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Piao Q, Bian X, Zhao Q, Sun L. Unraveling Glypican-3: From Structural to Pathophysiological Roles and Mechanisms-An Integrative Perspective. Cells 2025; 14:726. [PMID: 40422229 DOI: 10.3390/cells14100726] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2025] [Revised: 05/09/2025] [Accepted: 05/13/2025] [Indexed: 05/28/2025] Open
Abstract
Glypican3 (GPC3), initially cloned from rats 40 years ago, deeply participates in the development and homeostasis of multiple tissues and organs. Dysregulation of GPC3 is associated with cancerous and noncancerous diseases. Loss of the function of GPC3 leads to Simpson-Golabi-Behmel syndrome (SGBS), which is characterized by pre- and postnatal overgrowth. However, GPC3 exerts both promotive and inhibitory roles in cancer development. Recent studies suggest that the dual roles of GPC3 in cancer may be attributed to its structural features. This review comprehensively summarizes the structural features, pathophysiological functions, and underlying mechanism of GPC3 and finally discuss the relationship between its structural modification and functions, aiming to provide a theoretical basis for the development of novel therapeutic strategies targeting GPC3 to treat diseases including cancer.
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Affiliation(s)
- Qianling Piao
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
| | - Xiaona Bian
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
| | - Qi Zhao
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
| | - Luguo Sun
- National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
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Zhou X, Liu Y, Liu X, Song X, Li S, Chen P, Jiang X, Li Y. Novel GPC3 N-terminal bispecific antibody exhibits dual anti-tumor effect against tumor cells. Invest New Drugs 2025:10.1007/s10637-025-01530-x. [PMID: 40307410 DOI: 10.1007/s10637-025-01530-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2025] [Accepted: 04/10/2025] [Indexed: 05/02/2025]
Abstract
Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality worldwide, with poor prognosis and limited treatment options, particularly in advanced stages. Glypican-3 (GPC3) has emerged as a promising therapeutic target, but existing antibodies primarily bind its C-terminal region, where glycosylation can mask epitopes and compromise efficacy. To address this limitation, we focused on the GPC3 N-terminal region, which offers better accessibility and potential for tumor signaling regulation. We developed Pro-12, a high-affinity humanized IgG1 antibody targeting the 25-45 peptide of the GPC3 N-terminus, avoiding glycosylation interference while modulating tumor pathways. Building on Pro-12, we engineered a GPC3/CD3 bispecific antibody (BsAb) using CrossMab and Knob-into-Hole technologies. This BsAb demonstrated dual anti-tumor effects by activating immune cells and inhibiting both the Wnt/β-catenin and PI3K/AKT pathways, achieving outcomes typically requiring tri-specific antibodies. Our findings highlight the GPC3 N-terminal region as a novel therapeutic target and introduce a promising bispecific antibody approach for the treatment of GPC3-positive HCC.
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Affiliation(s)
- Xinsheng Zhou
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, China
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Yixin Liu
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Xuan Liu
- Department of Pediatrics, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Xu Song
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Sijie Li
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Peng Chen
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, China
| | - Xiaotao Jiang
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
- Guangdong Provincial Key Laboratory of Proteomics, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China.
| | - Yongyin Li
- Department of Infectious Diseases, Nanfang Hospital, Southern Medical University; State Key Laboratory of Organ Failure Research; Guangdong Provincial Key Laboratory for Prevention and Control of Major Liver Diseases, Key Laboratory of Infectious Diseases Research in South China (Southern Medical University), Ministry of Education, Guangzhou, China.
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Zheng Z, Zhao L, Zhao S, Wu Z, Wu N. A rare germline mutation reverses the suppressive effect of GPC5 thereby promoting lung adenocarcinoma development and tumorigenesis. Front Genet 2025; 16:1582504. [PMID: 40352786 PMCID: PMC12062016 DOI: 10.3389/fgene.2025.1582504] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2025] [Accepted: 04/14/2025] [Indexed: 05/14/2025] Open
Abstract
Background and Objective Glypican-5 (GPC5) has been well-characterized as a tumor suppressor in lung adenocarcinoma (LUAD); however, the functional implications of its germline mutations in cancer pathogenesis remain largely unexplored. In this study, we identified and characterized a pathogenic GPC5 variant (c.776C>T, p.Pro259Leu) within a Chinese LUAD pedigree, systematically investigating its oncogenic mechanisms through comprehensive molecular and cellular analyses. Methods Our investigation employed a multifaceted approach beginning with the recruitment of a LUAD-affected family cohort (n=4 patients, 1 healthy control), followed by exome sequencing of matched blood and FFPE tumor samples. Through rigorous rare variant analysis, we prioritized the GPC5 c.776C>T variant, subsequently validating its pathogenicity via integrated computational modeling and immunohistochemical profiling. Mechanistic studies in A549 and H2009 LUAD cell lines encompassed: (1) comprehensive proliferation and apoptosis assessment using CCK-8, colony formation, EdU incorporation, and flow cytometry; (2) migration and invasion evaluation through Transwell and wound healing assays; (3) EMT/Wnt pathway interrogation via Western blot analysis of E-cadherin, N-cadherin, Vimentin, and β-catenin expression patterns; and (4) definitive functional validation through GPC5 overexpression and knockdown experiments. Results Genetic analysis revealed the GPC5 c.776C>T variant exhibited complete cosegregation with LUAD phenotype in the pedigree while being absent in control populations (gnomAD frequency: 0.000003989), accompanied by significantly reduced GPC5 expression in tumor tissues. Functional characterization demonstrated that compared to wild-type, the mutant variant conferred aggressive oncogenic properties: significantly enhanced proliferative capacity, impaired apoptosis induction, and markedly increased migratory potential. Molecular analyses revealed the mutant promoted EMT activation through nuclear β-catenin accumulation and subsequent upregulation of mesenchymal markers. Crucially, siRNA-mediated GPC5 knockdown phenocopied these oncogenic effects, providing definitive evidence of its tumor-suppressive function. Discussion Our findings establish that the GPC5 c.776C>T mutation drives LUAD progression through a novel molecular mechanism involving impaired β-catenin degradation, subsequent nuclear translocation, and consequent EMT activation. These results position GPC5 as a critical nodal regulator of Wnt/β-catenin signaling in LUAD pathogenesis and suggest its germline mutations may serve as valuable biomarkers for hereditary LUAD risk assessment. Therapeutically, these findings highlight the potential utility of Wnt pathway inhibitors in managing GPC5-mutant LUAD cases, while also providing a molecular framework for future investigations into glypican family members in cancer biology.
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Affiliation(s)
- Zhifa Zheng
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care, Beijing, China
- Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
| | - Lina Zhao
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care, Beijing, China
- Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
| | - Sen Zhao
- Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States
| | - Zhihong Wu
- Medical Research Center, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care, Beijing, China
- Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
| | - Nan Wu
- Department of Orthopedic Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
- Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care, Beijing, China
- Key Laboratory of Big Data for Spinal Deformities, Chinese Academy of Medical Sciences, Beijing, China
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Tsao HE, Ho M. Structural Features of Glypicans and their Impact on Wnt Signaling in Cancer. PROTEOGLYCAN RESEARCH 2025; 3:e70029. [PMID: 40416340 PMCID: PMC12101617 DOI: 10.1002/pgr2.70029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 03/31/2025] [Accepted: 04/30/2025] [Indexed: 05/27/2025]
Abstract
Glypicans (GPCs) are a family of cell surface proteoglycans involved in multiple signaling pathways that regulate cell fate and proliferation. They share a characteristic structure composed of a core protein with two or more heparan sulfate chains and a glycosyl-phosphatidylinositol anchor that attaches them to the cell membrane. Aberrant expression of certain glypicans such as GPC1, GPC2, and GPC3 has been found in multiple types of cancer and causes the dysregulation of Wnt, hedgehog, and other signaling pathways, making them emerging targets for cancer immunotherapy. The molecular mechanism by which glypicans interact with signaling factors will provide insights for the development of cancer therapeutics. However, the structural complexes of human glypicans with Wnt and other key signaling factors remain unsolved. In this brief review, we analyze the current protein structural evidence for glypicans, with an emphasis on their interaction with Wnt, in an effort to provide insights to understand the molecular mechanisms by which glypicans play positive or negative roles in Wnt signaling in cancer and to discuss their translational potentials.
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Affiliation(s)
- Hsi-En Tsao
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, United States of America
| | - Mitchell Ho
- Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, United States of America
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Tehrani HA, Zangi M, Fathi M, Vakili K, Hassan M, Rismani E, Hossein-Khannazer N, Vosough M. GPC-3 in hepatocellular carcinoma; A novel biomarker and molecular target. Exp Cell Res 2025; 444:114391. [PMID: 39725192 DOI: 10.1016/j.yexcr.2024.114391] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 12/11/2024] [Accepted: 12/19/2024] [Indexed: 12/28/2024]
Abstract
Hepatocellular carcinoma (HCC) is a global health issue due to its late diagnosis and high recurrence rate. The early detection and diagnosis of HCC with specific and sensitive biomarkers and using novel treatment approaches to improve patient outcomes are essential. Glypican-3 (GPC-3) is a cell surface proteoglycan that is overexpressed in many tumors, including HCC. GPC-3 could be used as a specific biomarker for HCC early detection and could be a potential target for precise therapeutic strategies. Effective identification of GPC-3 could improve both diagnosis and targeted therapy of HCC. Moreover, targeted therapy using GPC-3 could result in a better treatment outcome. Recently, GPC3-targeted therapies have been used in different investigational therapeutic approaches like bi-specific/monoclonal antibodies, peptide vaccines, and CAR T cell therapies. This study aims to highlight the theranostic potential of GPC-3 as a novel biomarker for early detection and as a potential molecular target for HCC treatment as well.
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Affiliation(s)
- Hamed Azhdari Tehrani
- Department of Hematology-Medical Oncology, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Masood Zangi
- Critical Care Quality Improvement Research Center, Loghman Hakim Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mobina Fathi
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kimia Vakili
- Faculty of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Elham Rismani
- Molecular Medicine Department, Biotechnology Research Center (BRC), Pasteur Institute of Iran, Tehran, Iran
| | - Nikoo Hossein-Khannazer
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Massoud Vosough
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden; Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran; Department of Cellular and Molecular Biology, Faculty of Sciences and Advanced Technology in Biology, University of Science and Culture, Tehran, Iran.
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Petit LM, Saber Cherif L, Devilliers MA, Hatoum S, Ancel J, Delepine G, Durlach A, Dubernard X, Mérol JC, Ruaux C, Polette M, Deslée G, Perotin JM, Dormoy V. Glypican-3 is a key tuner of the Hedgehog pathway in COPD. Heliyon 2025; 11:e41564. [PMID: 39844999 PMCID: PMC11751517 DOI: 10.1016/j.heliyon.2024.e41564] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Revised: 12/12/2024] [Accepted: 12/27/2024] [Indexed: 01/24/2025] Open
Abstract
Hedgehog (HH) pathway is involved in pulmonary development and lung homeostasis. It orchestrates airway epithelial cell (AEC) differentiation and contributes to respiratory pathogenesis. The core elements Gli2, Smo, and Shh were found altered in the bronchial epithelium of patients with chronic obstructive pulmonary disease (COPD). Here, we investigated the co-receptors to fully decipher the complex machinery of airway HH pathway activation in health and COPD. The core elements and co-receptors of HH signalling were investigated in lung cell populations using single-cell RNAseq analysis. The transcript levels of the principal co-receptor GPC3 were investigated on public RNAseq datasets and by RT-qPCR. The localisation of GPC3 was evaluated through immunofluorescent stainings on isolated bronchial AEC and tissues from non-COPD and COPD patients. GPC3 pharmacological modulation was achieved with Codrituzumab during AEC differentiation. We demonstrated that the core elements were not abundant in pulmonary cell populations. Focusing on co-receptors, GPC3 was the most expressed transcript in tracheobronchial epithelial cells. The decrease in GPC3 transcript levels correlated with the severity of airway obstrution in COPD patients. Finally, interfering with GPC3 signalling during AEC differentiation induced downregulation of the HH pathway attested by a decrease of Gli2 leading to reduced ciliogenesis and altered mucin production. GPC3 appears as a crucial co-receptor for the HH pathway in the respiratory context. The modulation of GPC3 may represent a novel experimental strategy to tune HH signalling in therapeutic perspectives.
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Affiliation(s)
- Laure M.G. Petit
- Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France
| | - Lynda Saber Cherif
- Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France
| | - Maëva A. Devilliers
- Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France
| | - Sarah Hatoum
- Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France
| | - Julien Ancel
- Université de Reims Champagne-Ardenne, INSERM, CHU de Reims, P3Cell UMR-S1250, Reims, France
| | - Gonzague Delepine
- Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France
| | - Anne Durlach
- Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France
| | - Xavier Dubernard
- Université de Reims Champagne-Ardenne, CHU de Reims, Reims, France
| | - Jean-Claude Mérol
- Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France
| | - Christophe Ruaux
- Clinique Mutualiste La Sagesse, Département d’Otorhinolaryngologie, Rennes, France
| | - Myriam Polette
- Université de Reims Champagne-Ardenne, INSERM, CHU de Reims, P3Cell UMR-S1250, Reims, France
| | - Gaëtan Deslée
- Université de Reims Champagne-Ardenne, INSERM, CHU de Reims, P3Cell UMR-S1250, Reims, France
| | - Jeanne-Marie Perotin
- Université de Reims Champagne-Ardenne, INSERM, CHU de Reims, P3Cell UMR-S1250, Reims, France
| | - Valérian Dormoy
- Université de Reims Champagne-Ardenne, INSERM, P3Cell UMR-S1250, Reims, France
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Batbaatar B, Gurbadam U, Tuvshinsaikhan O, Narmandakh NE, Khatanbaatar G, Radnaabazar M, Erdene-Ochir D, Boldbaatar M, Byambaragchaa M, Amankyeldi Y, Chogsom M, Ganbileg N, Batdelger A, Demchig T, Nyam-Osor L, Bayartugs B, Batmunkh E, Munkhjargal B, Lonjid T, Khasbagana B, Batmunkh M, Jav S, Semchin M. Evaluation of glypican‑3 in patients with hepatocellular carcinoma. Mol Clin Oncol 2025; 22:1. [PMID: 39534882 PMCID: PMC11552472 DOI: 10.3892/mco.2024.2796] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Accepted: 10/03/2024] [Indexed: 11/16/2024] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common cancers occurring worldwide, including Mongolia. Although alpha-fetoprotein (AFP) is a widely used marker for HCC, conflicting studies have been published regarding its specificity and sensitivity towards HCC. Glypican-3 (GPC3) is a different promising biomarker for HCC, and there is some evidence to suggest that this protein may be a more specific marker compared with AFP. GPC3 has been shown to fulfill important roles in cell proliferation and division during embryogenesis, and is rarely found in the tissues of healthy adults. The aim of the present study was to investigate the levels of serum GPC3 (sGPC3) and tissue GPC3 in Mongolian patients with HCC. Serum samples from a total of 270 individuals [HCC group, 90 patients; risk group (RG), 90 subjects; and control group, 90 subjects] were evaluated using enzyme-linked immunosorbent assay to identify the sGPC3 levels. In addition, immunohistochemical analysis of the GPC3 was performed on tissue samples from 50 patients with HCC to evaluate the expression of GPC3. sGPC3 level was found to be significantly increased in the HCC group compared with the RG and the control group, with the area under the curve=0.85 (P<0.001). sGPC3 was found to be significantly associated with hepatitis C virus status and cirrhosis (P<0.05). In addition, the tissue expression of GPC3 was associated with the serum AFP (sAFP) level. Finally, positive staining of GPC3 was observed when the sAFP level of the patient was >20 ng/ml. In conclusion, the results from the present study have supported that GPC3 may be a promising marker for HCC, and can be used as a diagnostic marker alongside AFP.
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Affiliation(s)
- Batchimeg Batbaatar
- Department of Molecular biology and Genetics, School of Bio Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia
- Institute of Medical Sciences, Mongolian National University of Medical Sciences, The Third Central Hospital, Ulaanbaatar 16081, Mongolia
| | | | - Odonchimeg Tuvshinsaikhan
- Institute of Medical Sciences, Mongolian National University of Medical Sciences, The Third Central Hospital, Ulaanbaatar 16081, Mongolia
| | - Nyam-Erdene Narmandakh
- Institute of Medical Sciences, Mongolian National University of Medical Sciences, The Third Central Hospital, Ulaanbaatar 16081, Mongolia
| | | | | | | | | | | | | | | | | | | | | | - Lkham Nyam-Osor
- National Cancer Center of Mongolia, Ulaanbaatar 13370, Mongolia
| | | | | | - Batkhishig Munkhjargal
- Institute of Medical Sciences, Mongolian National University of Medical Sciences, The Third Central Hospital, Ulaanbaatar 16081, Mongolia
| | - Tulgaa Lonjid
- Institute of Medical Sciences, Mongolian National University of Medical Sciences, The Third Central Hospital, Ulaanbaatar 16081, Mongolia
| | - Batbayar Khasbagana
- Institute of Biomedical Sciences, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia
| | - Munkhbat Batmunkh
- School of Medicine, International University of Health and Welfare, Narita, Chiba 286-8686, Japan
| | - Sarantuya Jav
- Department of Molecular biology and Genetics, School of Bio Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar 14210, Mongolia
| | - Munkhbayar Semchin
- Institute of Medical Sciences, Mongolian National University of Medical Sciences, The Third Central Hospital, Ulaanbaatar 16081, Mongolia
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Rismani E, Hossein-Khannazer N, Hassan M, Shams E, Najimi M, Vosough M. Targeting glypican 3 by immunotoxins: the promise of immunotherapy in hepatocellular carcinoma. Expert Opin Ther Targets 2025; 29:59-73. [PMID: 39985417 DOI: 10.1080/14728222.2025.2471581] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Revised: 01/21/2025] [Accepted: 02/20/2025] [Indexed: 02/24/2025]
Abstract
INTRODUCTION Tumor cell's resistance, high recurrence rate, and low overall survival rate have made hepatocellular carcinoma (HCC) a major health concern. The combination of advanced targeted therapies such as immunotherapy, with conventional treatments has gained traction for application on HCC. Immunotoxins (ITs) represent a category of biomolecules that combine the targeted affinity of antibodies with the cytotoxic properties of toxins. AREAS COVERED This study highlights Glypican3 (GPC3) as a potential candidate for targeted therapeutic interventions using ITs. It presents a comprehensive overview of the advantages and challenges associated with these modalities, and their promising outcomes in HCC treatment. A systematic literature review was conducted using PubMed, Web of Science and Scopus from 2015 to 2024. EXPERT OPINION Despite potential applicability, many concerns should be addressed before the employment of GPC3-based ITs. These include improving efficient penetration of ITs into the solid tumors, considering neutralizing antibodies against the drugs, and enhancing serum half-life of ITs. Furthermore, the ITs potential in eliminating cancer stem cells (CSCs) and residual tumor cells is discussed. The ability to target CSCs can significantly reduce the likelihood of recurrence and improve overall survival rate. This could make ITs a pivotal component in the future of HCC treatment.
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Affiliation(s)
- Elham Rismani
- Molecular Medicine Department, Biotechnology Research Center (BRC), Pasteur Institute of Iran, Tehran, Iran
| | - Nikoo Hossein-Khannazer
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Moustapha Hassan
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Elahe Shams
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Mustapha Najimi
- Laboratory of Pediatric Hepatology and Cell Therapy, Institute of Experimental and Clinical Research (IREC), UCLouvain, Brussels, Belgium
| | - Massoud Vosough
- Experimental Cancer Medicine, Institution for Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Cellular and Molecular Biology, Faculty of Sciences and Advanced Technology in Biology, University of Science and Culture, Tehran, Iran
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Vaisfeld A, Neri G. Simpson-Golabi-Behmel syndrome. AMERICAN JOURNAL OF MEDICAL GENETICS. PART C, SEMINARS IN MEDICAL GENETICS 2024; 196:e32088. [PMID: 38766979 DOI: 10.1002/ajmg.c.32088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 04/18/2024] [Accepted: 04/27/2024] [Indexed: 05/22/2024]
Abstract
The Simpson-Golabi-Behmel syndrome (SGBS; OMIM 312870) is an overgrowth/multiple congenital anomalies/dysplasia condition, inherited as an X-linked semi-dominant trait, with variable expressivity in males and reduced penetrance and expressivity in females. The clinical spectrum is broad, ranging from mild manifestations in both males and females to multiple malformations and neonatal death in the more severely affected cases. An increased risk of neoplasia is reported, requiring periodical surveillance. Intellectual development is normal in most cases. SGBS is caused by a loss-of-function mutation of the GPC3 gene, either deletions or point mutations, distributed all over the gene. Notably, GPC3 deletion/point mutations are not found in a significant proportion of clinically diagnosed SGBS cases. The protein product GPC3 is a glypican functioning as a receptor for Hh at the cell surface, involved in the Hh-Ptc-Smo signaling pathway, a regulator of cellular growth.
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Affiliation(s)
- Alessandro Vaisfeld
- Medical Genetics Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Giovanni Neri
- Institute of Genomic Medicine, Catholic University School of Medicine, Rome, Italy
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Lamson DR, Tarpley M, Addo K, Ji X, Abu Rabe D, Ehe B, Hughes M, Smith GR, Daye LR, Musso DL, Zheng W, Williams KP. Identification of small molecule antagonists of sonic hedgehog/heparin binding with activity in hedgehog functional assays. Biochim Biophys Acta Gen Subj 2024; 1868:130692. [PMID: 39151833 PMCID: PMC11486593 DOI: 10.1016/j.bbagen.2024.130692] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Revised: 07/30/2024] [Accepted: 08/07/2024] [Indexed: 08/19/2024]
Abstract
Sonic hedgehog (Shh) is a morphogen with important roles in embryonic development and in the development of a number of cancers. Its activity is modulated by interactions with binding partners and co-receptors including heparin and heparin sulfate proteoglycans (HSPG). To identify antagonists of Shh/heparin binding, a diverse collection of 34,560 chemicals was screened in single point 384-well format. We identified and confirmed twenty six novel small molecule antagonists with diverse structures including four scaffolds that gave rise to multiple hits. Nineteen of the confirmed hits blocked binding of the N-terminal fragment of Shh (ShhN) to heparin with IC50 values < 50 μM. In the Shh-responsive C3H10T1/2 cell model, four of the compounds demonstrated the ability to block ShhN-induced alkaline phosphatase activity. To demonstrate a direct and selective effect on ShhN ligand mediated activity, two of the compounds were able to block induction of Gli1 mRNA, a primary downstream marker for Shh signaling activity, in Shh-mediated but not Smoothened agonist (SAG)-mediated C3H10T1/2 cells. Direct binding of the two compounds to ShhN was confirmed by thermal shift assay and molecular docking simulations, with both compounds docking with the N-terminal heparin binding domain of Shh. Overall, our findings indicate that small molecule compounds that block ShhN binding to heparin and act to inhibit Shh mediated activity in vitro can be identified. We propose that the interaction between Shh and HSPGs provides a novel target for identifying small molecules that bind Shh, potentially leading to novel tool compounds to probe Shh ligand function.
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Affiliation(s)
- David R Lamson
- Biomanufacturing Research Institute and Technology Enterprise, USA
| | - Michael Tarpley
- Biomanufacturing Research Institute and Technology Enterprise, USA
| | - Kezia Addo
- Biomanufacturing Research Institute and Technology Enterprise, USA
| | - Xiaojia Ji
- Biomanufacturing Research Institute and Technology Enterprise, USA
| | - Dina Abu Rabe
- Biomanufacturing Research Institute and Technology Enterprise, USA; INBS PhD Program, USA
| | - Ben Ehe
- Biomanufacturing Research Institute and Technology Enterprise, USA
| | - Mark Hughes
- Biomanufacturing Research Institute and Technology Enterprise, USA
| | - Ginger R Smith
- Biomanufacturing Research Institute and Technology Enterprise, USA
| | - Laura R Daye
- Biomanufacturing Research Institute and Technology Enterprise, USA
| | - David L Musso
- Biomanufacturing Research Institute and Technology Enterprise, USA
| | - Weifan Zheng
- Biomanufacturing Research Institute and Technology Enterprise, USA; Department of Pharmaceutical Sciences, North Carolina Central University, Durham, NC 27707, USA
| | - Kevin P Williams
- Biomanufacturing Research Institute and Technology Enterprise, USA; Department of Pharmaceutical Sciences, North Carolina Central University, Durham, NC 27707, USA.
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11
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Joladarashi D, Thej C, Mallaredy V, Magadum A, Cimini M, Gonzalez C, Truongcao M, Nigro JT, Sethi MK, Gibb AA, Benedict C, Koch WJ, Kishore R. GPC3-mediated metabolic rewiring of diabetic mesenchymal stromal cells enhances their cardioprotective functions via PKM2 activation. iScience 2024; 27:111021. [PMID: 39429777 PMCID: PMC11490746 DOI: 10.1016/j.isci.2024.111021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 08/02/2024] [Accepted: 09/20/2024] [Indexed: 10/22/2024] Open
Abstract
Mesenchymal stromal cells (MSC) are promising stem cell therapy for treating cardiovascular and other degenerative diseases. Diabetes affects the functional capability of MSC and impedes cell-based therapy. Despite numerous studies, the impact of diabetes on MSC myocardial reparative activity, metabolic fingerprint, and the mechanism of dysfunction remains inadequately perceived. We demonstrated that the transplantation of diabetic-MSC (db/db-MSC) into the ischemic myocardium of mice does not confer cardiac benefit post-MI. Metabolomic studies identified defective energy metabolism in db/db-MSC. Furthermore, we found that glypican-3 (GPC3), a heparan sulfate proteoglycan, is highly upregulated in db/db-MSC and is involved in metabolic alterations in db/db-MSC via pyruvate kinase M2 (PKM2) activation. GPC3-knockdown reprogrammed-db/db-MSC restored their energy metabolic rates, immunomodulation, angiogenesis, and cardiac reparative activities. Together, these data indicate that GPC3-metabolic reprogramming in diabetic MSC may represent a strategy to enhance MSC-based therapeutics for myocardial repair in diabetic patients.
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Affiliation(s)
- Darukeshwara Joladarashi
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Charan Thej
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Vandana Mallaredy
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Ajit Magadum
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Maria Cimini
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Carolina Gonzalez
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - May Truongcao
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Joseph T. Nigro
- Center for Biomedical Mass Spectrometry, Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Manveen K. Sethi
- Center for Biomedical Mass Spectrometry, Department of Biochemistry & Cell Biology, Boston University Chobanian and Avedisian School of Medicine, Boston, MA, USA
| | - Andrew A. Gibb
- Center for Cardiometabolic Science, Christina Lee Brown Envirome Institute, University of Louisville, 580 South Preston Street, Louisville, KY, USA
| | - Cindy Benedict
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
| | - Walter J. Koch
- Department of Surgery, Duke University School of Medicine, Durham, NC 27710, USA
| | - Raj Kishore
- Aging and Cardiovascular Discovery Center, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
- Department of Cardiovascular Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA
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12
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Robinson L, Smit C, van Heerden MB, Moolla H, Afrogheh AH, Opperman JF, Ambele MA, van Heerden WFP. Surrogate Immunohistochemical Markers of Proliferation and Embryonic Stem Cells in Distinguishing Ameloblastoma from Ameloblastic Carcinoma. Head Neck Pathol 2024; 18:92. [PMID: 39365497 PMCID: PMC11452366 DOI: 10.1007/s12105-024-01704-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/05/2024] [Accepted: 09/13/2024] [Indexed: 10/05/2024]
Abstract
PURPOSE The current study aimed to investigate the use of surrogate immunohistochemical (IHC) markers of proliferation and stem cells to distinguish ameloblastoma (AB) from ameloblastic carcinoma (AC). METHODS The study assessed a total of 29 ACs, 6 ABs that transformed into ACs, and a control cohort of 20 ABs. The demographics and clinicopathologic details of the included cases of AC were recorded. The Ki-67 proliferation index was scored through automated methods with the QuPath open-source software platform. For SOX2, OCT4 and Glypican-3 IHC, each case was scored using a proportion of positivity score combined with an intensity score to produce a total score. RESULTS All cases of AC showed a relatively high median proliferation index of 41.7%, with statistically significant higher scores compared to ABs. ABs that transformed into ACs had similar median proliferation scores to the control cohort of ABs. Most cases of AC showed some degree of SOX2 expression, with 58.6% showing high expression. OCT4 expression was not seen in any case of AC. GPC-3 expression in ACs was limited, with high expression in 17.2% of ACs. Primary ACs showed higher median proliferation scores and degrees of SOX2 and GPC-3 expression than secondary cases. Regarding SOX2, OCT4 and GPC-3 IHC expression, no statistically significant differences existed between the cohort of ABs and ACs. CONCLUSION Ki-67 IHC as a proliferation marker, particularly when assessed via automated methods, was helpful in distinguishing AC from AB cases. In contrast to other studies, surrogate IHC markers of embryonic stem cells, SOX2, OCT4 and GPC-3, were unreliable in distinguishing the two entities.
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Affiliation(s)
- Liam Robinson
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa.
| | - Chané Smit
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa
| | - Marlene B van Heerden
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa
| | - Haroon Moolla
- Centre for Infectious Disease Epidemiology and Research, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa
| | - Amir H Afrogheh
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, University of the Western Cape, Cape Town, South Africa
- Division of Anatomical Pathology, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Johan F Opperman
- Department of Oral and Maxillofacial Pathology, Faculty of Dentistry, University of the Western Cape, Cape Town, South Africa
- Division of Anatomical Pathology, Faculty of Health Sciences, Stellenbosch University, Cape Town, South Africa
| | - Melvin A Ambele
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa
- Institute for Cellular and Molecular Medicine, Extramural Unit for Stem Cell Research and Therapy, Faculty of Health Sciences, South African Medical Research Council, University of Pretoria, Pretoria, South Africa
| | - Willie F P van Heerden
- Department of Oral and Maxillofacial Pathology, Faculty of Health Sciences, University of Pretoria, Pretoria Oral Health Care Centre, Office 6-11, Corner of Steve Biko and Dr Savage Roads, Pretoria, 0084, South Africa
- PathCare Vermaak Histopathology Laboratory, Pretoria, South Africa
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13
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Yamamoto K, Scilabra SD, Bonelli S, Jensen A, Scavenius C, Enghild JJ, Strickland DK. Novel insights into the multifaceted and tissue-specific roles of the endocytic receptor LRP1. J Biol Chem 2024; 300:107521. [PMID: 38950861 PMCID: PMC11325810 DOI: 10.1016/j.jbc.2024.107521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2024] [Revised: 06/22/2024] [Accepted: 06/26/2024] [Indexed: 07/03/2024] Open
Abstract
Receptor-mediated endocytosis provides a mechanism for the selective uptake of specific molecules thereby controlling the composition of the extracellular environment and biological processes. The low-density lipoprotein receptor-related protein 1 (LRP1) is a widely expressed endocytic receptor that regulates cellular events by modulating the levels of numerous extracellular molecules via rapid endocytic removal. LRP1 also participates in signalling pathways through this modulation as well as in the interaction with membrane receptors and cytoplasmic adaptor proteins. LRP1 SNPs are associated with several diseases and conditions such as migraines, aortic aneurysms, cardiopulmonary dysfunction, corneal clouding, and bone dysmorphology and mineral density. Studies using Lrp1 KO mice revealed a critical, nonredundant and tissue-specific role of LRP1 in regulating various physiological events. However, exactly how LRP1 functions to regulate so many distinct and specific processes is still not fully clear. Our recent proteomics studies have identified more than 300 secreted proteins that either directly interact with LRP1 or are modulated by LRP1 in various tissues. This review will highlight the remarkable ability of this receptor to regulate secreted molecules in a tissue-specific manner and discuss potential mechanisms underpinning such specificity. Uncovering the depth of these "hidden" specific interactions modulated by LRP1 will provide novel insights into a dynamic and complex extracellular environment that is involved in diverse biological and pathological processes.
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Affiliation(s)
- Kazuhiro Yamamoto
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom.
| | - Simone D Scilabra
- Proteomics Group of Ri.MED Foundation, Research Department IRCCS ISMETT, Palermo, Italy
| | - Simone Bonelli
- Proteomics Group of Ri.MED Foundation, Research Department IRCCS ISMETT, Palermo, Italy; Department of Biological, Chemical and Pharmaceutical Sciences and Technologies, University of Palermo, Palermo, Italy
| | - Anders Jensen
- Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, United Kingdom
| | - Carsten Scavenius
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Jan J Enghild
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Dudley K Strickland
- Center for Vascular and Inflammatory Diseases, University of Maryland School of Medicine, Baltimore, Maryland, USA
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14
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de Haan LR, van Golen RF, Heger M. Molecular Pathways Governing the Termination of Liver Regeneration. Pharmacol Rev 2024; 76:500-558. [PMID: 38697856 DOI: 10.1124/pharmrev.123.000955] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2023] [Revised: 01/24/2024] [Accepted: 02/08/2024] [Indexed: 05/05/2024] Open
Abstract
The liver has the unique capacity to regenerate, and up to 70% of the liver can be removed without detrimental consequences to the organism. Liver regeneration is a complex process involving multiple signaling networks and organs. Liver regeneration proceeds through three phases: the initiation phase, the growth phase, and the termination phase. Termination of liver regeneration occurs when the liver reaches a liver-to-body weight that is required for homeostasis, the so-called "hepatostat." The initiation and growth phases have been the subject of many studies. The molecular pathways that govern the termination phase, however, remain to be fully elucidated. This review summarizes the pathways and molecules that signal the cessation of liver regrowth after partial hepatectomy and answers the question, "What factors drive the hepatostat?" SIGNIFICANCE STATEMENT: Unraveling the pathways underlying the cessation of liver regeneration enables the identification of druggable targets that will allow us to gain pharmacological control over liver regeneration. For these purposes, it would be useful to understand why the regenerative capacity of the liver is hampered under certain pathological circumstances so as to artificially modulate the regenerative processes (e.g., by blocking the cessation pathways) to improve clinical outcomes and safeguard the patient's life.
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Affiliation(s)
- Lianne R de Haan
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Rowan F van Golen
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
| | - Michal Heger
- Jiaxing Key Laboratory for Photonanomedicine and Experimental Therapeutics, Department of Pharmaceutics, College of Medicine, Jiaxing University, Jiaxing, China (L.R.d.H., M.H.); Department of Internal Medicine, Noordwest Ziekenhuisgroep, Alkmaar, The Netherlands (L.R.d.H.); Department of Gastroenterology and Hepatology, Leiden University Medical Center, Leiden, The Netherlands (R.F.v.G.); Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands (M.H.); and Membrane Biochemistry and Biophysics, Department of Chemistry, Faculty of Science, Utrecht University, Utrecht, The Netherlands (M.H.)
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15
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Melrose J. Hippo cell signaling and HS-proteoglycans regulate tissue form and function, age-dependent maturation, extracellular matrix remodeling, and repair. Am J Physiol Cell Physiol 2024; 326:C810-C828. [PMID: 38223931 DOI: 10.1152/ajpcell.00683.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2023] [Revised: 01/09/2024] [Accepted: 01/09/2024] [Indexed: 01/16/2024]
Abstract
This review examined how Hippo cell signaling and heparan sulfate (HS)-proteoglycans (HSPGs) regulate tissue form and function. Despite being a nonweight-bearing tissue, the brain is regulated by Hippo mechanoresponsive cell signaling pathways during embryonic development. HS-proteoglycans interact with growth factors, morphogens, and extracellular matrix components to regulate development and pathology. Pikachurin and Eyes shut (Eys) interact with dystroglycan to stabilize the photoreceptor axoneme primary cilium and ribbon synapse facilitating phototransduction and neurotransduction with bipolar retinal neuronal networks in ocular vision, the primary human sense. Another HSPG, Neurexin interacts with structural and adaptor proteins to stabilize synapses and ensure specificity of neural interactions, and aids in synaptic potentiation and plasticity in neurotransduction. HSPGs also stabilize the blood-brain barrier and motor neuron basal structures in the neuromuscular junction. Agrin and perlecan localize acetylcholinesterase and its receptors in the neuromuscular junction essential for neuromuscular control. The primary cilium is a mechanosensory hub on neurons, utilized by YES associated protein (YAP)-transcriptional coactivator with PDZ-binding motif (TAZ) Hippo, Hh, Wnt, transforming growth factor (TGF)-β/bone matrix protein (BMP) receptor tyrosine kinase cell signaling. Members of the glypican HSPG proteoglycan family interact with Smoothened and Patched G-protein coupled receptors on the cilium to regulate Hh and Wnt signaling during neuronal development. Control of glycosyl sulfotransferases and endogenous protease expression by Hippo TAZ YAP represents a mechanism whereby the fine structure of HS-proteoglycans can be potentially modulated spatiotemporally to regulate tissue morphogenesis in a similar manner to how Hippo signaling controls sialyltransferase expression and mediation of cell-cell recognition, dysfunctional sialic acid expression is a feature of many tumors.
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Affiliation(s)
- James Melrose
- Raymond Purves Laboratory, Institute of Bone and Joint Research, Kolling Institute of Medical Research, University of Sydney, Northern Sydney Local Health District, Royal North Shore Hospital, St. Leonards, New South Wales, Australia
- Sydney Medical School-Northern, University of Sydney at Royal North Shore Hospital, St. Leonards, New South Wales, Australia
- Graduate School of Biomedical Engineering, University of New South Wales, Sydney, New South Wales, Australia
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16
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Qin Y, Xu Y, Yi H, Shi L, Wang X, Wang W, Li F. Unique structural characteristics and biological activities of heparan sulfate isolated from the mantle of the scallop Chlamys farreri. Carbohydr Polym 2024; 324:121431. [PMID: 37985034 DOI: 10.1016/j.carbpol.2023.121431] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2023] [Accepted: 09/23/2023] [Indexed: 11/22/2023]
Abstract
Marine animals are a huge resource of various glycosaminoglycans (GAGs) with specific structures and functions. A large number of byproducts, such as low-edible mantle, are produced during the processing of Chlamys farreri, which is one of the most cultured scallops in China. In this study, a major GAG component was isolated from the mantle of C. farreri, and its structural characteristics and biological activities were determined in detail. Preliminary analysis by agarose electrophoresis combined with specific enzymatic degradation evaluations showed that this component was heparan sulfate and was named CMHS. Further analysis by HPLC and NMR revealed that CMHS has an average molecular weight of 35.9 kDa and contains a high proportion (80%) of 6-O-sulfated N-acetyl-D-glucosamine/N-sulfated-D-glucosamine (6-O-sulfated GlcNAc/GlcNS) residues and rare 3-O-sulfated β-D-glucuronic acid residues. Bioactivity analysis showed that CMHS has much lower anticoagulant activity than heparin and it can interact with various growth factors with high affinity. Moreover, CMHS binds strongly to the morphogen Wnt 3a to inhibit glypican-3-stimulated Wnt 3a signaling. Thus, the identification of CMHS with unique structural and bioactive features will provide a promising candidate for the development of GAG-type pharmaceutical products and promote the high-value utilization of C. farreri mantle.
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Affiliation(s)
- Yong Qin
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology and State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Rd, Qingdao 266237, People's Republic of China
| | - Yingying Xu
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology and State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Rd, Qingdao 266237, People's Republic of China
| | - Haixin Yi
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology and State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Rd, Qingdao 266237, People's Republic of China
| | - Liran Shi
- CSPC Megalith Biopharmaceutical Co., Ltd., Shijiazhuang 050000, People's Republic of China
| | - Xu Wang
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology and State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Rd, Qingdao 266237, People's Republic of China
| | - Wenshuang Wang
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology and State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Rd, Qingdao 266237, People's Republic of China.
| | - Fuchuan Li
- National Glycoengineering Research Center, Shandong Key Laboratory of Carbohydrate Chemistry and Glycobiology and State Key Laboratory of Microbial Technology, Shandong University, 72 Binhai Rd, Qingdao 266237, People's Republic of China.
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17
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Nakato E, Kamimura K, Knudsen C, Masutani S, Takemura M, Hayashi Y, Akiyama T, Nakato H. Differential heparan sulfate dependency of the Drosophila glypicans. J Biol Chem 2024; 300:105544. [PMID: 38072044 PMCID: PMC10796981 DOI: 10.1016/j.jbc.2023.105544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 11/28/2023] [Accepted: 11/29/2023] [Indexed: 01/05/2024] Open
Abstract
Heparan sulfate proteoglycans (HSPGs) are composed of a core protein and glycosaminoglycan (GAG) chains and serve as coreceptors for many growth factors and morphogens. To understand the molecular mechanisms by which HSPGs regulate morphogen gradient formation and signaling, it is important to determine the relative contributions of the carbohydrate and protein moieties to the proteoglycan function. To address this question, we generated ΔGAG alleles for dally and dally-like protein (dlp), two Drosophila HSPGs of the glypican family, in which all GAG-attachment serine residues are substituted to alanine residues using CRISPR/Cas9 mutagenesis. In these alleles, the glypican core proteins are expressed from the endogenous loci with no GAG modification. Analyses of the dallyΔGAG allele defined Dally functions that do not require heparan sulfate (HS) chains and that need both core protein and HS chains. We found a new, dallyΔGAG-specific phenotype, the formation of a posterior ectopic vein, which we have never seen in the null mutants. Unlike dallyΔGAG, dlpΔGAG mutants do not show most of the dlp null mutant phenotypes, suggesting that HS chains are dispensable for these dlp functions. As an exception, HS is essentially required for Dlp's activity at the neuromuscular junction. Thus, Drosophila glypicans show strikingly different levels of HS dependency. The ΔGAG mutant alleles of the glypicans serve as new molecular genetic toolsets highly useful to address important biological questions, such as molecular mechanisms of morphogen gradient formation.
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Affiliation(s)
- Eriko Nakato
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Keisuke Kamimura
- Developmental Neuroscience Project, Department of Brain and Neurosciences, Tokyo Metropolitan Institute of Medical Science, Tokyo, Japan
| | - Collin Knudsen
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Suzuka Masutani
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Masahiko Takemura
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA
| | - Yoshiki Hayashi
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Japan
| | - Takuya Akiyama
- Department of Biology, Indiana State University, Terre Haute, Indiana, USA
| | - Hiroshi Nakato
- Department of Genetics, Cell Biology, and Development, University of Minnesota, Minneapolis, Minnesota, USA.
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18
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Pressé MT, Malgrange B, Delacroix L. The cochlear matrisome: Importance in hearing and deafness. Matrix Biol 2024; 125:40-58. [PMID: 38070832 DOI: 10.1016/j.matbio.2023.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 11/20/2023] [Accepted: 12/06/2023] [Indexed: 02/12/2024]
Abstract
The extracellular matrix (ECM) consists in a complex meshwork of collagens, glycoproteins, and proteoglycans, which serves a scaffolding function and provides viscoelastic properties to the tissues. ECM acts as a biomechanical support, and actively participates in cell signaling to induce tissular changes in response to environmental forces and soluble cues. Given the remarkable complexity of the inner ear architecture, its exquisite structure-function relationship, and the importance of vibration-induced stimulation of its sensory cells, ECM is instrumental to hearing. Many factors of the matrisome are involved in cochlea development, function and maintenance, as evidenced by the variety of ECM proteins associated with hereditary deafness. This review describes the structural and functional ECM components in the auditory organ and how they are modulated over time and following injury.
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Affiliation(s)
- Mary T Pressé
- Developmental Neurobiology Unit, GIGA-Neurosciences, University of Liège, 15 avenue Hippocrate - CHU - B36 (1st floor), Liège B-4000, Belgium
| | - Brigitte Malgrange
- Developmental Neurobiology Unit, GIGA-Neurosciences, University of Liège, 15 avenue Hippocrate - CHU - B36 (1st floor), Liège B-4000, Belgium
| | - Laurence Delacroix
- Developmental Neurobiology Unit, GIGA-Neurosciences, University of Liège, 15 avenue Hippocrate - CHU - B36 (1st floor), Liège B-4000, Belgium.
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19
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Imon RR, Aktar S, Morshed N, Nur SM, Mahtarin R, Rahman FA, Talukder MEK, Alam R, Karpiński TM, Ahammad F, Zamzami MA, Tan SC. Biological and clinical significance of the glypican-3 gene in human lung adenocarcinoma: An in silico analysis. Medicine (Baltimore) 2023; 102:e35347. [PMID: 37960765 PMCID: PMC10637541 DOI: 10.1097/md.0000000000035347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 09/01/2023] [Indexed: 11/15/2023] Open
Abstract
Glypican-3 (GPC3), a membrane-bound heparan sulfate proteoglycan, has long been found to be dysregulated in human lung adenocarcinomas (LUADs). Nevertheless, the function, mutational profile, epigenetic regulation, co-expression profile, and clinicopathological significance of the GPC3 gene in LUAD progression are not well understood. In this study, we analyzed cancer microarray datasets from publicly available databases using bioinformatics tools to elucidate the above parameters. We observed significant downregulation of GPC3 in LUAD tissues compared to their normal counterparts, and this downregulation was associated with shorter overall survival (OS) and relapse-free survival (RFS). Nevertheless, no significant differences in the methylation pattern of GPC3 were observed between LUAD and normal tissues, although lower promoter methylation was observed in male patients. GPC3 expression was also found to correlate significantly with infiltration of B cells, CD8+, CD4+, macrophages, neutrophils, and dendritic cells in LUAD. In addition, a total of 11 missense mutations were identified in LUAD patients, and ~1.4% to 2.2% of LUAD patients had copy number amplifications in GPC3. Seventeen genes, mainly involved in dopamine receptor-mediated signaling pathways, were frequently co-expressed with GPC3. We also found 11 TFs and 7 miRNAs interacting with GPC3 and contributing to disease progression. Finally, we identified 3 potential inhibitors of GPC3 in human LUAD, namely heparitin, gemcitabine and arbutin. In conclusion, GPC3 may play an important role in the development of LUAD and could serve as a promising biomarker in LUAD.
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Affiliation(s)
- Raihan Rahman Imon
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore, Bangladesh
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Sharmin Aktar
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore, Bangladesh
- Department of Microbiology, Faculty of Biological Science, University of Dhaka, Dhaka, Bangladesh
| | - Niaz Morshed
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore, Bangladesh
- Department of Pharmacy, Faculty of Biological Science, University of Dhaka, Dhaka, Bangladesh
| | - Suza Mohammad Nur
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Rumana Mahtarin
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore, Bangladesh
- Department of Biochemistry and Molecular Biology, Shahjalal University of Science and Technology, Sylhet, Bangladesh
| | - Farazi Abinash Rahman
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore, Bangladesh
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Md. Enamul Kabir Talukder
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore, Bangladesh
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Rahat Alam
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore, Bangladesh
- Department of Genetic Engineering and Biotechnology, Faculty of Biological Science and Technology, Jashore University of Science and Technology, Jashore, Bangladesh
| | - Tomasz M. Karpiński
- Chair and Department of Medical Microbiology, Poznań University of Medical Sciences, Wieniawskiego, Poland
| | - Foysal Ahammad
- Laboratory of Computational Biology, Biological Solution Centre (BioSol Centre), Jashore, Bangladesh
- Department of Biological Sciences, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Mazin A. Zamzami
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
- Centre of Artificial Intelligence for Precision Medicines, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Shing Cheng Tan
- UKM Medical Molecular Biology Institute, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
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20
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Novoseletskaya ES, Evdokimov PV, Efimenko AY. Extracellular matrix-induced signaling pathways in mesenchymal stem/stromal cells. Cell Commun Signal 2023; 21:244. [PMID: 37726815 PMCID: PMC10507829 DOI: 10.1186/s12964-023-01252-8] [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: 06/16/2023] [Accepted: 07/31/2023] [Indexed: 09/21/2023] Open
Abstract
The extracellular matrix (ECM) is a crucial component of the stem cell microenvironment, or stem-cell niches, and contributes to the regulation of cell behavior and fate. Accumulating evidence indicates that different types of stem cells possess a large variety of molecules responsible for interactions with the ECM, mediating specific epigenetic rearrangements and corresponding changes in transcriptome profile. Signals from the ECM are crucial at all stages of ontogenesis, including embryonic and postnatal development, as well as tissue renewal and repair. The ECM could regulate stem cell transition from a quiescent state to readiness to perceive the signals of differentiation induction (competence) and the transition between different stages of differentiation (commitment). Currently, to unveil the complex networks of cellular signaling from the ECM, multiple approaches including screening methods, the analysis of the cell matrixome, and the creation of predictive networks of protein-protein interactions based on experimental data are used. In this review, we consider the existing evidence regarded the contribution of ECM-induced intracellular signaling pathways into the regulation of stem cell differentiation focusing on mesenchymal stem/stromal cells (MSCs) as well-studied type of postnatal stem cells totally depended on signals from ECM. Furthermore, we propose a system biology-based approach for the prediction of ECM-mediated signal transduction pathways in target cells. Video Abstract.
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Affiliation(s)
- Ekaterina Sergeevna Novoseletskaya
- Faculty of Biology, Dayun New Town, Shenzhen MSU-BIT University, 1 International University Park Road, Dayun New Town, Longgang District, Shenzhen, Guangdong Province, P. R. China.
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Lomonosov Ave., 27/10, 119991, Moscow, Russia.
| | - Pavel Vladimirovich Evdokimov
- Materials Science Department, Lomonosov Moscow State University, Leninskie Gory, 1, Building 73, 119991, Moscow, Russia
- Chemistry Department, Lomonosov Moscow State University, GSP-1, Leninskiye Gory, 1-3, Moscow, Russia
| | - Anastasia Yurievna Efimenko
- Institute for Regenerative Medicine, Medical Research and Education Center, Lomonosov Moscow State University, Lomonosov Ave., 27/10, 119991, Moscow, Russia
- Faculty of Medicine, Lomonosov Moscow State University, Lomonosov Ave., 27/1, 119991, Moscow, Russia
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21
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Wishart TFL, Lovicu FJ. Spatiotemporal Localisation of Heparan Sulphate Proteoglycans throughout Mouse Lens Morphogenesis. Cells 2023; 12:1364. [PMID: 37408198 DOI: 10.3390/cells12101364] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2023] [Revised: 05/05/2023] [Accepted: 05/09/2023] [Indexed: 07/07/2023] Open
Abstract
Heparan sulphate proteoglycans (HSPGs) consist of a core protein decorated with sulphated HS-glycosaminoglycan (GAG) chains. These negatively charged HS-GAG chains rely on the activity of PAPSS synthesising enzymes for their sulfation, which allows them to bind to and regulate the activity of many positively charged HS-binding proteins. HSPGs are found on the surfaces of cells and in the pericellular matrix, where they interact with various components of the cell microenvironment, including growth factors. By binding to and regulating ocular morphogens and growth factors, HSPGs are positioned to orchestrate growth factor-mediated signalling events that are essential for lens epithelial cell proliferation, migration, and lens fibre differentiation. Previous studies have shown that HS sulfation is essential for lens development. Moreover, each of the full-time HSPGs, differentiated by thirteen different core proteins, are differentially localised in a cell-type specific manner with regional differences in the postnatal rat lens. Here, the same thirteen HSPG-associated GAGs and core proteins as well as PAPSS2, are shown to be differentially regulated throughout murine lens development in a spatiotemporal manner. These findings suggest that HS-GAG sulfation is essential for growth factor-induced cellular processes during embryogenesis, and the unique and divergent localisation of different lens HSPG core proteins indicates that different HSPGs likely play specialized roles during lens induction and morphogenesis.
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Affiliation(s)
- Tayler F L Wishart
- Molecular and Cellular Biomedicine, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia
| | - Frank J Lovicu
- Molecular and Cellular Biomedicine, School of Medical Sciences, The University of Sydney, Sydney, NSW 2006, Australia
- Save Sight Institute, The University of Sydney, Sydney, NSW 2006, Australia
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22
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Iyer KS, Prabhakara C, Mayor S, Rao M. Cellular compartmentalisation and receptor promiscuity as a strategy for accurate and robust inference of position during morphogenesis. eLife 2023; 12:e79257. [PMID: 36877545 PMCID: PMC9988261 DOI: 10.7554/elife.79257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2022] [Accepted: 01/14/2023] [Indexed: 03/07/2023] Open
Abstract
Precise spatial patterning of cell fate during morphogenesis requires accurate inference of cellular position. In making such inferences from morphogen profiles, cells must contend with inherent stochasticity in morphogen production, transport, sensing and signalling. Motivated by the multitude of signalling mechanisms in various developmental contexts, we show how cells may utilise multiple tiers of processing (compartmentalisation) and parallel branches (multiple receptor types), together with feedback control, to bring about fidelity in morphogenetic decoding of their positions within a developing tissue. By simultaneously deploying specific and nonspecific receptors, cells achieve a more accurate and robust inference. We explore these ideas in the patterning of Drosophila melanogaster wing imaginal disc by Wingless morphogen signalling, where multiple endocytic pathways participate in decoding the morphogen gradient. The geometry of the inference landscape in the high dimensional space of parameters provides a measure for robustness and delineates stiff and sloppy directions. This distributed information processing at the scale of the cell highlights how local cell autonomous control facilitates global tissue scale design.
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Affiliation(s)
- Krishnan S Iyer
- Simons Center for the Study of Living Machines, National Center for Biological Sciences - TIFRBangaloreIndia
| | | | - Satyajit Mayor
- National Center for Biological Sciences - TIFRBangaloreIndia
| | - Madan Rao
- Simons Center for the Study of Living Machines, National Center for Biological Sciences - TIFRBangaloreIndia
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23
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Schepers EJ, Lake C, Glaser K, Bondoc AJ. Inhibition of Glypican-3 Cleavage Results in Reduced Cell Proliferation in a Liver Cancer Cell Line. J Surg Res 2023; 282:118-128. [PMID: 36272230 PMCID: PMC10893758 DOI: 10.1016/j.jss.2022.09.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 08/09/2022] [Accepted: 09/15/2022] [Indexed: 11/23/2022]
Abstract
INTRODUCTION Glypican-3 (GPC3) is a surface-bound proteoglycan overexpressed in pediatric liver cancer and utilized clinically as an immunohistochemical tumor marker. Furin is a proprotein convertase that is ubiquitously expressed and shown to modify GPC3 post-translationally. In experimental models of epithelial-based cancers, furin inhibition decreased tumor cell migration and proliferation representing a potential therapeutic target. METHODS Using a synthetic furin inhibitor, we evaluated proliferation, migration, protein, and RNA expression in two liver cancer cell lines, HepG2 (GPC3-positive) and SKHep1 cells (GPC3-negative). Total furin protein and GPC3 protein expression were assessed to evaluate functional levels of furin. RESULTS There was a reduction in HepG2 proliferation with addition of furin inhibitor at the 48-h timepoint, however there was an increase in HepG2 migration. CONCLUSIONS GPC3 cleavage in hepatoblastoma (HB) has a role in cell proliferation with therapeutic potential, however furin inhibition is not an appropriate target for GPC3-expressing HB due to increased migration which may enhance metastatic potential.
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Affiliation(s)
- Emily J Schepers
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.
| | - Charissa Lake
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Kathryn Glaser
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
| | - Alexander J Bondoc
- Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
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24
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Douceau S, Deutsch Guerrero T, Ferent J. Establishing Hedgehog Gradients during Neural Development. Cells 2023; 12:225. [PMID: 36672161 PMCID: PMC9856818 DOI: 10.3390/cells12020225] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2022] [Revised: 12/23/2022] [Accepted: 12/25/2022] [Indexed: 01/07/2023] Open
Abstract
A morphogen is a signaling molecule that induces specific cellular responses depending on its local concentration. The concept of morphogenic gradients has been a central paradigm of developmental biology for decades. Sonic Hedgehog (Shh) is one of the most important morphogens that displays pleiotropic functions during embryonic development, ranging from neuronal patterning to axon guidance. It is commonly accepted that Shh is distributed in a gradient in several tissues from different origins during development; however, how these gradients are formed and maintained at the cellular and molecular levels is still the center of a great deal of research. In this review, we first explored all of the different sources of Shh during the development of the nervous system. Then, we detailed how these sources can distribute Shh in the surrounding tissues via a variety of mechanisms. Finally, we addressed how disrupting Shh distribution and gradients can induce severe neurodevelopmental disorders and cancers. Although the concept of gradient has been central in the field of neurodevelopment since the fifties, we also describe how contemporary leading-edge techniques, such as organoids, can revisit this classical model.
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Affiliation(s)
- Sara Douceau
- INSERM UMR-S 1270, F-75005 Paris, France
- Institut du Fer à Moulin, INSERM, Sorbonne Univeristy, F-75005 Paris, France
| | - Tanya Deutsch Guerrero
- INSERM UMR-S 1270, F-75005 Paris, France
- Institut du Fer à Moulin, INSERM, Sorbonne Univeristy, F-75005 Paris, France
| | - Julien Ferent
- INSERM UMR-S 1270, F-75005 Paris, France
- Institut du Fer à Moulin, INSERM, Sorbonne Univeristy, F-75005 Paris, France
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25
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Abstract
Wnts are secreted proteins that control stem cell maintenance, cell fate decisions, and growth during development and adult homeostasis. Wnts carry a post-translational modification not seen in any other secreted protein: during biosynthesis, they are appended with a palmitoleoyl moiety that is required for signaling but also impairs solubility and hence diffusion in the extracellular space. In some contexts, Wnts act only in a juxtacrine manner but there are also instances of long range action. Several proteins and processes ensure that active Wnts reach the appropriate target cells. Some, like Porcupine, Wntless, and Notum are dedicated to Wnt function; we describe their activities in molecular detail. We also outline how the cell infrastructure (secretory, endocytic, and retromer pathways) contribute to the progression of Wnts from production to delivery. We then address how Wnts spread in the extracellular space and form a signaling gradient despite carrying a hydrophobic moiety. We highlight particularly the role of lipid-binding Wnt interactors and heparan sulfate proteoglycans. Finally, we briefly discuss how evolution might have led to the emergence of this unusual signaling pathway.
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26
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Wang H, Lin X, Wang Z, He S, Dong B, Lyu G. Differential lncRNA/mRNA expression profiling and ceRNA network analyses in amniotic fluid from foetuses with ventricular septal defects. PeerJ 2023; 11:e14962. [PMID: 36874970 PMCID: PMC9979828 DOI: 10.7717/peerj.14962] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/06/2023] [Indexed: 03/02/2023] Open
Abstract
Background Long noncoding RNAs (lncRNAs) have been shown to be involved in the regulation of numerous biological processes in embryonic development. We aimed to explore lncRNA expression profiles in ventricular septal defects (VSDs) and reveal their potential roles in heart development. Methods Microarray analyses were performed to screen differentially expressed lncRNAs (DE-lncRNAs) and mRNAs (DE-mRNAs) in the amniotic fluid between the VSD group and the control group. Bioinformatics analyses were further used to identify the functional enrichment and signaling pathways of important mRNAs. Then, a coding-noncoding gene coexpression (CNC) network and competitive endogenous RNAs (ceRNA) network were drawn. Finally, qRT‒PCR was performed to verify several hub lncRNAs and mRNAs in the network. Results A total of 710 DE-lncRNAs and 397 DE-mRNAs were identified in the VSD group. GO and KEGG analyses revealed that the DE-mRNAs were enriched in cardiac development-related biological processes and pathways, including cell proliferation, cell apoptosis, and the Sonic Hedgehog signaling pathway. Four VSD related mRNAs was used to construct the CNC network, which included 149 pairs of coexpressing lncRNAs and mRNAs. In addition, a ceRNA network, including 15 lncRNAs, 194 miRNAs, and four mRNAs, was constructed to reveal the potential regulatory relationship between lncRNAs and protein-coding genes. Finally, seven RNAs in the ceRNA network were validated, including IDS, NR2F2, GPC3, LINC00598, GATA3-AS1, PWRN1, and LINC01551. Conclusion Our study identified some lncRNAs and mRNAs may be potential biomarkers and therapeutic targets for foetuses with VSD, and described the lncRNA-associated ceRNA network in the progression of VSD.
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Affiliation(s)
- Huaming Wang
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Xi Lin
- Department of Diagnostic Radiology, Fujian Cancer Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Zecheng Wang
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Shaozheng He
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Bingtian Dong
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China
| | - Guorong Lyu
- Department of Ultrasound, The Second Affiliated Hospital of Fujian Medical University, Quanzhou, Fujian, China.,Collaborative Innovation Center of Maternal and Child Health Service Technology, Quanzhou Medical College, Quanzhou, Fujian, China
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27
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Colin-Pierre C, El Baraka O, Danoux L, Bardey V, André V, Ramont L, Brézillon S. Regulation of stem cell fate by HSPGs: implication in hair follicle cycling. NPJ Regen Med 2022; 7:77. [PMID: 36577752 PMCID: PMC9797564 DOI: 10.1038/s41536-022-00267-y] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Accepted: 11/30/2022] [Indexed: 12/29/2022] Open
Abstract
Heparan sulfate proteoglycans (HSPGs) are part of proteoglycan family. They are composed of heparan sulfate (HS)-type glycosaminoglycan (GAG) chains covalently linked to a core protein. By interacting with growth factors and/or receptors, they regulate numerous pathways including Wnt, hedgehog (Hh), bone morphogenic protein (BMP) and fibroblast growth factor (FGF) pathways. They act as inhibitor or activator of these pathways to modulate embryonic and adult stem cell fate during organ morphogenesis, regeneration and homeostasis. This review summarizes the knowledge on HSPG structure and classification and explores several signaling pathways regulated by HSPGs in stem cell fate. A specific focus on hair follicle stem cell fate and the possibility to target HSPGs in order to tackle hair loss are discussed in more dermatological and cosmeceutical perspectives.
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Affiliation(s)
- Charlie Colin-Pierre
- Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France.
- CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, Reims, France.
- BASF Beauty Care Solutions France SAS, Pulnoy, France.
| | | | - Louis Danoux
- BASF Beauty Care Solutions France SAS, Pulnoy, France
| | | | - Valérie André
- BASF Beauty Care Solutions France SAS, Pulnoy, France
| | - Laurent Ramont
- Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France
- CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, Reims, France
- CHU de Reims, Service Biochimie-Pharmacologie-Toxicologie, Reims, France
| | - Stéphane Brézillon
- Université de Reims Champagne-Ardenne, SFR CAP-Santé (FED 4231), Laboratoire de Biochimie Médicale et Biologie Moléculaire, Reims, France
- CNRS UMR 7369, Matrice Extracellulaire et Dynamique Cellulaire-MEDyC, Reims, France
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Shi W, Filmus J. Glypican-6 and Glypican-4 stimulate embryonic stomach growth by regulating Hedgehog and noncanonical Wnt signaling. Dev Dyn 2022; 251:2015-2028. [PMID: 36057966 DOI: 10.1002/dvdy.533] [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: 03/17/2022] [Revised: 07/28/2022] [Accepted: 08/15/2022] [Indexed: 01/30/2023] Open
Abstract
BACKGROUND Glypicans are a family of proteoglycans that play important roles in embryonic morphogenesis. The mammalian genome contains six glypicans (GPC1 to GPC6). GPC6 and GPC4 are the pair of glypicans that show the highest degree of homology within the family. GPC6-null embryos display bone abnormalities and severely shortened intestines. RESULTS We show that GPC6-null embryos display significantly smaller stomachs, and that Hedgehog and noncanonical Wnt signaling are dysregulated in GPC6-null stomachs. Like GPC6, GPC4 is expressed by the developing stomach. However, GPC4-null embryos have normal stomachs. To investigate whether GPC6 and GPC4 display functional overlap in the developing stomach, we crossed GPC4-null mice with GPC6 conditional mutants in which the expression of this glypican is severely reduced in the stomach. Notably, we found that the compound mutants display stomachs that are smaller than those of the GPC6 conditional mutants. We also found that this functional overlap between GPC6 and GPC4 is mediated by the noncanonical Wnt pathway. CONCLUSION This study demonstrates that GPC6 stimulates the growth of the embryonic stomach via Wnt and Hh signaling. In addition, we uncovered a Wnt-mediated functional overlap between GPC6 and GPC4 in the developing stomach.
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Affiliation(s)
- Wen Shi
- Department of Medical Biophysics, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
| | - Jorge Filmus
- Department of Medical Biophysics, Sunnybrook Research Institute, University of Toronto, Toronto, Ontario, Canada
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29
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Wang Y, Dong Z, Yang R, Zong S, Wei X, Wang C, Guo L, Sun J, Li H, Li P. Inactivation of Ihh in Sp7-Expressing Cells Inhibits Osteoblast Proliferation, Differentiation, and Bone Formation, Resulting in a Dwarfism Phenotype with Severe Skeletal Dysplasia in Mice. Calcif Tissue Int 2022; 111:519-534. [PMID: 35731246 DOI: 10.1007/s00223-022-00999-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Accepted: 06/02/2022] [Indexed: 11/02/2022]
Abstract
Indian hedgehog (Ihh) is an indispensable paracrine factor for proper tissue patterning, skeletogenesis, and cellular proliferation. Recent genetic studies have revealed critical roles of chondrocyte-derived Ihh in regulating chondrocyte proliferation, hypertrophy and cartilage ossification. However, the functions of Sp7-expressing cell-derived Ihh in osteoblast differentiation and bone formation remain unclear. Sp7 is an essential transcription factor for osteoblast differentiation. In the current study, we generated Sp7-iCre; Ihhfl/fl mice, in which the Ihh gene was specifically deleted in Sp7-expressing cells to investigate the roles of Ihh. Ihh ablation in Sp7-expressing cells resulted in a dwarfism phenotype with severe skeletal dysplasia and lethality at birth, but with normal joint segmentation. Sp7-iCre; Ihhfl/fl mice had fewer osteoblasts, almost no cortical and trabecular bones, smaller skulls, and wider cranial sutures. Additionally, the levels of osteogenesis- and angiogenesis-related genes, and of major bone matrix protein genes were significantly reduced. These results demonstrated that Ihh regulates bone formation in Sp7-expressing cells. Ihh deficiency in primary osteoblasts cultured in vitro inhibited their proliferation, differentiation, and mineralization ability, and reduced the expression of osteogenesis-related genes. Moreover, the deletion of Ihh also attenuated the Bmp2/Smad/Runx2 pathway in E18.5 tibial and primary osteoblasts. The activity of primary osteoblasts in mutant mice was rescued after treatment with rhBMP2. In summary, our data revealed that Ihh in Sp7-expressing cells plays an indispensable role in osteoblast differentiation, mineralization, and embryonic osteogenesis, further implicated that its pro-osteogenic role may be mediated through the canonical Bmp2/Smad/Runx2 pathway.
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Affiliation(s)
- YunFei Wang
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
- Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Zhengquan Dong
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Ruijia Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Sujing Zong
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Xiaochun Wei
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Chunfang Wang
- Laboratory Animal Center, Shanxi Medical University, Taiyuan, Shanxi, China
| | - Li Guo
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Jian Sun
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Haoqian Li
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China
| | - Pengcui Li
- Department of Orthopedics, Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, The Second Hospital of Shanxi Medical University, Taiyuan, Shanxi, China.
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30
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Akkermans O, Delloye-Bourgeois C, Peregrina C, Carrasquero-Ordaz M, Kokolaki M, Berbeira-Santana M, Chavent M, Reynaud F, Raj R, Agirre J, Aksu M, White ES, Lowe E, Ben Amar D, Zaballa S, Huo J, Pakos I, McCubbin PTN, Comoletti D, Owens RJ, Robinson CV, Castellani V, Del Toro D, Seiradake E. GPC3-Unc5 receptor complex structure and role in cell migration. Cell 2022; 185:3931-3949.e26. [PMID: 36240740 PMCID: PMC9596381 DOI: 10.1016/j.cell.2022.09.025] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2022] [Revised: 07/22/2022] [Accepted: 09/15/2022] [Indexed: 11/09/2022]
Abstract
Neural migration is a critical step during brain development that requires the interactions of cell-surface guidance receptors. Cancer cells often hijack these mechanisms to disseminate. Here, we reveal crystal structures of Uncoordinated-5 receptor D (Unc5D) in complex with morphogen receptor glypican-3 (GPC3), forming an octameric glycoprotein complex. In the complex, four Unc5D molecules pack into an antiparallel bundle, flanked by four GPC3 molecules. Central glycan-glycan interactions are formed by N-linked glycans emanating from GPC3 (N241 in human) and C-mannosylated tryptophans of the Unc5D thrombospondin-like domains. MD simulations, mass spectrometry and structure-based mutants validate the crystallographic data. Anti-GPC3 nanobodies enhance or weaken Unc5-GPC3 binding and, together with mutant proteins, show that Unc5/GPC3 guide migrating pyramidal neurons in the mouse cortex, and cancer cells in an embryonic xenograft neuroblastoma model. The results demonstrate a conserved structural mechanism of cell guidance, where finely balanced Unc5-GPC3 interactions regulate cell migration.
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Affiliation(s)
- Onno Akkermans
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Céline Delloye-Bourgeois
- MeLis, University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U1314, Institut NeuroMyoGène, 8 avenue Rockefeller 69008 Lyon, Lyon, France
| | - Claudia Peregrina
- Department of Biological Sciences, Institute of Neurosciences, IDIBAPS, CIBERNED, University of Barcelona, Barcelona, Spain
| | - Maria Carrasquero-Ordaz
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Maria Kokolaki
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Miguel Berbeira-Santana
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Matthieu Chavent
- Institut de Pharmacologie et Biologie Structurale, Université de Toulouse, Toulouse, France
| | - Florie Reynaud
- MeLis, University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U1314, Institut NeuroMyoGène, 8 avenue Rockefeller 69008 Lyon, Lyon, France
| | - Ritu Raj
- Department of Chemistry, University of Oxford, Oxford, UK
| | - Jon Agirre
- York Structural Biology Laboratory, Department of Chemistry, University of York, York, UK
| | - Metin Aksu
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Eleanor S White
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Edward Lowe
- Department of Biochemistry, University of Oxford, Oxford, UK
| | - Dounia Ben Amar
- MeLis, University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U1314, Institut NeuroMyoGène, 8 avenue Rockefeller 69008 Lyon, Lyon, France
| | - Sofia Zaballa
- Department of Biological Sciences, Institute of Neurosciences, IDIBAPS, CIBERNED, University of Barcelona, Barcelona, Spain
| | - Jiandong Huo
- Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus, Didcot, UK; Division of Structural Biology, University of Oxford, Oxford, UK
| | - Irene Pakos
- Child Health Institute of New Jersey, New Brunswick, NJ 08901, USA
| | - Patrick T N McCubbin
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Davide Comoletti
- Child Health Institute of New Jersey, New Brunswick, NJ 08901, USA; School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand
| | - Raymond J Owens
- Structural Biology, The Rosalind Franklin Institute, Harwell Science Campus, Didcot, UK; Division of Structural Biology, University of Oxford, Oxford, UK
| | - Carol V Robinson
- Department of Chemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK
| | - Valérie Castellani
- MeLis, University of Lyon, Université Claude Bernard Lyon 1, CNRS UMR 5284, INSERM U1314, Institut NeuroMyoGène, 8 avenue Rockefeller 69008 Lyon, Lyon, France.
| | - Daniel Del Toro
- Department of Biological Sciences, Institute of Neurosciences, IDIBAPS, CIBERNED, University of Barcelona, Barcelona, Spain.
| | - Elena Seiradake
- Department of Biochemistry, University of Oxford, Oxford, UK; Kavli Institute for Nanoscience Discovery, University of Oxford, Oxford, UK.
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Pathogenic Roles of Heparan Sulfate and Its Use as a Biomarker in Mucopolysaccharidoses. Int J Mol Sci 2022; 23:ijms231911724. [PMID: 36233030 PMCID: PMC9570396 DOI: 10.3390/ijms231911724] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2022] [Revised: 09/29/2022] [Accepted: 09/30/2022] [Indexed: 11/17/2022] Open
Abstract
Heparan sulfate (HS) is an essential glycosaminoglycan (GAG) as a component of proteoglycans, which are present on the cell surface and in the extracellular matrix. HS-containing proteoglycans not only function as structural constituents of the basal lamina but also play versatile roles in various physiological processes, including cell signaling and organ development. Thus, inherited mutations of genes associated with the biosynthesis or degradation of HS can cause various diseases, particularly those involving the bones and central nervous system (CNS). Mucopolysaccharidoses (MPSs) are a group of lysosomal storage disorders involving GAG accumulation throughout the body caused by a deficiency of GAG-degrading enzymes. GAGs are stored differently in different types of MPSs. Particularly, HS deposition is observed in patients with MPS types I, II, III, and VII, all which involve progressive neuropathy with multiple CNS system symptoms. While therapies are available for certain symptoms in some types of MPSs, significant unmet medical needs remain, such as neurocognitive impairment. This review presents recent knowledge on the pathophysiological roles of HS focusing on the pathogenesis of MPSs. We also discuss the possible use and significance of HS as a biomarker for disease severity and therapeutic response in MPSs.
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Jiang LH, Mu LL, Jin L, Anjum AA, Li GQ. Silencing uridine diphosphate N-acetylglucosamine pyrophosphorylase gene impairs larval development in Henosepilachna vigintioctopunctata. PEST MANAGEMENT SCIENCE 2022; 78:3894-3902. [PMID: 34523212 DOI: 10.1002/ps.6643] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Revised: 08/29/2021] [Accepted: 09/15/2021] [Indexed: 06/13/2023]
Abstract
BACKGROUND Uridine diphosphate-N-acetylglucosamine (UDP-GlcNAc) diphosphorylase (UAP) catalyzes the formation of UDP-GlcNAc, the precursor for the production of chitin in ectodermally derived epidermal cells and midgut, for GlcNAcylation of proteins and for generation of glycosyl-phosphatidyl-inositol anchors in all tissues in Drosophila melanogaster. RESULTS Here, we identified a putative HvUAP gene in Henosepilachna vigintioctopunctata. Knockdown of HvUAP at the second-, third- and fourth-instar stages impaired larval development. Most resultant HvUAP hypomorphs showed arrested development at the third-, fourth-instar larval or prepupal stages, and became paralyzed, depending on the age when treated. Some HvUAP-silenced larvae had weak and soft scoli. A portion of HvUAP-depleted beetles formed misshapen pupae. No HvUAP RNA interference pupae successfully emerged as adults. Dissection and microscopic observation revealed that knockdown of HvUAP affected gut growth and food ingestion, reduced cuticle thickness, and negatively affected the formation of newly generated cuticle layers during ecdysis. Furthermore, HvUAP deficiency inhibited development of the tracheal respiratory system and thinned tracheal taenidia. CONCLUSION The phenotypical defects in HvUAP hypomorphs suggest that HvUAP is involved in the production of chitin. Moreover, our findings will enable the development of a double-stranded RNA-based pesticide to control H. vigintioctopunctata. © 2021 Society of Chemical Industry.
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Affiliation(s)
- Lin-Hong Jiang
- Agriculture Ministry Key Laboratory of Integrated Pest Management on Crops in East China/State & Local Joint Engineering Research Center of Green Pesticide Invention and Application, Department of Entomology, College of Plant Protection, Nanjing Agricultural University, Nanjing, China
| | - Li-Li Mu
- Agriculture Ministry Key Laboratory of Integrated Pest Management on Crops in East China/State & Local Joint Engineering Research Center of Green Pesticide Invention and Application, Department of Entomology, College of Plant Protection, Nanjing Agricultural University, Nanjing, China
| | - Lin Jin
- Agriculture Ministry Key Laboratory of Integrated Pest Management on Crops in East China/State & Local Joint Engineering Research Center of Green Pesticide Invention and Application, Department of Entomology, College of Plant Protection, Nanjing Agricultural University, Nanjing, China
| | - Ahmad A Anjum
- Agriculture Ministry Key Laboratory of Integrated Pest Management on Crops in East China/State & Local Joint Engineering Research Center of Green Pesticide Invention and Application, Department of Entomology, College of Plant Protection, Nanjing Agricultural University, Nanjing, China
| | - Guo-Qing Li
- Agriculture Ministry Key Laboratory of Integrated Pest Management on Crops in East China/State & Local Joint Engineering Research Center of Green Pesticide Invention and Application, Department of Entomology, College of Plant Protection, Nanjing Agricultural University, Nanjing, China
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Liu C, Liu X, Li X. PFKP and GPC6 Variants Were Correlated with Alcohol-Induced Femoral Head Necrosis Risk in the Chinese Han Population. Pharmgenomics Pers Med 2022; 15:797-808. [PMID: 36110408 PMCID: PMC9469939 DOI: 10.2147/pgpm.s369957] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2022] [Accepted: 08/30/2022] [Indexed: 11/23/2022] Open
Abstract
Background Osteonecrosis of the femoral head (ONFH) is a common joint disease caused by excessive drinking, genetic factors, etc. The purpose of this study was to investigate the association between PFKP and GPC6 variants and alcohol-induced ONFH (AIONFH) risk in the Chinese Han population. Methods This study genotyped 9 selected single nucleotide polymorphisms (SNPs) in 402 males by Agena MassARRAY Assay. By calculating odds ratios (ORs) and 95% confidence intervals (CIs), we assessed the effect of gene polymorphisms on AIONFH occurrence. False-positive report probability (FPRP) analysis and power were also used to evaluate the significant results. Multifactor dimensionality reduction (MDR) software was also utilized to predict the association between the selected SNPs and AIONFH risk. Results The overall analysis showed that PFKP rs10903966 and GPC6 rs7320969 were correlated with AIONFH risk. GPC6 rs4773724 was associated with a reduced risk of AIONFH, while individuals with GPC6 rs9523981 CC genotype had a higher risk of AIONFH than individuals with the other genotypes among people under 42 years old. Based on stratified analysis of necrotic sites, rs7320969 was related to a decreased risk of AIONFH, while rs10903966 and rs9523981 were related to an increased risk of AIONFH. In addition, rs1008993 and rs7320969 were observed to be linked to AIONFH risk in patients at different clinical stages. Meanwhile, there were significant differences in TC, TG, platelet, ApoA1 and ApoB levels among subjects with different genotypes of rs1008993, rs9523981, rs7320969 and rs59624626. The results of MDR showed that rs11251720 and rs7320969 may play a synergistic role in predicting the risk of AIONFH. Conclusion PFKP rs10903966 and GPC6 rs9523981 were associated with an increased risk of AIONFH, while GPC6 (rs7320969 and rs4773724) were correlated with a decreased risk of AIONFH. This result will need further experiments to verify.
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Affiliation(s)
- Chang Liu
- Emergency Department, The Second Hospital of Tangshan, Tangshan, 063000, People’s Republic of China
- Correspondence: Chang Liu, Emergency Department, The Second Hospital of Tangshan, #21, Jianshe North Road, North District, Tangshan City, Hebei, 063000, People’s Republic of China, Tel +86-18633328305, Email
| | - Xuan Liu
- The Fourth Department of Orthopaedics, Tangshan Hongqiao Orthopaedic Hospital, Tangshan, 064100, People’s Republic of China
| | - Xiaolin Li
- The Fourth Department of Orthopaedics, Tangshan Hongqiao Orthopaedic Hospital, Tangshan, 064100, People’s Republic of China
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Colitti M, Ali U, Wabitsch M, Tews D. Transcriptomic analysis of Simpson Golabi Behmel syndrome cells during differentiation exhibit BAT-like function. Tissue Cell 2022; 77:101822. [DOI: 10.1016/j.tice.2022.101822] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Revised: 05/13/2022] [Accepted: 05/13/2022] [Indexed: 11/25/2022]
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DeCasien AR, Trujillo AE, Janiak MC, Harshaw EP, Caes ZN, Galindo GA, Petersen RM, Higham JP. Equivocal evidence for a link between megalencephaly-related genes and primate brain size evolution. Sci Rep 2022; 12:10902. [PMID: 35764790 PMCID: PMC9239989 DOI: 10.1038/s41598-022-12953-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Accepted: 05/19/2022] [Indexed: 11/08/2022] Open
Abstract
A large brain is a defining feature of modern humans, and much work has been dedicated to exploring the molecular underpinnings of this trait. Although numerous studies have focused on genes associated with human microcephaly, no studies have explicitly focused on genes associated with megalencephaly. Here, we investigate 16 candidate genes that have been linked to megalencephaly to determine if: (1) megalencephaly-associated genes evolved under positive selection across primates; and (2) selection pressure on megalencephaly-associated genes is linked to primate brain size. We found evidence for positive selection for only one gene, OFD1, with 1.8% of the sites estimated to have dN/dS values greater than 1; however, we did not detect a relationship between selection pressure on this gene and brain size across species, suggesting that selection for changes to non-brain size traits drove evolutionary changes to this gene. In fact, our primary analyses did not identify significant associations between selection pressure and brain size for any candidate genes. While we did detect positive associations for two genes (GPC3 and TBC1D7) when two phyletic dwarfs (i.e., species that underwent recent evolutionary decreases in brain size) were excluded, these associations did not withstand FDR correction. Overall, these results suggest that sequence alterations to megalencephaly-associated genes may have played little to no role in primate brain size evolution, possibly due to the highly pleiotropic effects of these genes. Future comparative studies of gene expression levels may provide further insights. This study enhances our understanding of the genetic underpinnings of brain size evolution in primates and identifies candidate genes that merit further exploration.
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Affiliation(s)
- Alex R DeCasien
- Department of Anthropology, New York University, New York, USA.
- New York Consortium in Evolutionary Primatology (NYCEP), New York, USA.
- Section on Developmental Neurogenomics, National Institute of Mental Health (NIMH), Bethesda, USA.
| | - Amber E Trujillo
- Department of Anthropology, New York University, New York, USA
- New York Consortium in Evolutionary Primatology (NYCEP), New York, USA
| | - Mareike C Janiak
- School of Science, Engineering and Environment, University of Salford, Salford, UK
- Department of Anthropology, Rutgers University, New Brunswick, USA
| | - Etta P Harshaw
- Department of Art History, University of Southern California, Los Angeles, USA
- Eleanor Roosevelt High School, New York, USA
| | - Zosia N Caes
- Department of Chemistry, Yale University, New Haven, USA
- Columbia Secondary School for Math, Science, and Engineering, New York, USA
| | | | - Rachel M Petersen
- Department of Anthropology, New York University, New York, USA
- New York Consortium in Evolutionary Primatology (NYCEP), New York, USA
- Department of Biological Sciences, Vanderbilt University, Nashville, USA
| | - James P Higham
- Department of Anthropology, New York University, New York, USA
- New York Consortium in Evolutionary Primatology (NYCEP), New York, USA
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36
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Uchida Y, Shigenobu S, Takeda H, Furusawa C, Irie N. Potential contribution of intrinsic developmental stability toward body plan conservation. BMC Biol 2022; 20:82. [PMID: 35399082 PMCID: PMC8996622 DOI: 10.1186/s12915-022-01276-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2021] [Accepted: 03/10/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Despite the morphological diversity of animals, their basic anatomical patterns-the body plans in each animal phylum-have remained highly conserved over hundreds of millions of evolutionary years. This is attributed to conservation of the body plan-establishing developmental period (the phylotypic period) in each lineage. However, the evolutionary mechanism behind this phylotypic period conservation remains under debate. A variety of hypotheses based on the concept of modern synthesis have been proposed, such as negative selection in the phylotypic period through its vulnerability to embryonic lethality. Here we tested a new hypothesis that the phylotypic period is developmentally stable; it has less potential to produce phenotypic variations than the other stages, and this has most likely led to the evolutionary conservation of body plans. RESULTS By analyzing the embryos of inbred Japanese medaka embryos raised under the same laboratory conditions and measuring the whole embryonic transcriptome as a phenotype, we found that the phylotypic period has greater developmental stability than other stages. Comparison of phenotypic differences between two wild medaka populations indicated that the phylotypic period and its genes in this period remained less variational, even after environmental and mutational modifications accumulated during intraspecies evolution. Genes with stable expression levels were enriched with those involved in cell-cell signalling and morphological specification such as Wnt and Hox, implying possible involvement in body plan development of these genes. CONCLUSIONS This study demonstrated the correspondence between the developmental stage with low potential to produce phenotypic variations and that with low diversity in micro- and macroevolution, namely the phylotypic period. Whereas modern synthesis explains evolution as a process of shaping of phenotypic variations caused by mutations, our results highlight the possibility that phenotypic variations are readily limited by the intrinsic nature of organisms, namely developmental stability, thus biasing evolutionary outcomes.
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Affiliation(s)
- Yui Uchida
- Center for Biosystems Dynamics Research, RIKEN, 6-2-3 Furuedai, Suita, Osaka, 565-0874, Japan.
| | - Shuji Shigenobu
- NIBB Core Research Facilities, National Institute for Basic Biology, Okazaki, 444-8585, Japan
| | - Hiroyuki Takeda
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033, Japan
| | - Chikara Furusawa
- Center for Biosystems Dynamics Research, RIKEN, 6-2-3 Furuedai, Suita, Osaka, 565-0874, Japan
- Universal Biology Institute, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan
| | - Naoki Irie
- Department of Biological Sciences, Graduate School of Science, The University of Tokyo, Tokyo, 113-0033, Japan.
- Universal Biology Institute, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
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Yan Q, Sun YS, An R, Liu F, Fang Q, Wang Z, Xu T, Chen L, Du J. Application and progress of the detection technologies in hepatocellular carcinoma. Genes Dis 2022. [PMID: 37492708 PMCID: PMC10363596 DOI: 10.1016/j.gendis.2022.04.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Hepatocellular carcinoma (HCC) has a very high incidence and fatality rate, and in most cases, it is already at an advanced stage when diagnosed. Therefore, early prevention and detection of HCC are two of the most effective strategies. However, the methods recommended in the practice guidelines for the detection of HCC cannot guarantee high sensitivity and specificity except for the liver biopsy, which is known as the "gold standard". In this review, we divided the detection of HCC into pre-treatment diagnosis and post-treatment monitoring, and found that in addition to the traditional imaging detection and liver biopsy, alpha fetoprotein (AFP), lens culinaris-agglutinin-reactive fraction of AFP (AFP-L3), protein induced by vitamin K absence or antagonist-II (PIVKA-II) and other biomarkers are excellent biomarkers for HCC, especially when they are combined together. Most notably, the emerging liquid biopsy shows great promise in detecting HCC. In addition, lactic dehydrogenase (LDH), suppressor of cytokine signaling (SOCS) and other relevant biomarkers may become promising biomarkers for HCC post-treatment monitoring. Through the detailed introduction of the diagnostic technology of HCC, we can have a detailed understanding of its development process and then obtain some enlightenment from the diagnosis, to improve the diagnostic rate of HCC and reduce its mortality.
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Hayashida K, Aquino RS, Park PW. Coreceptor Functions of Cell Surface Heparan Sulfate Proteoglycans. Am J Physiol Cell Physiol 2022; 322:C896-C912. [PMID: 35319900 PMCID: PMC9109798 DOI: 10.1152/ajpcell.00050.2022] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Receptor-ligand interactions play an important role in many biological processes by triggering specific cellular responses. These interactions are frequently regulated by coreceptors that facilitate, alter, or inhibit signaling. Coreceptors work in parallel with other specific and accessory molecules to coordinate receptor-ligand interactions. Cell surface heparan sulfate proteoglycans (HSPGs) function as unique coreceptors because they can bind to many ligands and receptors through their HS and core protein motifs. Cell surface HSPGs are typically expressed in abundance of the signaling receptors and, thus, are capable of mediating the initial binding of ligands to the cell surface. HSPG coreceptors do not possess kinase domains or intrinsic enzyme activities and, for the most part, binding to cell surface HSPGs does not directly stimulate intracellular signaling. Because of these features, cell surface HSPGs primarily function as coreceptors for many receptor-ligand interactions. Given that cell surface HSPGs are widely conserved, they likely serve fundamental functions to preserve basic physiological processes. Indeed, cell surface HSPGs can support specific cellular interactions with growth factors, morphogens, chemokines, extracellular matrix (ECM) components, and microbial pathogens and their secreted virulence factors. Through these interactions, HSPG coreceptors regulate cell adhesion, proliferation, migration and differentiation, and impact the onset, progression, and outcome of pathophysiological processes, such as development, tissue repair, inflammation, infection, and tumorigenesis. This review seeks to provide an overview of the various mechanisms of how cell surface HSPGs function as coreceptors.
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Affiliation(s)
- Kazutaka Hayashida
- Department of Medicine, Boston Children's Hospital, Boston, MA, United States
| | - Rafael S Aquino
- Department of Medicine, Boston Children's Hospital, Boston, MA, United States
| | - Pyong Woo Park
- Department of Medicine, Boston Children's Hospital, Boston, MA, United States.,Department of Pediatrics, Harvard Medical School, Boston, MA, United States
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Liu YC, Wierbowski BM, Salic A. Hedgehog pathway modulation by glypican 3-conjugated heparan sulfate. J Cell Sci 2022; 135:274739. [PMID: 35142364 PMCID: PMC8977055 DOI: 10.1242/jcs.259297] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 02/04/2022] [Indexed: 11/20/2022] Open
Abstract
Glypicans are a family of cell surface heparan sulfate proteoglycans that play critical roles in multiple cell signaling pathways. Glypicans consist of a globular core, an unstructured stalk modified with sulfated glycosaminoglycan chains, and a glycosylphosphatidylinositol anchor. Though these structural features are conserved, their individual contribution to glypican function remains obscure. Here, we investigate how glypican 3 (GPC3), which is mutated in Simpson-Golabi-Behmel tissue overgrowth syndrome, regulates Hedgehog signaling. We find that GPC3 is necessary for the Hedgehog response, surprisingly controlling a downstream signal transduction step. Purified GPC3 ectodomain rescues signaling when artificially recruited to the surface of GPC3-deficient cells but has dominant-negative activity when unattached. Strikingly, the purified stalk, modified with heparan sulfate but not chondroitin sulfate, is necessary and sufficient for activity. Our results demonstrate a novel function for GPC3-associated heparan sulfate and provide a framework for the functional dissection of glycosaminoglycans by in vivo biochemical complementation. This article has an associated First Person interview with the first author of the paper.
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Affiliation(s)
- Yulu Cherry Liu
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.,Department of Biology, Hood College, Frederick, MD 21701, USA
| | | | - Adrian Salic
- Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA
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40
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Zheng X, Liu X, Lei Y, Wang G, Liu M. Glypican-3: A Novel and Promising Target for the Treatment of Hepatocellular Carcinoma. Front Oncol 2022; 12:824208. [PMID: 35251989 PMCID: PMC8889910 DOI: 10.3389/fonc.2022.824208] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2021] [Accepted: 01/18/2022] [Indexed: 02/05/2023] Open
Abstract
Glypican-3 (GPC3) is a membrane-associated proteoglycan that is specifically up-regulated in hepatocellular carcinoma (HCC) although rarely or not expressed in normal liver tissues, making it a perfect diagnostic and treatment target for HCC. Several GPC3-based clinical trials are ongoing and recently several innovative GPC3-targeted therapeutic methods have emerged with exciting results, including GPC3 vaccine, anti-GPC3 immunotoxin, combined therapy with immune checkpoint blockades (ICBs), and chimeric antigen receptor (CAR) T or NK cells. Here, we review the value of GPC3 in the diagnosis and prognosis of HCC, together with its signaling pathways, with a specific focus on GPC3-targeted treatments of HCC and some prospects for the future GPC3-based therapeutic strategies in HCC.
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Affiliation(s)
- Xiufeng Zheng
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Xun Liu
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Yanna Lei
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
| | - Gang Wang
- National Engineering Research Center for Biomaterials, Sichuan University, Chengdu, China
| | - Ming Liu
- Department of Abdominal Oncology, West China Hospital, Sichuan University, Chengdu, China
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Abstract
Glypicans are proteoglycans that are bound to the outer surface of the plasma membrane by a glycosylphosphatidylinositol anchor. The mammalian genome contains six members of the glypican family (GPC1 to GPC6). Although the degree of sequence homology within the family is rather low, the three-dimensional structure of these proteoglycans is highly conserved. Glypicans are predominantly expressed during embryonic development. Genetic and biochemical studies have shown that glypicans can stimulate or inhibit the signaling pathways triggered by Wnts, Hedgehogs, Fibroblast Growth Factors, and Bone Morphogenetic Proteins. The study of mutant mouse strains demonstrated that glypicans have important functions in the developmental morphogenesis of various organs. In addition, a role of glypicans in synapsis formation has been established. Notably, glypican loss-of-function mutations are the cause of three human inherited syndromes. Recent analysis of glypican compound mutant mice have demonstrated that members of this protein family display redundant functions during embryonic development.
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Affiliation(s)
- Jorge Filmus
- Biological Sciences, Sunnybrook Research Institute, and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada
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Fan Q, Wu M, Li C, Li J. MiR-107 Aggravates Oxygen-Glucose Deprivation/Reoxygenation (OGD/R)-Induced Injury Through Inactivating PI3K-AKT Signalling Pathway by Targeting FGF9/FGF12 in PC12 Cells. J Stroke Cerebrovasc Dis 2022; 31:106295. [PMID: 35093630 DOI: 10.1016/j.jstrokecerebrovasdis.2021.106295] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 12/08/2021] [Accepted: 12/22/2021] [Indexed: 10/19/2022] Open
Abstract
OBJECTIVES The aberrant expression of miR-107 has been confirmed in some neurological diseases, including ischemic stroke (IS). However, the function of miR-107 and underlying mechanisms are ambiguous. MATERIALS AND METHODS Oxygen-Glucose Deprivation/Reoxygenation (OGD/R)-induced PC12 cells were used to mimic IS condition. MiR-107 expression and differentially expressed genes (DEGs) responding to IS were analyzed by GSE97532 and GSE61616 datasets, respectively. The target genes of miR-107 were predicted by TargetScan and confirmed by dual-luciferase reporter assay. Cell counting kit-8 and apoptosis assays were conducted to explore the role of miR-107 in biological behaviors of OGD/R-induced PC12 cells. RESULTS Bioinformatics analysis revealed that miR-107 expression was elevated in rats with middle cerebral artery occlusion (MCAO), which was confirmed in OGD/R-treated PC12 cells. Notably, miR-107 strongly inhibited the proliferation of OGD/R-treated PC12 cells. As most DEGs were enriched in PI3K-AKT signaling pathway, which was critical for IS, DEGs in this pathway was compared with the down-regulated genes and the predicted genes to obtain potential target genes of miR-107, and ultimately fibroblast growth factor (FGF)9 and FGF12 stood out. The experiments demonstrated that miR-107 inhibited viability and promoted apoptosis of OGD/R-treated PC12 cells by down-regulating FGF9/FGF12 level. Mechanically, for the first time, we clarified the mechanism via which miR-107 inactivated PI3K-AKT signaling pathway by targeting FGF9/FGF12. CONCLUSIONS We summarized that miR-107 aggravates OGD/R-induced injury through inactivating PI3K-AKT signaling pathway via targeting FGF9/FGF12. Therefore, our study elucidates the neurotoxicity of miR-107 in IS development and provides a new promising therapy strategy for IS.
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Affiliation(s)
- Qijiang Fan
- Department of Neurology, Binzhou Central Hospital, Binzhou, Shandong 251700, China
| | - Mingxin Wu
- Third Inpatient Ward of Department of Neurology, Gaotang County People's Hospital, Liaocheng, Shandong 252800, China
| | - Chunxiao Li
- ICU, Binzhou People's Hospital, Binzhou, Shandong 256600, China
| | - Jurong Li
- Department of Geriatrics, Dazhou Central Hospital, Dazhou, Sichuan 635000, China.
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Li D, Lin S, Hong J, Ho M. Immunotherapy for hepatobiliary cancers: Emerging targets and translational advances. Adv Cancer Res 2022; 156:415-449. [DOI: 10.1016/bs.acr.2022.01.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
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Aydin Y, Koksal AR, Thevenot P, Chava S, Heidari Z, Lin D, Sandow T, Moroz K, Parsi MA, Scott J, Cohen A, Dash S. Experimental Validation of Novel Glypican 3 Exosomes for the Detection of Hepatocellular Carcinoma in Liver Cirrhosis. J Hepatocell Carcinoma 2021; 8:1579-1596. [PMID: 34917553 PMCID: PMC8671108 DOI: 10.2147/jhc.s327339] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Accepted: 11/18/2021] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND AND AIMS Hepatocellular carcinoma (HCC) developing in the context of preexisting cirrhosis is characterized by impaired autophagy that results in increased exosome release. This study was conducted to determine whether circulating exosomes expressing glypican 3 (GPC3) could be utilized as a biomarker for HCC detection and treatment response in patients with cirrhosis. METHODS Immunohistochemistry was performed to assess p62 and GPC3 expression in the lesion and adjacent tissue from cirrhosis with HCC. GPC3-enriched exosomes were captured by an enzyme-linked immunosorbent assay (ELISA). The diagnostic specificity of serum exosome-derived GPC3 (eGPC3) was determined using samples obtained from malignancy-free controls, malignancy-free cirrhotics, cirrhotics with confirmed HCC, and patients with a non-HCC malignancy. The performance of eGPC3 was validated using serum samples of HCC patients received chemotherapy. RESULTS We found that the expression of p62 and GPC3 was significantly increased in HCC tissues compared to adjacent cirrhotic liver. Impaired autophagy and exosome shedding were confirmed in HCC cell lines. Mass spectroscopic analysis revealed that GPC3 was enriched in exosomes isolated from HCC cell lines. An affinity ELISA assay was developed that specifically captures GPC3 positive exosomes in the serum. Total exosome concentration and eGPC3 were significantly elevated in cirrhotic patients with HCC as compared to the reference control groups. Furthermore, decreases in post-treatment exosome concentration and eGPC3 levels were more closely correlated with response to locoregional chemotherapy compared to change in serum AFP in HCC patients awaiting liver transplantation. CONCLUSION We developed an affinity exosome capture assay to detect GPC3 enriched exosomes. Our preliminary assessment shows that GPC3 positive exosomes can be used for HCC detection and prediction of treatment outcomes.
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Affiliation(s)
- Yucel Aydin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Ali Riza Koksal
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
- Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Paul Thevenot
- Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
| | - Srinivas Chava
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Zahra Heidari
- Chemical and Biomedical Engineering, Tulane University, New Orleans, LA, USA
| | - Dong Lin
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Tyler Sandow
- Department of Radiology, Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
| | - Krzysztof Moroz
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Mansour A Parsi
- Department of Gastroenterology and Hepatology, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - John Scott
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
| | - Ari Cohen
- Institute of Translational Research, Ochsner Health, New Orleans, LA, USA
- Multi-Organ Transplant Institute, Ochsner Health, New Orleans, LA, USA
| | - Srikanta Dash
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA, USA
- Southeast Louisiana Veterans Health Care System, New Orleans, LA, USA
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Hu B, Rodriguez JJ, Kakkerla Balaraju A, Gao Y, Nguyen NT, Steen H, Suhaib S, Chen S, Lin F. Glypican 4 mediates Wnt transport between germ layers via signaling filopodia. J Cell Biol 2021; 220:212673. [PMID: 34591076 PMCID: PMC8488972 DOI: 10.1083/jcb.202009082] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Revised: 07/18/2021] [Accepted: 09/08/2021] [Indexed: 12/31/2022] Open
Abstract
Glypicans influence signaling pathways by regulating morphogen trafficking and reception. However, the underlying mechanisms in vertebrates are poorly understood. In zebrafish, Glypican 4 (Gpc4) is required for convergence and extension (C&E) of both the mesoderm and endoderm. Here, we show that transgenic expression of GFP-Gpc4 in the endoderm of gpc4 mutants rescued C&E defects in all germ layers. The rescue of mesoderm was likely mediated by Wnt5b and Wnt11f2 and depended on signaling filopodia rather than on cleavage of the Gpc4 GPI anchor. Gpc4 bound both Wnt5b and Wnt11f2 and regulated formation of the filopodia that transport Wnt5b and Wnt11f2 to neighboring cells. Moreover, this rescue was suppressed by blocking signaling filopodia that extend from endodermal cells. Thus, GFP-Gpc4–labeled protrusions that emanated from endodermal cells transported Wnt5b and Wnt11f2 to other germ layers, rescuing the C&E defects caused by a gpc4 deficiency. Our study reveals a new mechanism that could explain in vivo morphogen distribution involving Gpc4.
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Affiliation(s)
- Bo Hu
- Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Juan J Rodriguez
- Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Anurag Kakkerla Balaraju
- Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Yuanyuan Gao
- Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Nhan T Nguyen
- Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Heston Steen
- Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Saeb Suhaib
- Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Songhai Chen
- Department of Neuroscience and Pharmacology, Carver College of Medicine, The University of Iowa, Iowa City, IA
| | - Fang Lin
- Department of Anatomy and Cell Biology, Carver College of Medicine, The University of Iowa, Iowa City, IA
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Hu J, Yang Y, Ma Y, Ning Y, Chen G, Liu Y. Proliferation Cycle Transcriptomic Signatures are Strongly associated With Gastric Cancer Patient Survival. Front Cell Dev Biol 2021; 9:770994. [PMID: 34926458 PMCID: PMC8672820 DOI: 10.3389/fcell.2021.770994] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2021] [Accepted: 11/08/2021] [Indexed: 01/17/2023] Open
Abstract
Gastric cancer is one of the most heterogeneous tumors with multi-level molecular disturbances. Sustaining proliferative signaling and evading growth suppressors are two important hallmarks that enable the cancer cells to become tumorigenic and ultimately malignant, which enable tumor growth. Discovering and understanding the difference in tumor proliferation cycle phenotypes can be used to better classify tumors, and provide classification schemes for disease diagnosis and treatment options, which are more in line with the requirements of today's precision medicine. We collected 691 eligible samples from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) database, combined with transcriptome data, to explore different heterogeneous proliferation cycle phenotypes, and further study the potential genomic changes that may lead to these different phenotypes in this study. Interestingly, two subtypes with different clinical and biological characteristics were identified through cluster analysis of gastric cancer transcriptome data. The repeatability of the classification was confirmed in an independent Gene Expression Omnibus validation cohort, and consistent phenotypes were observed. These two phenotypes showed different clinical outcomes, and tumor mutation burden. This classification helped us to better classify gastric cancer patients and provide targeted treatment based on specific transcriptome data.
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Affiliation(s)
- Jianwen Hu
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yanpeng Yang
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yongchen Ma
- Department of Endoscopy Center, Peking University First Hospital, Beijing, China
| | - Yingze Ning
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Guowei Chen
- Department of General Surgery, Peking University First Hospital, Beijing, China
| | - Yucun Liu
- Department of General Surgery, Peking University First Hospital, Beijing, China
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Pan J, Ho M. Role of glypican-1 in regulating multiple cellular signaling pathways. Am J Physiol Cell Physiol 2021; 321:C846-C858. [PMID: 34550795 DOI: 10.1152/ajpcell.00290.2021] [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] [Indexed: 12/21/2022]
Abstract
Glypican-1 (GPC1) is one of the six glypican family members in humans. It is composed of a core protein with three heparan sulfate chains and attached to the cell membrane by a glycosyl-phosphatidylinositol anchor. GPC1 modulates various signaling pathways including fibroblast growth factors (FGF), vascular endothelial growth factor-A (VEGF-A), transforming growth factor-β (TGF-β), Wnt, Hedgehog (Hh), and bone morphogenic protein (BMP) through specific interactions with pathway ligands and receptors. The impact of these interactions on signaling pathways, activating or inhibitory, is dependent upon specific GPC1 domain interaction with pathway components, as well as cell surface context. In this review, we summarize the current understanding of the structure of GPC1, as well as its role in regulating multiple signaling pathways. We focus on the functions of GPC1 in cancer cells and how new insights into these signaling processes can inform its translational potential as a therapeutic target in cancer.
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Affiliation(s)
- Jiajia Pan
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.,School of Life Sciences, East China Normal University, Shanghai, China
| | - Mitchell Ho
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
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SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts. Nat Commun 2021; 12:4611. [PMID: 34326333 PMCID: PMC8322311 DOI: 10.1038/s41467-021-24819-w] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Accepted: 07/09/2021] [Indexed: 12/24/2022] Open
Abstract
Hedgehog signaling is essential for bone formation, including functioning as a means for the growth plate to drive skeletal mineralization. However, the mechanisms regulating hedgehog signaling specifically in bone-forming osteoblasts are largely unknown. Here, we identified SLIT and NTRK-like protein-5(Slitrk5), a transmembrane protein with few identified functions, as a negative regulator of hedgehog signaling in osteoblasts. Slitrk5 is selectively expressed in osteoblasts and loss of Slitrk5 enhanced osteoblast differentiation in vitro and in vivo. Loss of SLITRK5 in vitro leads to increased hedgehog signaling and overexpression of SLITRK5 in osteoblasts inhibits the induction of targets downstream of hedgehog signaling. Mechanistically, SLITRK5 binds to hedgehog ligands via its extracellular domain and interacts with PTCH1 via its intracellular domain. SLITRK5 is present in the primary cilium, and loss of SLITRK5 enhances SMO ciliary enrichment upon SHH stimulation. Thus, SLITRK5 is a negative regulator of hedgehog signaling in osteoblasts that may be attractive as a therapeutic target to enhance bone formation.
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Ho EK, Stearns T. Hedgehog signaling and the primary cilium: implications for spatial and temporal constraints on signaling. Development 2021; 148:dev195552. [PMID: 33914866 PMCID: PMC8126410 DOI: 10.1242/dev.195552] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The mechanisms of vertebrate Hedgehog signaling are linked to the biology of the primary cilium, an antenna-like organelle that projects from the surface of most vertebrate cell types. Although the advantages of restricting signal transduction to cilia are often noted, the constraints imposed are less frequently considered, and yet they are central to how Hedgehog signaling operates in developing tissues. In this Review, we synthesize current understanding of Hedgehog signal transduction, ligand secretion and transport, and cilia dynamics to explore the temporal and spatial constraints imposed by the primary cilium on Hedgehog signaling in vivo.
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Affiliation(s)
- Emily K. Ho
- Department of Developmental Biology, Stanford School of Medicine, Stanford, CA 94305, USA
| | - Tim Stearns
- Department of Biology, Stanford University, Stanford, CA 94305, USA
- Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA
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50
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Association of Sonic Hedgehog with the extracellular matrix requires its zinc-coordination center. BMC Mol Cell Biol 2021; 22:22. [PMID: 33863273 PMCID: PMC8052667 DOI: 10.1186/s12860-021-00359-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Accepted: 03/09/2021] [Indexed: 02/08/2023] Open
Abstract
Background Sonic Hedgehog (Shh) has a catalytic cleft characteristic for zinc metallopeptidases and has significant sequence similarities with some bacterial peptidoglycan metallopeptidases defining a subgroup within the M15A family that, besides having the characteristic zinc coordination motif, can bind two calcium ions. Extracellular matrix (ECM) components in animals include heparan-sulfate proteoglycans, which are analogs of bacterial peptidoglycan and are involved in the extracellular distribution of Shh. Results We found that the zinc-coordination center of Shh is required for its association to the ECM as well as for non-cell autonomous signaling. Association with the ECM requires the presence of at least 0.1 μM zinc and is prevented by mutations affecting critical conserved catalytical residues. Consistent with the presence of a conserved calcium binding domain, we find that extracellular calcium inhibits ECM association of Shh. Conclusions Our results indicate that the putative intrinsic peptidase activity of Shh is required for non-cell autonomous signaling, possibly by enzymatically altering ECM characteristics. Supplementary Information The online version contains supplementary material available at 10.1186/s12860-021-00359-5.
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