumulation that causes non-alcoholic fatty liver disease, triggering the embryonically conserved Hedgehog (Hh) pathway in the adult liver. The present study incorporates exploring the impact of chronically administered unsaturated (D-1) and saturated (D-2) fat-enriched diets on hematological parameters, liver functioning, and lipid profile in the rat model. Besides, hepatohistology and real time gene expression analysis of Hh signaling pathway genes i.e., Shh, Ihh, Hhip, Ptch1, Smo, Gli1, Gli2, and Gli3 were carried out. METHODS AND RESULTS Fifteen Rattus norvegicus (♂) of 200 ± 25 g weight were grouped into control, D-1, and D-2. Animals were fed on their respective diets for 16 weeks. Fatty diet intake resulted in neutropenia, lymphocytosis, monocytosis, polycythemia, and macrocytosis in both experimental groups. Altered liver injury biomarkers, hypertriglyceridemia, and significantly increased very-low-density lipoprotein VLDL were also noted in both high-fat diet (HFD) groups as compared to control. Hepatohistological examination showed disrupted microarchitecture, infiltration of inflammatory cells, cellular necrosis, widened sinusoidal spaces, and microvesicular steatotic hepatocytes in D-1 and D-2. Collagen deposition in both HFD groups marks the extent of fibrosis. Significant upregulation of hedgehog pathway genes was found in fatty diet groups. In comparison with the control group, Shh Ihh, Hhip, Ptch1, Smo, Gli1, Gli2, and Gli3 were upregulated in D-1. In D-2 Shh, Hhip, and Smo expressions were upregulated, Ihh exhibited downregulation as compared to control. CONCLUSION Excess fat deposits in liver due to chronic consumption of high-fat diet results in anomalous architecture and functioning. High-fat diet induced significant variations in Hh pathway genes expression; especially Shh, Ihh, Hhip, Ptch1, Smo, Gli1, Gli2, and Gli3 were upregulated. Infiltration of inflammatory cells ( ), widened sinusoidal spaces (▲), cellular necrosis, and micro vesicular steatotic hepatocytes (*) were shown in the liver. Significant collagen deposition in both HFD groups i.e. D-1 and D-2 confirmed liver fibrosis. Excessive intake of dietary fats impaired normal liver functioning and liver inflammation triggered Hh signaling in adult rats.
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Affiliation(s)
- Rabia Mehmood
- Institute of Zoology, University of the Punjab, Q-A- Campus, Lahore, 54590, Pakistan
| | - Nadeem Sheikh
- Institute of Zoology, University of the Punjab, Q-A- Campus, Lahore, 54590, Pakistan.
| | - Muhammad Babar Khawar
- Department of Zoology, Faculty of Sciences, University of Central Punjab, Lahore, Pakistan
| | - Muddasir Hassan Abbasi
- Institute of Zoology, University of the Punjab, Q-A- Campus, Lahore, 54590, Pakistan.,Department of Zoology, University of Okara, Okara, Punjab, Pakistan
| | - Maryam Mukhtar
- Institute of Zoology, University of the Punjab, Q-A- Campus, Lahore, 54590, Pakistan
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17
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Kim MN, Han K, Yoo J, Hwang SG, Ahn SH. Increased risk of hepatocellular carcinoma and mortality in chronic viral hepatitis with concurrent fatty liver. Aliment Pharmacol Ther 2022; 55:97-107. [PMID: 34820871 DOI: 10.1111/apt.16706] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2021] [Revised: 08/13/2021] [Accepted: 11/07/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND Population-based data are lacking regarding whether fatty liver is a risk factor for hepatocellular carcinoma (HCC) and mortality in patients with chronic viral hepatitis. AIM To investigate the association of fatty liver with HCC incidence and mortality in patients with chronic viral hepatitis using a nationwide cohort METHODS: We included 57,385 patients with chronic hepatitis B (CHB) or chronic hepatitis C (CHC) who underwent health examinations. The patients were divided into three groups: no fatty liver, fatty liver index (FLI) <30, grade 1 (G1) fatty liver: 30≤ FLI <60, and grade 2 (G2) fatty liver: FLI >60. RESULTS During a median 8.4-year follow-up, we documented 3496 HCC cases and 4146 deaths. Compared to patients with no fatty liver (n = 35,018), the risk of HCC was significantly higher in patients with G1 fatty liver (n = 14,544) (adjusted hazard ratio [aHR] = 1.50, 95% confidence interval [CI] = 1.38-1.64) and G2 fatty liver (n = 7,823) (aHR = 1.88, 95% CI = 1.67-2.12). The risk of mortality was significantly higher in patients with G1 fatty liver (aHR = 1.53, 95% CI = 1.41-1.66) and G2 fatty liver (aHR = 2.16, 95% CI = 1.94-2.42) compared to patients with no fatty liver. CONCLUSIONS Concurrent fatty liver was associated with a higher risk of HCC and mortality in patients with chronic viral hepatitis. Our results suggest the importance of management of fatty liver to reduce the risks of HCC and mortality in patients with chronic viral hepatitis.
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Affiliation(s)
- Mi Na Kim
- Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea.,Clinical and Translational Hepatology Laboratory, Seongnam, Republic of Korea
| | - Kyungdo Han
- Department of Statistics and Actuarial Science, Soongsil University, Seoul, Republic of Korea
| | - Juhwan Yoo
- Department of Biomedicine & Health Science, The Catholic University of Korea, Seoul, Korea
| | - Seong Gyu Hwang
- Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Republic of Korea
| | - Sang Hoon Ahn
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Republic of Korea
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18
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Li L, Zhao J, Zhang Q, Tao Y, Shen C, Li R, Ma Z, Li J, Wang Z. Cancer Cell-Derived Exosomes Promote HCC Tumorigenesis Through Hedgehog Pathway. Front Oncol 2021; 11:756205. [PMID: 34692546 PMCID: PMC8529041 DOI: 10.3389/fonc.2021.756205] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2021] [Accepted: 09/16/2021] [Indexed: 12/12/2022] Open
Abstract
Purpose Hepatocellular carcinoma (HCC) accounts for more than 80% of primary liver cancers and is one of the leading causes of cancer-related death in many countries. Cancer cell-derived exosomes are shown to mediate communications between cancer cells and the microenvironment, promoting tumorigenesis. Hedgehog signaling pathway plays important roles in cancer development of HCC. Methods Exosomes were isolated from culture medium of HCC cell lines PLC/PRF/5 and MHCC-97H and were found to promote cancer cell growth measured with cell proliferation and colony formation assay. HCC cells cultured with cancer cell-derived exosome had increased cancer stem cell (CSC) population demonstrated by increased cell sphere formation CSC marker expressions. Hedgehog protein Shh was found to be highly expressed in these two HCC cell lines and preferably carried by exosomes. When Shh was knocked down with shRNA, the resulting exosomes had a reduced effect on promoting cancer cell growth or CSC population increase compared to normal cell-derived exosomes. Results The ability of PLC/PRF/5 cells to form tumor in a xenograft model was increased by the addition of the exosomes from control cancer cells but not the exosomes from Shh knocked down cancer cells. Finally, the higher plasma Exo-Shh levels were associated with later tumor stages, higher histological grades, multiple tumors, and higher recurrence rates. Conclusion This study demonstrated that HCC cells secreted Shh via exosome and promote tumorigenesis through the activated Hedgehog pathway.
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Affiliation(s)
- Li Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Jing Zhao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Quanbao Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Yifeng Tao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Conghuan Shen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Ruidong Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Zhengyu Ma
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Jianhua Li
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institute of Organ Transplantation, Fudan University, Shanghai, China
| | - Zhengxin Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Institute of Organ Transplantation, Fudan University, Shanghai, China
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19
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Trivedi P, Patel SK, Bellavia D, Messina E, Palermo R, Ceccarelli S, Marchese C, Anastasiadou E, Minter LM, Felli MP. When Viruses Cross Developmental Pathways. Front Cell Dev Biol 2021; 9:691644. [PMID: 34422814 PMCID: PMC8375270 DOI: 10.3389/fcell.2021.691644] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Accepted: 07/20/2021] [Indexed: 12/24/2022] Open
Abstract
Aberrant regulation of developmental pathways plays a key role in tumorigenesis. Tumor cells differ from normal cells in their sustained proliferation, replicative immortality, resistance to cell death and growth inhibition, angiogenesis, and metastatic behavior. Often they acquire these features as a consequence of dysregulated Hedgehog, Notch, or WNT signaling pathways. Human tumor viruses affect the cancer cell hallmarks by encoding oncogenic proteins, and/or by modifying the microenvironment, as well as by conveying genomic instability to accelerate cancer development. In addition, viral immune evasion mechanisms may compromise developmental pathways to accelerate tumor growth. Viruses achieve this by influencing both coding and non-coding gene regulatory pathways. Elucidating how oncogenic viruses intersect with and modulate developmental pathways is crucial to understanding viral tumorigenesis. Many currently available antiviral therapies target viral lytic cycle replication but with low efficacy and severe side effects. A greater understanding of the cross-signaling between oncogenic viruses and developmental pathways will improve the efficacy of next-generation inhibitors and pave the way to more targeted antiviral therapies.
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Affiliation(s)
- Pankaj Trivedi
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | | | - Diana Bellavia
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Elena Messina
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Rocco Palermo
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
| | - Simona Ceccarelli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Cinzia Marchese
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Eleni Anastasiadou
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
| | - Lisa M Minter
- Department of Veterinary and Animal Sciences, University of Massachusetts Amherst, Amherst, MA, United States
| | - Maria Pia Felli
- Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy
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20
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Ruan T, Sun J, Liu W, Prinz RA, Peng D, Liu X, Xu X. H1N1 Influenza Virus Cross-Activates Gli1 to Disrupt the Intercellular Junctions of Alveolar Epithelial Cells. Cell Rep 2021; 31:107801. [PMID: 32610119 DOI: 10.1016/j.celrep.2020.107801] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2019] [Revised: 11/26/2019] [Accepted: 06/01/2020] [Indexed: 02/09/2023] Open
Abstract
Influenza A virus (IAV) primarily infects the airway and alveolar epithelial cells and disrupts the intercellular junctions, leading to increased paracellular permeability. Although this pathological change plays a critical role in lung tissue injury and secondary infection, the molecular mechanism of IAV-induced damage to the alveolar barrier remains obscure. Here, we report that Gli1, a transcription factor in the sonic hedgehog (Shh) signaling pathway, is cross-activated by the MAP and PI3 kinase pathways in H1N1 virus (PR8)-infected A549 cells and in the lungs of H1N1 virus-infected mice. Gli1 activation induces Snail expression, which downregulates the expression of intercellular junction proteins, including E-cadherin, ZO-1, and Occludin, and increases paracellular permeability. Inhibition of the Shh pathway restores the levels of Snail and intercellular junction proteins in H1N1-infected cells. Our study suggests that Gli1 activation plays an important role in disrupting the intercellular junctions and in promoting the pathogenesis of H1N1 virus infections.
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Affiliation(s)
- Tao Ruan
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
| | - Jing Sun
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
| | - Wei Liu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
| | - Richard A Prinz
- Department of Surgery, NorthShore University Health System, Evanston, IL 60201, USA
| | - Daxin Peng
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, PRC; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
| | - Xiufan Liu
- Animal Infectious Disease Laboratory, College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, PRC; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC
| | - Xiulong Xu
- College of Veterinary Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institute of Comparative Medicine, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Jiangsu Co-innovation Center for Prevention and Control of Important Animal Infectious Diseases and Zoonosis, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC; Institutes of Agricultural Science and Technology Development, Yangzhou University, Joint International Research Laboratory of Agriculture and Agri-Product Safety of Ministry of Education of China, Yangzhou University, Yangzhou 225009, Jiangsu Province, PRC.
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21
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Fattahi S, Nikbakhsh N, Ranaei M, Sabour D, Akhavan-Niaki H. Association of sonic hedgehog signaling pathway genes IHH, BOC, RAB23a and MIR195-5p, MIR509-3-5p, MIR6738-3p with gastric cancer stage. Sci Rep 2021; 11:7471. [PMID: 33811245 PMCID: PMC8018955 DOI: 10.1038/s41598-021-86946-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Accepted: 03/22/2021] [Indexed: 12/24/2022] Open
Abstract
Gastric cancer is the leading cause of cancer-related mortality worldwide. Given the importance of gastric cancer in public health, identifying biomarkers associated with disease onset is an important part of precision medicine. The hedgehog signaling pathway is considered as one of the most significant widespread pathways of intracellular signaling in the early events of embryonic development. This pathway contributes also to the maintenance of pluripotency of cancer stem cells pluripotency. In this study, we analyzed the expression levels of sonic hedgehog (Shh) signaling pathway genes IHH, BOC, RAB23a and their regulatory miRNAs including MIR-195-5p, MIR-509-3-5p, MIR-6738-3p in gastric cancer patients. In addition, the impact of infection status on the expression level of those genes and their regulatory miRNAs was investigated. One hundred samples taken from 50 gastric cancer patients (50 tumoral tissues and their adjacent non-tumoral counterparts) were included in this study. There was a significant difference in all studied genes and miRNAs in tumoral tissues in comparison with their adjacent non-tumoral counterparts. The lower expression of IHH, BOC, RAB23, miR-195-5p, and miR-6738-3p was significantly associated with more advanced cancer stage. Additionally, IHH upregulation was significantly associated with CMV infection (P < 0.001). Also, receiver operating characteristic (ROC) curve analysis indicated that mir-195 was significantly related to several clinicopathological features including tumor stage, grade, age, gender, and infection status of gastric cancer and can be considered as a potential diagnostic biomarker for gastric cancer. This study confirms the important role of Shh signaling pathway genes in gastric cancer tumorigenesis and their potential as novel molecular biomarkers and therapeutic targets.
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Affiliation(s)
- Sadegh Fattahi
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
| | - Novin Nikbakhsh
- Department of Surgery, Rouhani Hospital Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Ranaei
- Department of Pathology, Rouhani Hospital, Babol University of Medical Sciences, Babol, Iran
| | - Davood Sabour
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Haleh Akhavan-Niaki
- Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran.
- Department of Genetics, Faculty of Medicine, Babol University of Medical Sciences, Babol, Iran.
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22
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Yang CW, Shi ZL. Uncovering potential host proteins and pathways that may interact with eukaryotic short linear motifs in viral proteins of MERS, SARS and SARS2 coronaviruses that infect humans. PLoS One 2021; 16:e0246150. [PMID: 33534852 PMCID: PMC7857568 DOI: 10.1371/journal.pone.0246150] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2020] [Accepted: 01/14/2021] [Indexed: 12/30/2022] Open
Abstract
A coronavirus pandemic caused by a novel coronavirus (SARS-CoV-2) has spread rapidly worldwide since December 2019. Improved understanding and new strategies to cope with novel coronaviruses are urgently needed. Viruses (especially RNA viruses) encode a limited number and size (length of polypeptide chain) of viral proteins and must interact with the host cell components to control (hijack) the host cell machinery. To achieve this goal, the extensive mimicry of SLiMs in host proteins provides an effective strategy. However, little is known regarding SLiMs in coronavirus proteins and their potential targets in host cells. The objective of this study is to uncover SLiMs in coronavirus proteins that are present within host cells. These SLiMs have a high possibility of interacting with host intracellular proteins and hijacking the host cell machinery for virus replication and dissemination. In total, 1,479 SLiM hits were identified in the 16 proteins of 590 coronaviruses infecting humans. Overall, 106 host proteins were identified that may interact with SLiMs in 16 coronavirus proteins. These SLiM-interacting proteins are composed of many intracellular key regulators, such as receptors, transcription factors and kinases, and may have important contributions to virus replication, immune evasion and viral pathogenesis. A total of 209 pathways containing proteins that may interact with SLiMs in coronavirus proteins were identified. This study uncovers potential mechanisms by which coronaviruses hijack the host cell machinery. These results provide potential therapeutic targets for viral infections.
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Affiliation(s)
- Chu-Wen Yang
- Department of Microbiology, Center for Applied Artificial Intelligence Research, Soochow University, Taipei, Taiwan
- * E-mail:
| | - Zhi-Ling Shi
- Ocean School of Fuzhou University, Fuzhou University, Fuzhou, China
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23
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Iriana S, Asha K, Repak M, Sharma-Walia N. Hedgehog Signaling: Implications in Cancers and Viral Infections. Int J Mol Sci 2021; 22:1042. [PMID: 33494284 PMCID: PMC7864517 DOI: 10.3390/ijms22031042] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/11/2021] [Accepted: 01/14/2021] [Indexed: 12/14/2022] Open
Abstract
The hedgehog (SHH) signaling pathway is primarily involved in embryonic gut development, smooth muscle differentiation, cell proliferation, adult tissue homeostasis, tissue repair following injury, and tissue polarity during the development of vertebrate and invertebrate organisms. GLIoma-associated oncogene homolog (GLI) family of zinc-finger transcription factors and smoothened (SMO) are the signal transducers of the SHH pathway. Both SHH ligand-dependent and independent mechanisms activate GLI proteins. Various transcriptional mechanisms, posttranslational modifications (phosphorylation, ubiquitination, proteolytic processing, SUMOylation, and acetylation), and nuclear-cytoplasmic shuttling control the activity of SHH signaling pathway proteins. The dysregulated SHH pathway is associated with bone and soft tissue sarcomas, GLIomas, medulloblastomas, leukemias, and tumors of breast, lung, skin, prostate, brain, gastric, and pancreas. While extensively studied in development and sarcomas, GLI family proteins play an essential role in many host-pathogen interactions, including bacterial and viral infections and their associated cancers. Viruses hijack host GLI family transcription factors and their downstream signaling cascades to enhance the viral gene transcription required for replication and pathogenesis. In this review, we discuss a distinct role(s) of GLI proteins in the process of tumorigenesis and host-pathogen interactions in the context of viral infection-associated malignancies and cancers due to other causes. Here, we emphasize the potential of the Hedgehog (HH) pathway targeting as a potential anti-cancer therapeutic approach, which in the future could also be tested in infection-associated fatalities.
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24
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Ding J, Li HY, Zhang L, Zhou Y, Wu J. Hedgehog Signaling, a Critical Pathway Governing the Development and Progression of Hepatocellular Carcinoma. Cells 2021; 10:cells10010123. [PMID: 33440657 PMCID: PMC7826706 DOI: 10.3390/cells10010123] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2020] [Revised: 01/03/2021] [Accepted: 01/07/2021] [Indexed: 02/08/2023] Open
Abstract
Hedgehog (Hh) signaling is a classic morphogen in controlling embryonic development and tissue repairing. Aberrant activation of Hh signaling has been well documented in liver cancer, including hepatoblastoma, hepatocellular carcinoma (HCC) and cholangiocarcinoma. The present review aims to update the current understanding on how abnormal Hh signaling molecules modulate initiation, progression, drug resistance and metastasis of HCC. The latest relevant literature was reviewed with our recent findings to provide an overview regarding the molecular interplay and clinical relevance of the Hh signaling in HCC management. Hh signaling molecules are involved in the transformation of pre-carcinogenic lesions to malignant features in chronic liver injury, such as nonalcoholic steatohepatitis. Activation of GLI target genes, such as ABCC1 and TAP1, is responsible for drug resistance in hepatoma cells, with a CD133−/EpCAM− surface molecular profile, and GLI1 and truncated GLI1 account for the metastatic feature of the hepatoma cells, with upregulation of matrix metalloproteinases. A novel bioassay for the Sonic Hh ligand in tissue specimens may assist HCC diagnosis with negative α-fetoprotein and predict early microvascular invasion. In-depth exploration of the Hh signaling deepens our understanding of its molecular modulation in HCC initiation, drug sensitivity and metastasis, and guides precise management of HCC on an individual basis.
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Affiliation(s)
- Jia Ding
- Department of Gastroenterology, Shanghai Jing’an District Central Hospital, Fudan University, Shanghai 200040, China;
| | - Hui-Yan Li
- Department of Medical Microbiology and Parasitology, MOE/NHC Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (H.-Y.L.); (L.Z.); (Y.Z.)
| | - Li Zhang
- Department of Medical Microbiology and Parasitology, MOE/NHC Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (H.-Y.L.); (L.Z.); (Y.Z.)
| | - Yuan Zhou
- Department of Medical Microbiology and Parasitology, MOE/NHC Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (H.-Y.L.); (L.Z.); (Y.Z.)
| | - Jian Wu
- Department of Medical Microbiology and Parasitology, MOE/NHC Key Laboratory of Medical Molecular Virology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 200032, China; (H.-Y.L.); (L.Z.); (Y.Z.)
- Department of Gastroenterology & Hepatology, Zhongshan Hospital of Fudan University, Shanghai 200032, China
- Shanghai Institute of Liver Diseases, Shanghai Medical College, Fudan University, Shanghai 200032, China
- Correspondence: ; Tel.: +86-215-423-7705; Fax: +86-216-422-7201
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25
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Sepulveda-Crespo D, Resino S, Martinez I. Strategies Targeting the Innate Immune Response for the Treatment of Hepatitis C Virus-Associated Liver Fibrosis. Drugs 2021; 81:419-443. [PMID: 33400242 DOI: 10.1007/s40265-020-01458-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Direct-acting antivirals eliminate hepatitis C virus (HCV) in more than 95% of treated individuals and may abolish liver injury, arrest fibrogenesis, and reverse fibrosis and cirrhosis. However, liver regeneration is usually a slow process that is less effective in the late stages of fibrosis. What is more, fibrogenesis may prevail in patients with advanced cirrhosis, where it can progress to liver failure and hepatocellular carcinoma. Therefore, the development of antifibrotic drugs that halt and reverse fibrosis progression is urgently needed. Fibrosis occurs due to the repair process of damaged hepatic tissue, which eventually leads to scarring. The innate immune response against HCV is essential in the initiation and progression of liver fibrosis. HCV-infected hepatocytes and liver macrophages secrete proinflammatory cytokines and chemokines that promote the activation and differentiation of hepatic stellate cells (HSCs) to myofibroblasts that produce extracellular matrix (ECM) components. Prolonged ECM production by myofibroblasts due to chronic inflammation is essential to the development of fibrosis. While no antifibrotic therapy is approved to date, several drugs are being tested in phase 2 and phase 3 trials with promising results. This review discusses current state-of-the-art knowledge on treatments targeting the innate immune system to revert chronic hepatitis C-associated liver fibrosis. Agents that cause liver damage may vary (alcohol, virus infection, etc.), but fibrosis progression shows common patterns among them, including chronic inflammation and immune dysregulation, hepatocyte injury, HSC activation, and excessive ECM deposition. Therefore, mechanisms underlying these processes are promising targets for general antifibrotic therapies.
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Affiliation(s)
- Daniel Sepulveda-Crespo
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain
| | - Salvador Resino
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
| | - Isidoro Martinez
- Unidad de Infección Viral e Inmunidad, Centro Nacional de Microbiología, Instituto de Salud Carlos III (Campus Majadahonda), Carretera Majadahonda-Pozuelo, Km 2.2, 28220, Majadahonda, Madrid, Spain.
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26
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Lee HY, Hong IS. Targeting Liver Cancer Stem Cells: An Alternative Therapeutic Approach for Liver Cancer. Cancers (Basel) 2020; 12:cancers12102746. [PMID: 32987767 PMCID: PMC7598600 DOI: 10.3390/cancers12102746] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2020] [Revised: 09/18/2020] [Accepted: 09/22/2020] [Indexed: 12/12/2022] Open
Abstract
The first report of cancer stem cell (CSC) from Bruce et al. has demonstrated the relatively rare population of stem-like cells in acute myeloid leukemia (AML). The discovery of leukemic CSCs prompted further identification of CSCs in multiple types of solid tumor. Recently, extensive research has attempted to identity CSCs in multiple types of solid tumors in the brain, colon, head and neck, liver, and lung. Based on these studies, we hypothesize that the initiation and progression of most malignant tumors rely largely on the CSC population. Recent studies indicated that stem cell-related markers or signaling pathways, such as aldehyde dehydrogenase (ALDH), CD133, epithelial cell adhesion molecule (EpCAM), Wnt/β-catenin signaling, and Notch signaling, contribute to the initiation and progression of various liver cancer types. Importantly, CSCs are markedly resistant to conventional therapeutic approaches and current targeted therapeutics. Therefore, it is believed that selectively targeting specific markers and/or signaling pathways of hepatic CSCs is an effective therapeutic strategy for treating chemotherapy-resistant liver cancer. Here, we provide an overview of the current knowledge on the hepatic CSC hypothesis and discuss the specific surface markers and critical signaling pathways involved in the development and maintenance of hepatic CSC subpopulations.
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Affiliation(s)
- Hwa-Yong Lee
- Department of Biomedical Science, Jungwon University, 85 Goesan-eup, Munmu-ro, Goesan-gun, Chungcheongbuk-do 367700, Korea;
| | - In-Sun Hong
- Department of Health Sciences and Technology, GAIHST, Gachon University, Incheon 21999, Korea
- Department of Molecular Medicine, School of Medicine, Gachon University, Incheon 406840, Korea
- Correspondence: ; Tel.: +82-32-899-6315; Fax: +82-32-899-6350
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27
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Choi HSJ, Brouwer WP, Zanjir WMR, de Man RA, Feld JJ, Hansen BE, Janssen HLA, Patel K. Nonalcoholic Steatohepatitis Is Associated With Liver-Related Outcomes and All-Cause Mortality in Chronic Hepatitis B. Hepatology 2020; 71:539-548. [PMID: 31309589 DOI: 10.1002/hep.30857] [Citation(s) in RCA: 155] [Impact Index Per Article: 31.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Accepted: 07/27/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS Chronic hepatitis B (CHB) and nonalcoholic fatty liver disease are increasingly observed together in clinical practice, and development of nonalcoholic steatohepatitis (NASH) represents another leading cause of liver-related morbidity and mortality. Our aims were to determine whether biopsy-proven NASH impacts clinical outcomes in CHB patients and assess prognostic risk factors. APPROACH AND RESULTS CHB patients attending two tertiary centers in North America and Europe over 13 years with available clinical and biopsy data were included. Patients were categorized as no-NASH or probable/definite NASH based on standardized histological assessment. Clinical events (death, decompensation, transplant, and hepatoma) were evaluated, and Kaplan-Meier survival estimates and Cox proportional hazards regression were used to analyze the incidence of events. There were 1,089 CHB patients, classified as no-NASH (n = 904, 83%) or NASH (n = 185, 17%), with 52 (6%) versus 27 (15%) experiencing outcome events during follow-up, respectively. In the multivariable analysis adjusting for age, sex, hepatitis B e antigen serostatus, and diabetes, the presence of NASH and concomitant advanced fibrosis (AF) was significantly associated with clinical outcomes (hazard ratio [95% confidence interval], 4.8 [2.6-9.0], P < 0.01) when compared to absence of NASH and AF (reference). NASH and AF were associated with a greater risk of outcomes compared to AF (P = 0.01) or NASH alone (P < 0.01). Of the three histological determinants of NASH, ballooning and inflammation, but not steatosis, were independently associated with clinical outcomes (P < 0.05) in place of NASH. NASH was significantly associated with increased risk of hepatocellular carcinoma and death (P < 0.01) but not decompensation (P = 0.33). CONCLUSIONS In our large combined tertiary center cohort, patients with concomitant NASH and CHB had more AF and shorter time to development of liver-related outcomes or death compared to patients with CHB alone. Among patients with AF, superimposed NASH predicted poorer clinical outcomes.
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Affiliation(s)
- Hannah S J Choi
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada.,Institute of Medical Science, University of Toronto, Toronto, ON, Canada
| | - Willem P Brouwer
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Wayel M R Zanjir
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Robert A de Man
- Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Jordan J Feld
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Bettina E Hansen
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada.,Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, the Netherlands.,Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, ON, Canada
| | - Harry L A Janssen
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
| | - Keyur Patel
- Toronto Centre for Liver Disease, University Health Network, Toronto, ON, Canada
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28
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Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Rewiring Host Signaling: Hepatitis C Virus in Liver Pathogenesis. Cold Spring Harb Perspect Med 2020; 10:cshperspect.a037366. [PMID: 31501266 DOI: 10.1101/cshperspect.a037366] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Hepatitis C virus (HCV) is a major cause of liver disease including metabolic disease, fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). HCV induces and promotes liver disease progression by perturbing a range of survival, proliferative, and metabolic pathways within the proinflammatory cellular microenvironment. The recent breakthrough in antiviral therapy using direct-acting antivirals (DAAs) can cure >90% of HCV patients. However, viral cure cannot fully eliminate the HCC risk, especially in patients with advanced liver disease or comorbidities. HCV induces an epigenetic viral footprint that promotes a pro-oncogenic hepatic signature, which persists after DAA cure. In this review, we summarize the main signaling pathways deregulated by HCV infection, with potential impact on liver pathogenesis. HCV-induced persistent signaling patterns may serve as biomarkers for the stratification of HCV-cured patients at high risk of developing HCC. Moreover, these signaling pathways are potential targets for novel chemopreventive strategies.
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Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France.,Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, 67000 Strasbourg, France.,Institut Universitaire de France (IUF), 75231 Paris, France
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.,Université de Strasbourg, 67000 Strasbourg, France
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29
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Khajehahmadi Z, Mohagheghi S, Nikeghbalian S, Geramizadeh B, Khodadadi I, Karimi J, Tavilani H. Liver stiffness correlates with serum osteopontin and TAZ expression in human liver cirrhosis. Ann N Y Acad Sci 2019; 1465:117-131. [PMID: 31696937 DOI: 10.1111/nyas.14259] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2019] [Revised: 09/17/2019] [Accepted: 09/28/2019] [Indexed: 12/13/2022]
Abstract
The pivotal role of the extracellular matrix (ECM) as both a cause and consequence of liver fibrosis is striking. However, mechanotransducer molecules and profibrogenic factors induced by liver stiffness are still unclear. The current study aimed to investigate liver stiffness and its correlation with the expression of the transcriptional coactivator with PDZ-binding motif (TAZ) and serum osteopontin (OPN) in human cirrhosis. In this case-control study, liver tissue stiffness was determined using atomic force microscopy in cirrhotic livers (n = 38) of different etiologies and in controls (n = 10). Immunohistochemical and qRT-PCR analyses were performed to analyze TAZ expression. Besides, western blotting and ELISA were performed to assess liver Indian hedgehog and serum OPN levels, respectively. Liver stiffness, TAZ expression, and hepatic gene expression and serum protein levels of OPN were significantly increased in patients with cirrhosis compared with the control groups (all P < 0.001), specifically in autoimmune- and alcohol-related cirrhosis. In cirrhotic patients, liver stiffness was significantly associated with the expression of nuclear TAZ and OPN. The correlation between matrix stiffness as a mechanical property, TAZ as a potential mechanotransducer, and OPN as a matricellular factor suggests possible effects of mechanical features of the ECM on the expression of the aforementioned profibrogenic markers, which is predominant in autoimmune- and alcohol-related cirrhosis.
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Affiliation(s)
- Zohreh Khajehahmadi
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sina Mohagheghi
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Saman Nikeghbalian
- Shiraz Transplant Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Transplant Research Center, Pathology Department, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Iraj Khodadadi
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Jamshid Karimi
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Heidar Tavilani
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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30
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Jeng KS, Jeng CJ, Jeng WJ, Sheen IS, Li SY, Leu CM, Tsay YG, Chang CF. Sonic Hedgehog signaling pathway as a potential target to inhibit the progression of hepatocellular carcinoma. Oncol Lett 2019; 18:4377-4384. [PMID: 31611946 PMCID: PMC6781692 DOI: 10.3892/ol.2019.10826] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2018] [Accepted: 08/06/2019] [Indexed: 12/13/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-associated mortality worldwide. Hepatocarcinogenesis involves numerous interlinked factors and processes, including the Sonic hedgehog (Shh) signaling pathway, which participates in the carcinogenesis, progression, invasiveness, recurrence and cancer stem cell maintenance of HCC. The Shh signaling pathway is activated by ligands that bind to their receptor protein, Protein patched homolog (Ptch). The process of Shh ligand binding to Ptch weakens the inhibition of smoothened homolog (SMO) and activates signal transduction via glioma-associated oncogene homolog (Gli) transcription factors. The overexpression of Shh pathway molecules, including Shh, Ptch-1, Gli and SMO has been indicated in patients with HCC. It has also been suggested that the Shh signaling pathway exhibits cross-talk between numerous other signaling pathways. The inactivation of the Shh signaling pathway reduces HCC growth, increases radio-sensitivity and increases the beneficial effect of chemotherapy in HCC treatment. Therefore, inhibition of the Shh pathway may be an effective target therapy that can be used in the treatment of HCC.
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Affiliation(s)
- Kuo-Shyang Jeng
- Department of General Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan, R.O.C.,Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan, R.O.C
| | - Chi-Juei Jeng
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei City 10617, Taiwan, R.O.C
| | - Wen-Juei Jeng
- Department of Hepato-Gastroenterology, Chang-Gung Memorial Hospital, Linkou Medical Center, Chang-Gung University, Taoyuan City 33305, Taiwan, R.O.C
| | - I-Shyan Sheen
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei City 10617, Taiwan, R.O.C
| | - Shih-Yun Li
- Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan, R.O.C
| | - Chuen-Miin Leu
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei City 11221, Taiwan, R.O.C
| | - Yeou-Guang Tsay
- Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei City 11221, Taiwan, R.O.C
| | - Chiung-Fang Chang
- Department of General Surgery, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan, R.O.C.,Department of Medical Research, Far Eastern Memorial Hospital, New Taipei City 22060, Taiwan, R.O.C
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31
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Khajehahmadi Z, Mohagheghi S, Nikeghbalian S, Geramizadeh B, Khodadadi I, Karimi J, Ghaffari ME, Tavilani H. Downregulation of hedgehog ligands in human simple steatosis may protect against nonalcoholic steatohepatitis: Is TAZ a crucial regulator? IUBMB Life 2019; 71:1382-1390. [PMID: 31087761 DOI: 10.1002/iub.2068] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2019] [Revised: 04/10/2019] [Accepted: 04/26/2019] [Indexed: 12/13/2022]
Abstract
The conversion of simple steatosis into nonalcoholic steatohepatitis (NASH) in patients with nonalcoholic fatty liver disease (NAFLD) has attracted many attentions in recent years. The role of the hedgehog (HH) pathway in the regulation of lipogenesis has been addressed in the literature. This study aimed to investigate the levels of the sonic hedgehog (SHH) and Indian hedgehog (IHH) ligands and the correlation of these ligands with levels of proteins involved in the transforming growth factor-β1 (TGF-β1) pathway, as well as the evaluation of the transcriptional coactivator with PDZ binding motif (TAZ) expression in human simple steatosis, NASH cirrhosis, and controls. Patients were divided into two groups: the first group consisted of patients diagnosed with simple steatosis (n = 16) and the second group included those diagnosed with NASH cirrhosis (n = 15). As a control group, 18 histologically normal liver tissues were collected in this study. The expression of the TGF-β1pathway components and SHH and IHH ligands were analyzed by means of the quantitative real-time polymerase chain reaction and western blot analyses. A significant decrease was found in the hepatic expression of the SHH, IHH, and TGF-β1 pathways along with the expression of TAZ in tissue specimens with simple steatosis in comparison with patients affected by NASH cirrhosis and controls. Also, the levels of SHH and IHH proteins were significantly correlated with the expression of proteins involved in the TGF-β1 pathway. Moreover, the expression of the HH pathway ligands was positively associated with the expression of TAZ, supporting the notion that TAZ may play a role in the activation of the HH pathway thereby regulating the expression of its ligands. It seems that in patients with NAFLD, the downregulation of the HH pathway ligands may stem from steatosis; however, at the same time, it may prevent the conversion of simple steatosis into NASH in patients with liver diseases. © 2019 IUBMB Life, 71(9):1382-1390, 2019.
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Affiliation(s)
- Zohreh Khajehahmadi
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Sina Mohagheghi
- Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Saman Nikeghbalian
- Shiraz Transplant Center, Namazi Hospital, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Bita Geramizadeh
- Transplant Research Center, Pathology Department, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Iraj Khodadadi
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Jamshid Karimi
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Mohammad Ebrahim Ghaffari
- Dental Sciences Research Center, Faculty of Dentistry, Guilan University of Medical Sciences, Rasht, Iran
| | - Heidar Tavilani
- Department of Clinical Biochemistry, Faculty of Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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32
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Navas MC, Glaser S, Dhruv H, Celinski S, Alpini G, Meng F. Hepatitis C Virus Infection and Cholangiocarcinoma: An Insight into Epidemiologic Evidences and Hypothetical Mechanisms of Oncogenesis. THE AMERICAN JOURNAL OF PATHOLOGY 2019; 189:1122-1132. [PMID: 30953604 DOI: 10.1016/j.ajpath.2019.01.018] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2018] [Revised: 12/14/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023]
Abstract
Hepatitis C virus (HCV) infection is a global public health problem because it is a main cause of liver cirrhosis and hepatocellular carcinoma. This human oncogenic virus is also associated with the development of non-Hodgkin lymphoma and cholangiocarcinoma (CCA). The association between HCV infection and CCA has been examined in a number of epidemiologic studies. However, in vivo and in vitro results demonstrating the oncogenic mechanisms of HCV in CCA development and progression are insufficient. Here, we review the epidemiologic association of HCV and CCA and recent publications of studies of HCV infection of cholangiocytes and CCA cell lines as well as studies of viral infection performed with liver samples obtained from patients. In addition, we also discuss the preliminary results of in vitro assays of HCV protein expression in CCA cell lines. Finally, we discuss the hypothetical role of HCV infection in CCA development by induction of epithelial-mesenchymal transition and up-regulation of hedgehog signaling, and consequently biliary tree inflammation and liver fibrosis. Further studies are required to demonstrate these hypotheses and therefore to elucidate the mechanisms of HCV as a risk factor for CCA.
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Affiliation(s)
- Maria-Cristina Navas
- Grupo Gastrohepatologia, School of Medicine, University of Antioquia, Medellin, Colombia; Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas.
| | - Shannon Glaser
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Division of Research, Central Texas Veterans Health Care System, Temple, Texas
| | - Harshil Dhruv
- Translational Genomics Research Institute, Phoenix, Arizona
| | - Scott Celinski
- Department of Surgery, Baylor University Medical Center, Dallas, Texas
| | - Gianfranco Alpini
- Department of Medical Physiology, Texas A&M University College of Medicine, Temple, Texas; Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Division of Research, Central Texas Veterans Health Care System, Temple, Texas
| | - Fanyin Meng
- Baylor Scott & White Digestive Disease Research Center, Baylor Scott & White Health, Temple, Texas; Division of Research, Central Texas Veterans Health Care System, Temple, Texas.
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Wang Y, Chen W, Han C, Zhang J, Song K, Kwon H, Dash S, Yao L, Wu T. Adult Hepatocytes Are Hedgehog-Responsive Cells in the Setting of Liver Injury: Evidence for Smoothened-Mediated Activation of NF-κB/Epidermal Growth Factor Receptor/Akt in Hepatocytes that Counteract Fas-Induced Apoptosis. THE AMERICAN JOURNAL OF PATHOLOGY 2018; 188:2605-2616. [PMID: 30366594 PMCID: PMC6207910 DOI: 10.1016/j.ajpath.2018.07.018] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/26/2018] [Revised: 06/26/2018] [Accepted: 07/24/2018] [Indexed: 02/06/2023]
Abstract
Although hedgehog (Hh) signaling pathway is inactive in adult healthy liver, it becomes activated during acute and chronic liver injury and, thus, modulates the reparative process and disease progression. We developed a novel mouse model with liver-specific knockout of Smoothened (Smo LKO), and animals were subjected to Fas-induced liver injury in vivo. Results showed that Smo deletion in hepatocytes enhances Fas-induced liver injury. Activation of Hh signaling in hepatocytes in the setting of Fas-induced injury was indicated by the fact that Jo2 treatment enhanced hepatic expression of Ptch1, Smo, and its downstream target Gli1 in control but not Smo LKO mice. Primary hepatocytes from control mice showed increased Hh signaling activation in response to Jo2 treatment in vitro. On the other hand, the Smo KO hepatocytes were devoid of Hh activation and were more susceptible to Jo2-induced apoptosis. The levels of NF-κB and related signaling molecules, including epidermal growth factor receptor and Akt, were lower in Smo KO livers/hepatocytes than in control livers/hepatocytes. Accordingly, hydrodynamic gene delivery of active NK-κB prevented Jo2-induced liver injury in the Smo LKO mice. Our findings provide important evidence that adult hepatocytes become responsive to Hh signaling through up-regulation of Smo in the setting of Fas-induced liver injury and that such alteration leads to activation of NF-κB/epidermal growth factor receptor/Akt, which counteracts Fas-induced hepatocyte apoptosis.
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Affiliation(s)
- Ying Wang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana; Department of Gastroenterology and Internal Medicine, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Weina Chen
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Chang Han
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Jinqiang Zhang
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Kyoungsub Song
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Hyunjoo Kwon
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Lu Yao
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana
| | - Tong Wu
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, Louisiana.
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34
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Virzì A, Roca Suarez AA, Baumert TF, Lupberger J. Oncogenic Signaling Induced by HCV Infection. Viruses 2018; 10:v10100538. [PMID: 30279347 PMCID: PMC6212953 DOI: 10.3390/v10100538] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 09/29/2018] [Accepted: 09/30/2018] [Indexed: 02/07/2023] Open
Abstract
The liver is frequently exposed to toxins, metabolites, and oxidative stress, which can challenge organ function and genomic stability. Liver regeneration is therefore a highly regulated process involving several sequential signaling events. It is thus not surprising that individual oncogenic mutations in hepatocytes do not necessarily lead to cancer and that the genetic profiles of hepatocellular carcinomas (HCCs) are highly heterogeneous. Long-term infection with hepatitis C virus (HCV) creates an oncogenic environment by a combination of viral protein expression, persistent liver inflammation, oxidative stress, and chronically deregulated signaling events that cumulate as a tipping point for genetic stability. Although novel direct-acting antivirals (DAA)-based treatments efficiently eradicate HCV, the associated HCC risk cannot be fully eliminated by viral cure in patients with advanced liver disease. This suggests that HCV may persistently deregulate signaling pathways beyond viral cure and thereby continue to perturb cancer-relevant gene function. In this review, we summarize the current knowledge about oncogenic signaling pathways derailed by chronic HCV infection. This will not only help to understand the mechanisms of hepatocarcinogenesis but will also highlight potential chemopreventive strategies to help patients with a high-risk profile of developing HCC.
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Affiliation(s)
- Alessia Virzì
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Armando Andres Roca Suarez
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
| | - Thomas F Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
- Pôle Hépato-digestif, Institut Hospitalo-universitaire, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France.
| | - Joachim Lupberger
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, 67000 Strasbourg, France.
- Université de Strasbourg, 67000 Strasbourg, France.
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Abd El-Meguid M, Dawood RM, Mokhles MA, El Awady MK. Extrahepatic Upregulation of Transforming Growth Factor Beta 2 in HCV Genotype 4-Induced Liver Fibrosis. J Interferon Cytokine Res 2018; 38:341-347. [PMID: 30130153 DOI: 10.1089/jir.2018.0045] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Elevated levels of transforming growth factor-β (TGF-β) family mediate myofibroblast generation and extracellular matrix deposition, thus making TGF-β recognized as major profibrogenic cytokines. In this article, we provide evidence that extrahepatic TGF-β2 expression at RNA and protein levels in peripheral leucocytes and serum, respectively, correlate with hepatic fibrogenesis. Current study includes a total of 110 subjects [89 naive hepatitis C virus (HCV)-infected patients (f0-f4) and 21 healthy controls]. Array profiling of 84 fibrosis-related transcripts revealed that TGF-β2 RNA was significantly upregulated compared with controls. Transcription results were confirmed by specific qRT-PCR on TGF-β2 RNA in peripheral leucocytes and TGF-β2 protein by ELISA in serum. PCR array and qRT-PCR for TGF-β2 RNA in peripheral leucocytes revealed that HCV-infected patients, regardless of the degree of fibrosis, had significantly elevated TGF-β2 RNA levels compared with controls (P = 0.018 and 0.047, respectively). This extrahepatic upregulation of TGF-β2 RNA was confirmed by elevated levels of secretory TGF-β2 protein in infected sera (P = 0.001). The Area Under the Curve of the receiver operating characteristic curve for the TGF-β2 protein between patients and controls was 0.80, a value that renders serum TGF-β2 protein a promising biomarker for liver fibrosis.
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Affiliation(s)
- Mai Abd El-Meguid
- 1 Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | - Reham M Dawood
- 1 Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
| | | | - Mostafa K El Awady
- 1 Genetic Engineering Division, Department of Microbial Biotechnology, National Research Centre , Giza, Egypt
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36
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Immunohistochemical Coexpression of Epithelial Cell Adhesion Molecule and Alpha-Fetoprotein in Hepatocellular Carcinoma. Can J Gastroenterol Hepatol 2018; 2018:5970852. [PMID: 30112355 PMCID: PMC6077358 DOI: 10.1155/2018/5970852] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Accepted: 07/05/2018] [Indexed: 01/10/2023] Open
Abstract
BACKGROUND AND AIM The epithelial cell adhesion molecule (EpCAM) has been proposed as a marker for cancer stem cells in human hepatocellular carcinoma (HCC) as well as in the development of novel target therapies. This study aimed to investigate the immunohistochemical expression of EpCAM and alpha-fetoprotein (AFP) in HCC patients and their association with clinicopathological characteristics. METHODS This study included Child-Pugh A HCC patients undergoing curative surgical resection. RESULTS A significant difference was observed in the ratio between the different phenotypes (p = 0.002), identifying 12 (29.3%) EPCAM positive tumors and 29 (70.7%) negative tumors. EpCAM+ expression was associated with AFP + (OR = 12.5, 95% CI, 1.9-84.1, p<0.001). In univariate analysis, a significant association was observed between AFP+ and EPCAM+ and the serum AFP level. A diameter of ≤ 5 cm was associated with EPCAM+, while angiolymphatic invasion was associated with APF+. In a multivariate analysis, only tumors of ≤ 5 cm were significantly associated with EpCAM+ (OR = 8.7; 95%CI, 1.27-100.0; p = 0.022). The overall survival rate was 74.9%, 69.4%, 69.4%, and 53.5% at 12, 24, 36, and 48 months, respectively. CONCLUSION A considerable number of patients with EpCAM+ HCC would benefit from a specific target therapy.
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37
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Naggie S, Swiderska-Syn M, Choi S, Lusk S, Lan A, Ferrari G, Syn WK, Guy CD, Diehl AM. Markers of Tissue Repair and Cellular Aging Are Increased in the Liver Tissue of Patients With HIV Infection Regardless of Presence of HCV Coinfection. Open Forum Infect Dis 2018; 5:ofy138. [PMID: 29992177 PMCID: PMC6030967 DOI: 10.1093/ofid/ofy138] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 06/08/2018] [Indexed: 01/28/2023] Open
Abstract
Liver disease is a leading cause of HIV-related mortality. Hepatitis C virus (HCV)–related fibrogenesis is accelerated in the setting of HIV coinfection, yet the mechanisms underlying this aggressive pathogenesis are unclear. We identified formalin-fixed paraffin-embedded liver tissue for HIV-infected patients, HCV-infected patients, HIV/HCV-coinfected patients, and controls at Duke University Medical Center. De-identified sections were stained for markers against the wound repair Hedgehog (Hh) pathway, resident T-lymphocytes, and immune activation and cellular aging. HIV infection was independently associated with Hh activation and markers of immune dysregulation in the liver tissue.
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Affiliation(s)
- Susanna Naggie
- Duke University School of Medicine, Durham, North Carolina.,Duke Clinical Research Institute, Durham, North Carolina
| | | | - Steve Choi
- Duke University School of Medicine, Durham, North Carolina.,Durham VA Medical Center, Durham, North Carolina
| | - Sam Lusk
- Duke Clinical Research Institute, Durham, North Carolina
| | - Audrey Lan
- University of North Carolina School of Medicine, Chapel Hill, North Carolina
| | - Guido Ferrari
- Duke University School of Medicine, Durham, North Carolina
| | - Wing-Kin Syn
- Medical University of South Carolina, Charleston, South Carolina.,Ralph H. Johnson VA Medical Center, Charleston, South Carolina
| | - Cynthia D Guy
- Duke University School of Medicine, Durham, North Carolina
| | - Anna Mae Diehl
- Duke University School of Medicine, Durham, North Carolina
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38
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Machado MV, Diehl AM. Hedgehog signalling in liver pathophysiology. J Hepatol 2018; 68:550-562. [PMID: 29107151 PMCID: PMC5957514 DOI: 10.1016/j.jhep.2017.10.017] [Citation(s) in RCA: 104] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Revised: 10/11/2017] [Accepted: 10/18/2017] [Indexed: 12/13/2022]
Abstract
Liver disease remains a leading cause of mortality worldwide despite recent successes in the field of viral hepatitis, because increases in alcohol consumption and obesity are fuelling an epidemic of chronic fatty liver disease for which there are currently no effective medical therapies. About 20% of individuals with chronic liver injury ultimately develop end-stage liver disease due to cirrhosis. Hence, treatments to prevent and reverse cirrhosis in individuals with ongoing liver injury are desperately needed. The development of successful treatments requires an improved understanding of the mechanisms controlling liver disease progression. The liver responds to diverse insults with a conserved wound healing response, suggesting that it might be generally beneficial to optimise pathways that are crucial for effective liver repair. The Hedgehog pathway has emerged as a potential target based on compelling preclinical and clinical data, which demonstrate that it critically regulates the liver's response to injury. Herein, we will summarise evidence of the Hedgehog pathway's role in liver disease and discuss how modulating pathway activity might be applied to improve liver disease outcomes.
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Affiliation(s)
- Mariana Verdelho Machado
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA,Gastroenterology Department, Hospital de Santa Maria, CHLN, Lisbon, Portugal
| | - Anna Mae Diehl
- Division of Gastroenterology, Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
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39
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Gao L, Zhang Z, Zhang P, Yu M, Yang T. Role of canonical Hedgehog signaling pathway in liver. Int J Biol Sci 2018; 14:1636-1644. [PMID: 30416378 PMCID: PMC6216024 DOI: 10.7150/ijbs.28089] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2018] [Accepted: 08/01/2018] [Indexed: 12/19/2022] Open
Abstract
Hedgehog (Hh) signaling pathway plays an important role in embryonic development. It becomes reactivated in many types of acute and chronic liver injuries. Hh signaling is required for liver regeneration, regulates capillarisation, controls the fates of hepatic stellate cells, promotes liver fibrosis and liver cancers. In this review, we summarize the current knowledge of the role of canonical Hh signaling pathway in adult liver. This help to understand the pathogenesis of liver diseases and find out the new effective targeted therapeutic strategies for liver diseases treatments.
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Affiliation(s)
- Lili Gao
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
| | - Zhenya Zhang
- Department of general surgery, Hebei Medical University Fourth Hospital, Shijiazhuang, 050011, China
| | - Peng Zhang
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
| | - Minghua Yu
- Department of Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
- ✉ Corresponding authors: Dr. Minghua Yu, Department of Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China. Phone: 86-21-68030812; E-mail: and Dr. Tao Yang, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai 201399, China. Phone: 86-21-68036516; E-mail:
| | - Tao Yang
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai, 201399, China
- ✉ Corresponding authors: Dr. Minghua Yu, Department of Oncology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China. Phone: 86-21-68030812; E-mail: and Dr. Tao Yang, Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, 2800 Gongwei Road, Shanghai 201399, China. Phone: 86-21-68036516; E-mail:
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40
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Abstract
The Hedgehog (Hh) signaling pathway plays an essential role in the growth, development, and homeostatis of many tissues in vertebrates and invertebrates. Much of what is known about Hh signaling is in the context of embryonic development and tumor formation. However, a growing body of evidence is emerging indicating that Hh signaling is also involved in postnatal processes such as tissue repair and adult immune responses. To that extent, Hh signaling has also been shown to be a target for some pathogens that presumably utilize the pathway to control the local infected environment. In this review, we discuss what is currently known regarding pathogenic interactions with Hh signaling and speculate on the reasons for this pathway being a target. We also hope to shed light on the possibility of using small molecule modulators of Hh signaling as effective therapies for a wider range of human diseases beyond their current use in a limited number of cancers.
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41
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Smelkinson MG, Guichard A, Teijaro JR, Malur M, Loureiro ME, Jain P, Ganesan S, Zúñiga EI, Krug RM, Oldstone MB, Bier E. Influenza NS1 directly modulates Hedgehog signaling during infection. PLoS Pathog 2017; 13:e1006588. [PMID: 28837667 PMCID: PMC5587344 DOI: 10.1371/journal.ppat.1006588] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2017] [Revised: 09/06/2017] [Accepted: 08/16/2017] [Indexed: 12/31/2022] Open
Abstract
The multifunctional NS1 protein of influenza A viruses suppresses host cellular defense mechanisms and subverts other cellular functions. We report here on a new role for NS1 in modifying cell-cell signaling via the Hedgehog (Hh) pathway. Genetic epistasis experiments and FRET-FLIM assays in Drosophila suggest that NS1 interacts directly with the transcriptional mediator, Ci/Gli1. We further confirmed that Hh target genes are activated cell-autonomously in transfected human lung epithelial cells expressing NS1, and in infected mouse lungs. We identified a point mutation in NS1, A122V, that modulates this activity in a context-dependent fashion. When the A122V mutation was incorporated into a mouse-adapted influenza A virus, it cell-autonomously enhanced expression of some Hh targets in the mouse lung, including IL6, and hastened lethality. These results indicate that, in addition to its multiple intracellular functions, NS1 also modifies a highly conserved signaling pathway, at least in part via cell autonomous activities. We discuss how this new Hh modulating function of NS1 may influence host lethality, possibly through controlling cytokine production, and how these new insights provide potential strategies for combating infection.
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Affiliation(s)
- Margery G. Smelkinson
- Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, United States of America
| | - Annabel Guichard
- Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, United States of America
| | - John R. Teijaro
- Immunology and Microbial Science, Scripps Research Institute, La Jolla, California, United States of America
| | - Meghana Malur
- Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America
| | - Maria Eugenia Loureiro
- Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America
- Instituto de Ciencia y Tecnología Dr. César Milstein - CONICET, Saladillo, Argentina
| | - Prashant Jain
- Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, United States of America
| | - Sundar Ganesan
- Biological Imaging Section, Research Technologies Branch, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Elina I. Zúñiga
- Division of Biological Sciences, University of California San Diego, La Jolla, California, United States of America
| | - Robert M. Krug
- Department of Molecular Biosciences, University of Texas at Austin, Austin, Texas, United States of America
| | - Michael B. Oldstone
- Immunology and Microbial Science, Scripps Research Institute, La Jolla, California, United States of America
| | - Ethan Bier
- Section of Cell and Developmental Biology, University of California, San Diego, La Jolla, California, United States of America
- * E-mail:
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Yılmaz Y, Güneş A, Topel H, Atabey N. Signaling Pathways as Potential Therapeutic Targets in Hepatocarcinogenesis. J Gastrointest Cancer 2017; 48:225-237. [PMID: 28819741 DOI: 10.1007/s12029-017-9958-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Yeliz Yılmaz
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
- Department of Medical Biology and Genetics, Institute of Health Sciences, Dokuz Eylul University, 35340, Izmir, Turkey
| | - Ayşim Güneş
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
| | - Hande Topel
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey
- Department of Medical Biology and Genetics, Institute of Health Sciences, Dokuz Eylul University, 35340, Izmir, Turkey
| | - Neşe Atabey
- Izmir International Biomedicine & Genome Institute (iBG-izmir), Dokuz Eylul University, Balcova, 35340, Izmir, Turkey.
- Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, 35340, Izmir, Turkey.
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Cervello M, Augello G, Cusimano A, Emma MR, Balasus D, Azzolina A, McCubrey JA, Montalto G. Pivotal roles of glycogen synthase-3 in hepatocellular carcinoma. Adv Biol Regul 2017; 65:59-76. [PMID: 28619606 DOI: 10.1016/j.jbior.2017.06.002] [Citation(s) in RCA: 35] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 05/24/2017] [Accepted: 06/04/2017] [Indexed: 06/07/2023]
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers in the world, and represents the second most frequently cancer and third most common cause of death from cancer worldwide. At advanced stage, HCC is a highly aggressive tumor with a poor prognosis and with very limited response to common therapies. Therefore, there is still the need for new effective and well-tolerated therapeutic strategies. Molecular-targeted therapies hold promise for HCC treatment. One promising molecular target is the multifunctional serine/threonine kinase glycogen synthase kinase 3 (GSK-3). The roles of GSK-3β in HCC remain controversial, several studies suggested a possible role of GSK-3β as a tumor suppressor gene in HCC, whereas, other studies indicate that GSK-3β is a potential therapeutic target for this neoplasia. In this review, we will focus on the different roles that GSK-3 plays in HCC and its interaction with signaling pathways implicated in the pathogenesis of HCC, such as Insulin-like Growth Factor (IGF), Notch, Wnt/β-catenin, Hedgehog (HH), and TGF-β pathways. In addition, the pivotal roles of GSK3 in epithelial-mesenchymal transition (EMT), invasion and metastasis will be also discussed.
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Affiliation(s)
- Melchiorre Cervello
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy.
| | - Giuseppa Augello
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Antonella Cusimano
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Maria Rita Emma
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Daniele Balasus
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - Antonina Azzolina
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy
| | - James A McCubrey
- Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, NC, USA
| | - Giuseppe Montalto
- Institute of Biomedicine and Molecular Immunology "Alberto Monroy", National Research Council (CNR), Palermo, Italy; Biomedic Department of Internal Medicine and Specialties (DiBiMIS), University of Palermo, Palermo, Italy
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45
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Vishnoi K, Mahata S, Tyagi A, Pandey A, Verma G, Jadli M, Singh T, Singh SM, Bharti AC. Cross-talk between Human Papillomavirus Oncoproteins and Hedgehog Signaling Synergistically Promotes Stemness in Cervical Cancer Cells. Sci Rep 2016; 6:34377. [PMID: 27678330 PMCID: PMC5039669 DOI: 10.1038/srep34377] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2016] [Accepted: 09/12/2016] [Indexed: 12/22/2022] Open
Abstract
Viral oncoproteins E6/E7 play key oncogenic role in human papillomavirus (HPV)-mediated cervical carcinogenesis in conjunction with aberrant activation of cellular signaling events. GLI-signaling has been implicated in metastasis and tumor recurrence of cervical cancer. However, the interaction of GLI-signaling with HPV oncogenes is unknown. We examined this relationship in established HPV-positive and HPV-negative cervical cancer cell lines using specific GLI inhibitor, cyclopamine and HPVE6/E7 siRNAs. Cervical cancer cell lines showed variable expression of GLI-signaling components. HPV16-positive SiHa cells, overexpressed GLI1, Smo and Patch. Inhibition by cyclopamine resulted in dose-dependent reduction of Smo and GLI1 and loss of cell viability with a higher magnitude in HPV-positive cells. Cyclopamine selectively downregulated HPVE6 expression and resulted in p53 accumulation, whereas HPVE7 and pRb level remained unaffected. siRNA-mediated silencing of HPV16E6 demonstrated reduced GLI1 transcripts in SiHa cells. Cervical cancer stem-like cells isolated by side population analysis, displayed retention of E6 and GLI1 expression. Fraction of SP cells was reduced in cyclopamine-treated cultures. When combined with E6-silencing cyclopamine resulted in loss of SP cell’s sphere-forming ability. Co-inhibition of GLI1 and E6 in cervical cancer cells showed additive anti-cancer effects. Overall, our data show existence of a cooperative interaction between GLI signaling and HPVE6.
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Affiliation(s)
- Kanchan Vishnoi
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.,Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.,School of Biotechnology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Sutapa Mahata
- Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India
| | - Abhishek Tyagi
- Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.,Molecular Oncology Laboratory, B.R. Ambedkar Center for Biomedical Research (ACBR), University of Delhi, New Delhi, India
| | - Arvind Pandey
- Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India
| | - Gaurav Verma
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.,Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India.,School of Biotechnology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Mohit Jadli
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.,Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India
| | - Tejveer Singh
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.,Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India
| | - Sukh Mahendra Singh
- School of Biotechnology, Banaras Hindu University, Varanasi, Uttar Pradesh, India
| | - Alok C Bharti
- Molecular Oncology Laboratory, Department of Zoology, University of Delhi, Delhi, India.,Division of Molecular Oncology, Institute of Cytology &Preventive Oncology (ICMR), Noida, Uttar Pradesh, India
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Hyun J, Jung Y. MicroRNAs in liver fibrosis: Focusing on the interaction with hedgehog signaling. World J Gastroenterol 2016; 22:6652-6662. [PMID: 27547008 PMCID: PMC4970468 DOI: 10.3748/wjg.v22.i29.6652] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 06/08/2016] [Accepted: 06/29/2016] [Indexed: 02/06/2023] Open
Abstract
Liver fibrosis is a repair process in response to damage in the liver; however, severe and chronic injury promotes the accumulation of fibrous matrix, destroying the normal functions and architecture of liver. Hepatic stellate cells (HSCs) are quiescent in normal livers, but in damaged livers, they transdifferentiate into myofibroblastic HSCs, which produce extracellular matrix proteins. Hedgehog (Hh) signaling orchestrates tissue reconstruction in damaged livers and contributes to liver fibrogenesis by regulating HSC activation. MicroRNAs (miRNAs), endogenous small non-coding RNAs interfering with RNA post-transcriptionally, regulate various cellular processes in healthy organisms. The dysregulation of miRNAs is closely associated with diseases, including liver diseases. Thus, miRNAs are good targets in the diagnosis and treatment of various diseases, including liver fibrosis; however, the regulatory mechanisms of miRNAs that interact with Hh signaling in liver fibrosis remain unclear. We review growing evidence showing the association of miRNAs with Hh signaling. Recent studies suggest that Hh-regulating miRNAs induce inactivation of HSCs, leading to decreased hepatic fibrosis. Although miRNA-delivery systems and further knowledge of interacting miRNAs with Hh signaling need to be improved for the clinical usage of miRNAs, recent findings indicate that the miRNAs regulating Hh signaling are promising therapeutic agents for treating liver fibrosis.
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Hyun J, Wang S, Kim J, Rao KM, Park SY, Chung I, Ha CS, Kim SW, Yun YH, Jung Y. MicroRNA-378 limits activation of hepatic stellate cells and liver fibrosis by suppressing Gli3 expression. Nat Commun 2016; 7:10993. [PMID: 27001906 PMCID: PMC4804167 DOI: 10.1038/ncomms10993] [Citation(s) in RCA: 183] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2015] [Accepted: 02/09/2016] [Indexed: 12/14/2022] Open
Abstract
Hedgehog (Hh) signalling regulates hepatic fibrogenesis. MicroRNAs (miRNAs) mediate various cellular processes; however, their role in liver fibrosis is unclear. Here we investigate regulation of miRNAs in chronically damaged fibrotic liver. MiRNA profiling shows that expression of miR-378 family members (miR-378a-3p, miR-378b and miR-378d) declines in carbon tetrachloride (CCl4)-treated compared with corn-oil-treated mice. Overexpression of miR-378a-3p, directly targeting Gli3 in activated hepatic stellate cells (HSCs), reduces expression of Gli3 and profibrotic genes but induces gfap, the inactivation marker of HSCs, in CCl4-treated liver. Smo blocks transcriptional expression of miR-378a-3p by activating the p65 subunit of nuclear factor-κB (NF-κB). The hepatic level of miR-378a-3p is inversely correlated with the expression of Gli3 in tumour and non-tumour tissues in human hepatocellular carcinoma. Our results demonstrate that miR-378a-3p suppresses activation of HSCs by targeting Gli3 and its expression is regulated by Smo-dependent NF-κB signalling, suggesting miR-378a-3p has therapeutic potential for liver fibrosis.
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Affiliation(s)
- Jeongeun Hyun
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea
| | - Sihyung Wang
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea
| | - Jieun Kim
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea
| | - Kummara Madhusudana Rao
- Department of Polymer Science and Engineering, College of Engineering, Pusan National University, Pusan, 46241, Korea
| | - Soo Yong Park
- Department of Polymer Science and Engineering, College of Engineering, Pusan National University, Pusan, 46241, Korea
| | - Ildoo Chung
- Department of Polymer Science and Engineering, College of Engineering, Pusan National University, Pusan, 46241, Korea
| | - Chang-Sik Ha
- Department of Polymer Science and Engineering, College of Engineering, Pusan National University, Pusan, 46241, Korea
| | - Sang-Woo Kim
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea
- Department of Biological Sciences, College of Natural Science, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan 46241, Korea
| | - Yang H. Yun
- Department of Biomedical Engineering, College of Engineering, The University of Akron, Akron, Ohio 44685-0302, USA
| | - Youngmi Jung
- Department of Integrated Biological Science, College of Natural Science, Pusan National University, Pusan 46241, Korea
- Department of Biological Sciences, College of Natural Science, Pusan National University, 63-2 Pusandaehak-ro, Kumjeong-gu, Pusan 46241, Korea
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Liver X receptor α is essential for the capillarization of liver sinusoidal endothelial cells in liver injury. Sci Rep 2016; 6:21309. [PMID: 26887957 PMCID: PMC4758044 DOI: 10.1038/srep21309] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Accepted: 01/20/2016] [Indexed: 02/06/2023] Open
Abstract
Liver X receptors (LXRs) play essential roles in lipogenesis, anti-inflammatory action and hepatic stellate cells (HSCs) activation in the liver. However, the effects of LXRs on the capillarization of liver sinusoidal endothelial cells (LSECs) in liver fibrosis remain undetermined. Here, we demonstrated that LXRα plays an important role in LSECs capillarization in a manner that involved Hedgehog (Hh) signaling. We found that LXRα expression in LSECs was increased in the carbon tetrachloride (CCl4)-induced fibrosis model. LXRα deletion markedly exacerbated CCl4-induced lesions assessed by histopathology, as well as inflammation and collagen deposition. Furthermore, capillarization of the sinusoids was aggravated in CCl4 -treated LXRα-deficient mice, as evidenced by increased CD34 expression, the formation of continuous basement membranes and aggravation of the loss of fenestrae. In vitro, LXR agonist could maintain freshly isolated LSECs differentiation on day 3. Furthermore, LXRα deletion led to increased expression of Hedgehog (Hh)-regulated gene in LSECs in the injured liver. Conversely, the LXR agonist could inhibit the Hh pathway in cultured LSECs. These responses indicated that LXRα suppressed the process of LSECs capillarization by repressing Hh signaling. Overall, our findings suggest that LXRα, by restoring the differentiation of LSECs, may be critical for the regression of liver fibrosis.
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Macrophages and endothelial cells orchestrate tumor-associated angiogenesis in oral cancer via hedgehog pathway activation. Tumour Biol 2016; 37:9233-41. [DOI: 10.1007/s13277-015-4763-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2015] [Accepted: 12/29/2015] [Indexed: 12/16/2022] Open
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50
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New Mechanism of Hepatic Fibrogenesis: Hepatitis C Virus Infection Induces Transforming Growth Factor β1 Production through Glucose-Regulated Protein 94. J Virol 2015; 90:3044-55. [PMID: 26719248 DOI: 10.1128/jvi.02976-15] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2015] [Accepted: 12/23/2015] [Indexed: 12/19/2022] Open
Abstract
UNLABELLED Hepatitis C virus (HCV) is one of the leading causes of chronic liver inflammatory disease (hepatitis), which often leads to more severe diseases, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma. Liver fibrosis, in particular, is a major pathogenic consequence of HCV infection, and transforming growth factor β1 (TGF-β1) plays a key role in its pathogenesis. Several HCV proteins have been suggested to either augment or suppress the expression of TGF-β1 by HCV-infected cells. Here, we report that TGF-β1 levels are elevated in HCV-infected hepatocytes cultured in vitro and in liver tissue of HCV patients. Notably, the level of TGF-β1 in media from in vitro-cultured HCV-infected hepatocytes was high enough to activate primary hepatic stellate cells isolated from rats. This indicates that TGF-β1 secreted by HCV-infected hepatocytes is likely to play a key role in the liver fibrosis observed in HCV patients. Moreover, we showed that HCV E2 protein triggers the production of TGF-β1 by HCV-infected cells through overproduction of glucose-regulated protein 94 (GRP94). IMPORTANCE Hepatic fibrosis is a critical step in liver cirrhosis caused by hepatitis C virus infection. It is already known that immune cells, including Kupffer cells, mediate liver fibrosis. Recently, several papers have suggested that HCV-infected hepatocytes also significantly produce TGF-β1. Here, we provide the first examination of TGF-β1 levels in the hepatocytes of HCV patients. Using an HCV culture system, we showed that HCV infection increases TGF-β1 production in hepatocytes. Furthermore, we confirmed that the amount of TGF-β1 secreted by HCV-infected hepatocytes was sufficient to activate primary hepatic stellate cells. To understand the molecular basis of TGF-β1 production in HCV-infected hepatocytes, we used HCV replicons and various stable cell lines. Finally, we elucidated that HCV E2 triggered TGF-β1 secretion via GRP94 mediated NF-κB activation. This study contributes to the understanding of liver fibrosis by HCV and suggests a new potential target (GRP94) for blocking liver cirrhosis in HCV patients.
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