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Zeng C, Lv X, Wang F, Huang Y, Ren Y, Zhang H. Matrix Remodeling Associated Genes (MXRAs): structural diversity, functional significance, and therapeutic potential in tumor microenvironments. Discov Oncol 2025; 16:833. [PMID: 40394417 PMCID: PMC12092922 DOI: 10.1007/s12672-025-02728-4] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2025] [Accepted: 05/16/2025] [Indexed: 05/22/2025] Open
Abstract
The Matrix Remodeling Associated Genes (MXRAs) family, comprising eight distinct members (MXRA1-8), plays a crucial role in the development and maintenance of higher vertebrate cells. These proteins are primarily involved in the regulation of intercellular adhesion and the remodeling of the extracellular matrix (ECM). Recent investigations have highlighted the significant roles of MXRAs in the modulation of tumor growth and progression, establishing them as vital components in the oncogenic landscape. Notably, each MXRA member exhibits unique structural characteristics and functional properties, contributing to a diverse array of regulatory effects within the tumor context. This review seeks to provide a comprehensive analysis of the structural attributes, functional contributions, and activities of MXRAs within the tumor microenvironment. By elucidating the underlying mechanisms of action, this paper aims to offer novel insights and strategic approaches for the identification of early diagnostic biomarkers, as well as potential therapeutic targets that may facilitate molecular interventions aimed at inhibiting tumor development.
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Affiliation(s)
- Chao Zeng
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Xiao Lv
- Department of Obstetrics and Gynecology, The First Hospital of Lanzhou University, Lanzhou, 730000, China
- Department of Obstetrics and Gynecology, Key Laboratory of Gynecologic Oncology Gansu Province, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Feng Wang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, China
- The First School of Clinical Medicne, Lanzhou University, Lanzhou, 730030, China
| | - Yaomin Huang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, China
- The First School of Clinical Medicne, Lanzhou University, Lanzhou, 730030, China
| | - Yanxian Ren
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, China
- The First School of Clinical Medicne, Lanzhou University, Lanzhou, 730030, China
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, China
| | - Hengwei Zhang
- Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
- The First School of Clinical Medicne, Lanzhou University, Lanzhou, 730030, China.
- Gansu Province Key Laboratory of Biological Therapy and Regenerative Medicine Transformation, Lanzhou, 730030, China.
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Ghosh A, Coffin M, Diaz DM, Barndt S, Schulz V, Gallagher P, Lo SH, Fowler VM. A novel isoform of Tensin1 promotes actin filament assembly for efficient erythroblast enucleation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.12.13.628322. [PMID: 39763869 PMCID: PMC11702514 DOI: 10.1101/2024.12.13.628322] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/11/2025]
Abstract
Mammalian red blood cells are generated via a terminal erythroid differentiation pathway culminating in cell polarization and enucleation. Actin filament polymerization is critical for enucleation, but the molecular regulatory mechanisms remain poorly understood. We utilized publicly available RNA-seq and proteomics datasets to mine for actin-binding proteins and actin-nucleation factors differentially expressed during human erythroid differentiation and discovered that a focal adhesion protein-Tensin-1-dramatically increases in expression late in differentiation. Remarkably, we found that differentiating human CD34+ cells express a novel truncated form of Tensin-1 (eTNS1; Mr ~125 kDa) missing the N-terminal half of the protein, due to an internal mRNA translation start site resulting in a unique exon 1. eTNS1 localized to the cytoplasm during terminal erythroid differentiation, with no apparent membrane association or focal adhesion formation. Knocking out eTNS1 had no effect on assembly of the spectrin membrane skeleton but led to impaired enucleation and absent or mis-localized actin filament foci in enucleating erythroblasts. We conclude that eTNS1 is a novel regulator of actin filament assembly during human erythroid terminal differentiation required for efficient enucleation.
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Affiliation(s)
- Arit Ghosh
- Department of Biological Sciences, University of Delaware, Newark, DE
- Delaware Biotechnology Institute, UD Flow Cytometry Core, Newark, DE
- Department of Medical and Molecular Sciences, University of Delaware, Newark, DE
| | - Megan Coffin
- Department of Biological Sciences, University of Delaware, Newark, DE
| | - Dimitri M. Diaz
- Department of Biological Sciences, University of Delaware, Newark, DE
| | - Sarah Barndt
- Department of Medical and Molecular Sciences, University of Delaware, Newark, DE
| | - Vincent Schulz
- Department of Pediatrics, Yale University, New Haven, CT
| | | | - Su Hao Lo
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95817, USA
- Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
- Institute of Molecular and Genomic Medicine, National Health of Research Institutes, Miaoli 35053, Taiwan
| | - Velia M. Fowler
- Department of Biological Sciences, University of Delaware, Newark, DE
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Di X, Wang D, Wu J, Zhu X, Wang Y, Yan J, Wen L, Jiang H, Wen D, Shu B, Zhang S. Characterization of a germline variant TNS1 c.2999-1G > C in a hereditary cancer syndrome family. Gene 2024; 908:148304. [PMID: 38387708 DOI: 10.1016/j.gene.2024.148304] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Revised: 02/17/2024] [Accepted: 02/19/2024] [Indexed: 02/24/2024]
Abstract
Hereditary cancer syndromes result from the presence of inherited pathogenic variants within susceptibility genes. However, the susceptibility genes associated with hereditary cancer syndrome remain predominantly unidentified. Here, we reported a case of hereditary cancer syndrome observed in a Chinese family harboring a germline mutation in Tensin1 (TNS1). We described a 59-year-old female patient presented with Multiple myeloma and Thyroid carcinoma. The proband and her family members exhibited suspected tumor syndrome due to occurrences of other cancer cases. After oncogenetic counseling, whole-exome sequencing and Sanger sequencing were conducted and a primary driver mutation of TNS1 (NM_022648.7:c.2999-1G > C) was detected. Gene Expression Profiling Interactive Analysis revealed that TNS1 was expressed lower in different tumors when compared to normal, including Pancreatic adenocarcinoma, Breast invasive carcinoma, Thyroid carcinoma andColon adenocarcinoma cells. Despite the well-established role of TNS1 as a tumor suppressor in breast cancer and colorectal cancer, its potential utility as a marker gene for diagnosis and treatment of pancreatic cancer remains uncertain. Here, our data demonstrated that knockdown of TNS1 could promote cell proliferation and migration in Pancreatic adenocarcinoma (PDAC) cells. In addition, TNS1 regulated migration through EMT signaling pathway in PDAC cells. Our findings proposed that this variant was likely involved in cancer predisposition by disrupting the normal splicing process. In summary, we presented a genetic disease by linking an intronic mutation inTNS1. We aim to provide early detection of cancers by identifying germline variants in susceptibility genes.
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Affiliation(s)
- Xiaotang Di
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, 410013, China
| | - Ding Wang
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, 410013, China
| | - Jinzheng Wu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Xiaofang Zhu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Yang Wang
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, 410013, China
| | - Jinhua Yan
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, 410013, China
| | - Liang Wen
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China
| | - Hao Jiang
- Department of Biomedical Informatics, School of Life Sciences, Central South University, Changsha, Hunan, 410013, China
| | - Doudou Wen
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, 410013, China
| | - Bo Shu
- Department of General Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan, 410011, China.
| | - Shubing Zhang
- Department of Cell Biology, School of Life Sciences, Central South University, Changsha, Hunan, 410013, China; Hunan Key Laboratory of Animal Models for Human Diseases, Central South University, Changsha, Hunan, 410013, China.
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Juilland M, Alouche N, Ubezzi I, Gonzalez M, Rashid HO, Scarpellino L, Erdmann T, Grau M, Lenz G, Luther SA, Thome M. Identification of Tensin-3 as a MALT1 substrate that controls B cell adhesion and lymphoma dissemination. Proc Natl Acad Sci U S A 2023; 120:e2301155120. [PMID: 38109544 PMCID: PMC10756297 DOI: 10.1073/pnas.2301155120] [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: 01/20/2023] [Accepted: 10/24/2023] [Indexed: 12/20/2023] Open
Abstract
The protease MALT1 promotes lymphocyte activation and lymphomagenesis by cleaving a limited set of cellular substrates, most of which control gene expression. Here, we identified the integrin-binding scaffold protein Tensin-3 as a MALT1 substrate in activated human B cells. Activated B cells lacking Tensin-3 showed decreased integrin-dependent adhesion but exhibited comparable NF-κB1 and Jun N-terminal kinase transcriptional responses. Cells expressing a noncleavable form of Tensin-3, on the other hand, showed increased adhesion. To test the role of Tensin-3 cleavage in vivo, mice expressing a noncleavable version of Tensin-3 were generated, which showed a partial reduction in the T cell-dependent B cell response. Interestingly, human diffuse large B cell lymphomas and mantle cell lymphomas with constitutive MALT1 activity showed strong constitutive Tensin-3 cleavage and a decrease in uncleaved Tensin-3 levels. Moreover, silencing of Tensin-3 expression in MALT1-driven lymphoma promoted dissemination of xenografted lymphoma cells to the bone marrow and spleen. Thus, MALT1-dependent Tensin-3 cleavage reveals a unique aspect of the function of MALT1, which negatively regulates integrin-dependent B cell adhesion and facilitates metastatic spread of B cell lymphomas.
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Affiliation(s)
- Mélanie Juilland
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Nagham Alouche
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Ivana Ubezzi
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Montserrat Gonzalez
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Harun-Or Rashid
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Leonardo Scarpellino
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Tabea Erdmann
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Münster, MünsterD-48149, Germany
| | - Michael Grau
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Münster, MünsterD-48149, Germany
| | - Georg Lenz
- Department of Medicine A for Hematology, Oncology and Pneumology, University Hospital Münster, MünsterD-48149, Germany
| | - Sanjiv A. Luther
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
| | - Margot Thome
- Department of Immunobiology, University of Lausanne, EpalingesCH-1066, Switzerland
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Zhang S, van de Peppel J, Koedam M, van Leeuwen JPTM, van der Eerden BCJ. Tensin-3 is involved in osteogenic versus adipogenic fate of human bone marrow stromal cells. Cell Mol Life Sci 2023; 80:277. [PMID: 37668682 PMCID: PMC10480249 DOI: 10.1007/s00018-023-04930-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2023] [Revised: 07/25/2023] [Accepted: 08/21/2023] [Indexed: 09/06/2023]
Abstract
BACKGROUND The tightly controlled balance between osteogenic and adipogenic differentiation of human bone marrow-derived stromal cells (BMSCs) is critical to maintain bone homeostasis. Age-related osteoporosis is characterized by low bone mass with excessive infiltration of adipose tissue in the bone marrow compartment. The shift of BMSC differentiation from osteoblasts to adipocytes could result in bone loss and adiposity. METHODS TNS3 gene expression during osteogenic and adipogenic differentiation of BMSCs was evaluated by qPCR and Western blot analyses. Lentiviral-mediated knockdown or overexpression of TNS3 was used to assess its function. The organization of cytoskeleton was examined by immunofluorescent staining at multiple time points. The role of TNS3 and its domain function in osteogenic differentiation were evaluated by ALP activity, calcium assay, and Alizarin Red S staining. The expression of Rho-GTP was determined using the RhoA pull-down activation assay. RESULTS Loss of TNS3 impaired osteogenic differentiation of BMSCs but promoted adipogenic differentiation. Conversely, TNS3 overexpression hampered adipogenesis while enhancing osteogenesis. The expression level of TNS3 determined cell shape and cytoskeletal reorganization during osteogenic differentiation. TNS3 truncation experiments revealed that for optimal osteogenesis to occur, all domains proved essential. Pull-down and immunocytochemical experiments suggested that TNS3 mediates osteogenic differentiation through RhoA. CONCLUSIONS Here, we identify TNS3 to be involved in BMSC fate decision. Our study links the domain structure in TNS3 to RhoA activity via actin dynamics and implicates an important role for TNS3 in regulating osteogenesis and adipogenesis from BMSCs. Furthermore, it supports the critical involvement of cytoskeletal reorganization in BMSC differentiation.
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Affiliation(s)
- Shuang Zhang
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, The Netherlands
| | - Jeroen van de Peppel
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, The Netherlands
| | - Marijke Koedam
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, The Netherlands
| | - Johannes P T M van Leeuwen
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, The Netherlands
| | - Bram C J van der Eerden
- Laboratory for Calcium and Bone Metabolism, Department of Internal Medicine, Erasmus MC, Erasmus University Medical Center, Doctor Molewaterplein 40, 3015GD, Rotterdam, The Netherlands.
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Mainsiouw L, Ryan ME, Hafizi S, Fleming JC. The molecular and clinical role of Tensin 1/2/3 in cancer. J Cell Mol Med 2023. [PMID: 37296531 DOI: 10.1111/jcmm.17714] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Revised: 02/07/2023] [Accepted: 02/10/2023] [Indexed: 06/12/2023] Open
Abstract
Tensin 1 was originally described as a focal adhesion adaptor protein, playing a role in extracellular matrix and cytoskeletal interactions. Three other Tensin proteins were subsequently discovered, and the family was grouped as Tensin. It is now recognized that these proteins interact with multiple cell signalling cascades that are implicated in tumorigenesis. To understand the role of Tensin 1-3 in neoplasia, current molecular evidence is categorized by the hallmarks of cancer model. Additionally, clinical data involving Tensin 1-3 are reviewed to investigate the correlation between cellular effects and clinical phenotype. Tensin proteins commonly interact with the tumour suppressor, DLC1. The ability of Tensin to promote tumour progression is directly correlated with DLC1 expression. Members of the Tensin family appear to have tumour subtype-dependent effects on oncogenesis; despite numerous data evidencing a tumour suppressor role for Tensin 2, association of Tensins 1-3 with an oncogenic role notably in colorectal carcinoma and pancreatic ductal adenocarcinoma is of potential clinical relevance. The complex interplay between these focal adhesion adaptor proteins and signalling pathways are discussed to provide an up to date review of their role in cancer biology.
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Affiliation(s)
| | - Matthew Edward Ryan
- Department of Molecular and Clinical Cancer Medicine, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
- Liverpool Head and Neck Centre, University of Liverpool, Liverpool, UK
| | - Sassan Hafizi
- School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK
| | - Jason C Fleming
- Department of Molecular and Clinical Cancer Medicine, Faculty of Health and Life Sciences, University of Liverpool, Liverpool, UK
- Liverpool Head and Neck Centre, University of Liverpool, Liverpool, UK
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Wang YX, Huang CY, Chiu HJ, Huang PH, Chien HT, Jwo SH, Liao YC. Nuclear-localized CTEN is a novel transcriptional regulator and promotes cancer cell migration through its downstream target CDC27. J Physiol Biochem 2023; 79:163-174. [PMID: 36399312 DOI: 10.1007/s13105-022-00932-2] [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: 08/24/2022] [Accepted: 11/11/2022] [Indexed: 11/21/2022]
Abstract
C-terminal tensin-like (CTEN) is a tensin family protein typically localized to the cytoplasmic side of focal adhesions, and primarily contributes to cell adhesion and migration. Elevated expression and nuclear accumulation of CTEN have been reported in several types of cancers and found to be associated with malignant behaviors. However, the function of nuclear CTEN remains elusive. In this study, we report for the first time that nuclear CTEN associates with chromatin DNA and occupies the region proximal to the transcription start site in several genes. The mRNA expression level of CTEN positively correlates with that of one of its putative target genes, cell division cycle protein 27 (CDC27), in a clinical colorectal cancer dataset, suggesting that CTEN may play a role in the regulation of CDC27 gene expression. Furthermore, we demonstrated that CTEN is recruited to the promoter region of the CDC27 gene and that the mRNA expression and promoter activity of CDC27 are both reduced when CTEN is downregulated. In addition, we found that enhanced nuclear accumulation of CTEN in HCT116 cells by overexpression of CTEN fused with nuclear localization signals increases CDC27 transcript levels and promoter activity. The increased nuclear-localized CTEN also significantly promotes cell migration, and the migratory ability is suppressed when CDC27 is knocked down. These results demonstrate that nuclear CTEN regulates CDC27 expression transcriptionally and promotes cell migration through CDC27. Our findings provide new insights into CTEN moonlighting in the nucleus as a DNA-associated protein and transcriptional regulator involved in modulating cancer cell migration.
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Affiliation(s)
- Yi-Xuan Wang
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, 10617, Taiwan
| | - Chun-Yang Huang
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, 10617, Taiwan
| | - Hsiao-Ju Chiu
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, 10617, Taiwan
| | - Po-Han Huang
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, 10617, Taiwan
| | - Hung-Ting Chien
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, 10617, Taiwan
| | - Si-Han Jwo
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, 10617, Taiwan
| | - Yi-Chun Liao
- Department of Biochemical Science and Technology, National Taiwan University, Taipei, 10617, Taiwan.
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Monteiro A, Delgado L, Monteiro L, Pires I, Prada J, Raposo T. Immunohistochemical Expression of Tensin-4/CTEN in Squamous Cell Carcinoma in Dogs. Vet Sci 2023; 10:86. [PMID: 36851390 PMCID: PMC9960384 DOI: 10.3390/vetsci10020086] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Revised: 01/21/2023] [Accepted: 01/22/2023] [Indexed: 01/26/2023] Open
Abstract
C-terminal tensin-like (tensin-4/TNS4/CTEN) is the fourth member of the tensin family, frequently described as displaying oncological functions, including cellular migration, invasion, adhesion, growth, metastasis, epithelial to mesenchymal transition, and apoptosis, in several different types of cancer. To investigate, for the first time, the clinical significance of CTEN in squamous cell carcinoma (SCC) of dogs, we studied a total of 45 SCC sections from various dog breeds. The mean age of the affected dogs was 8.9 ± 3.6 years. Immunohistochemistry confirmed strong cytoplasmatic CTEN expression in the basal layer of the epidermis next to the tumor. We detected high CTEN expression associated with the highest grade of the tumor (grade III) and observed 100% of immunopositivity for this tumor grading (p < 0.0001). These data suggest that CTEN is an oncogene in SCC of dogs and a promising biomarker and a therapeutic target for dogs affected by SCC.
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Affiliation(s)
- Alexandra Monteiro
- Department of Biology and Environment, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- Instituto de Investigação e Inovação em Saúde, Universidade do Porto (i3S), 4200-135 Porto, Portugal
| | - Leonor Delgado
- UNIPRO-Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences-CESPU (IUCS-CESPU), 4585-116 Gandra, Portugal
- Pathology Department, INNO Serviços Especializados em Veterinária, 4710-503 Braga, Portugal
| | - Luís Monteiro
- UNIPRO-Oral Pathology and Rehabilitation Research Unit, University Institute of Health Sciences-CESPU (IUCS-CESPU), 4585-116 Gandra, Portugal
- Pathology Department, INNO Serviços Especializados em Veterinária, 4710-503 Braga, Portugal
| | - Isabel Pires
- Department of Veterinary Science, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- CECAV-Veterinary and Animal Research Center, University of Trás-os-Montes and Alto Douro, 5001-801 Vila Real, Portugal
| | - Justina Prada
- Department of Veterinary Science, University of Trás-os-Montes and Alto Douro, 5000-801 Vila Real, Portugal
- CECAV-Veterinary and Animal Research Center, University of Trás-os-Montes and Alto Douro, 5001-801 Vila Real, Portugal
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TNS1: Emerging Insights into Its Domain Function, Biological Roles, and Tumors. BIOLOGY 2022; 11:biology11111571. [PMID: 36358270 PMCID: PMC9687257 DOI: 10.3390/biology11111571] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Revised: 10/24/2022] [Accepted: 10/25/2022] [Indexed: 01/25/2023]
Abstract
Tensins are a family of cellular-adhesion constituents that have been extensively studied. They have instrumental roles in the pathogenesis of numerous diseases. The mammalian tensin family comprises four members: tensin1 (TNS1), tensin2, tensin3, and tensin4. Among them, TNS1 has recently received attention from researchers because of its structural properties. TNS1 engages in various biological processes, such as cell adhesion, polarization, migration, invasion, proliferation, apoptosis, and mechano-transduction, by interacting with various partner proteins. Moreover, the abnormal expression of TNS1 in vivo is associated with the development of various diseases, especially tumors. Interestingly, the role of TNS1 in different tumors is still controversial. Here, we systematically summarize three aspects of TNS1: the gene structure, the biological processes underlying its action, and the dual regulatory role of TNS1 in different tumors through different mechanisms, of which we provide the first overview.
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10
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Uthailak N, Adisakwattana P, Thiangtrongjit T, Limpanont Y, Chusongsang P, Chusongsang Y, Tanasarnprasert K, Reamtong O. Discovery of Schistosoma mekongi circulating proteins and antigens in infected mouse sera. PLoS One 2022; 17:e0275992. [PMID: 36227939 PMCID: PMC9562170 DOI: 10.1371/journal.pone.0275992] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2022] [Accepted: 09/27/2022] [Indexed: 11/24/2022] Open
Abstract
Schistosomiasis is a neglected tropical disease caused by an infection of the parasitic flatworms schistosomes. Schistosoma mekongi is a restricted Schistosoma species found near the Mekong River, mainly in southern Laos and northern Cambodia. Because there is no vaccine or effective early diagnosis available for S. mekongi, additional biomarkers are required. In this study, serum biomarkers associated with S. mekongi-infected mice were identified at 14-, 28-, 42-, and 56-days post-infection. Circulating proteins and antigens of S. mekongi in mouse sera were analyzed using mass spectrometry-based proteomics. Serine protease inhibitors and macrophage erythroblast attacher were down-regulated in mouse sera at all infection timepoints. In addition, 54 circulating proteins and 55 antigens of S. mekongi were identified. Notable circulating proteins included kyphoscoliosis peptidase and putative tuberin, and antigens were detected at all four infection timepoints, particularly in the early stages (12 days). The putative tuberin sequence of S. mekongi was highly similar to homologs found in other members of the genus Schistosoma and less similar to human and murine sequences. Our study provided the identity of promising diagnostic biomarkers that could be applicable in early schistosomiasis diagnosis and vaccine development.
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Affiliation(s)
- Naphatsamon Uthailak
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Poom Adisakwattana
- Department of Helminthology, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Tipparat Thiangtrongjit
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Yanin Limpanont
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Phiraphol Chusongsang
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Yupa Chusongsang
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Kanthi Tanasarnprasert
- Department of Social and Environmental Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
| | - Onrapak Reamtong
- Department of Molecular Tropical Medicine and Genetics, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand
- * E-mail:
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11
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Liu D, Zhang Y, Fang H, Yuan J, Ji L. The progress of research into pseudophosphatases. Front Public Health 2022; 10:965631. [PMID: 36106167 PMCID: PMC9464862 DOI: 10.3389/fpubh.2022.965631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Accepted: 08/09/2022] [Indexed: 01/24/2023] Open
Abstract
Pseudophosphatases are a class of phosphatases that mutate at the catalytically active site. They play important parts in many life processes and disorders, e.g., cell apoptosis, stress reaction, tumorigenesis, axon differentiation, Charcot-Marie-Tooth, and metabolic dysfunction. The present review considers the structures and action types of pseudophosphatases in four families, protein tyrosine phosphatases (PTPs), myotube protein phosphatases (MTMs), phosphatases and tensin homologues (PTENs) and dual specificity phosphatases (DUSPs), as well as their mechanisms in signaling and disease. We aimed to provide reference material for the research and treatment of related diseases.
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Affiliation(s)
- Deqiang Liu
- College of Life Sciences, Shandong Normal University, Jinan, China
| | - Yiming Zhang
- College of Life Sciences, Shandong Normal University, Jinan, China
| | - Hui Fang
- College of Life Sciences, Shandong Normal University, Jinan, China
| | - Jinxiang Yuan
- College of Life Sciences, Shandong Normal University, Jinan, China,The Collaborative Innovation Center, Jining Medical University, Jining, China,*Correspondence: Jinxiang Yuan
| | - Lizhen Ji
- College of Life Sciences, Shandong Normal University, Jinan, China,Lizhen Ji
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12
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Tensin Regulates Fundamental Biological Processes by Interacting with Integrins of Tonsil-Derived Mesenchymal Stem Cells. Cells 2022; 11:cells11152333. [PMID: 35954177 PMCID: PMC9367440 DOI: 10.3390/cells11152333] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2022] [Revised: 07/26/2022] [Accepted: 07/28/2022] [Indexed: 12/04/2022] Open
Abstract
Human tonsil-derived mesenchymal stem cells (TMSCs) have a superior proliferation rate and differentiation potential compared to adipose-tissue-derived MSCs (AMSCs) or bone-marrow-derived MSCs (BMSCs). TMSCs exhibit a significantly higher expression of the tensin3 gene (TNS3) than AMSCs or BMSCs. TNS is involved in cell adhesion and migration by binding to integrin beta-1 (ITG β1) in focal adhesion. Here, we investigated the roles of four TNS isoforms, including TNS3 and their relationship with integrin in various biological processes of TMSCs. Suppressing TNS1 and TNS3 significantly decreased the cell count. The knockdown of TNS1 and TNS3 increased the gene and protein expression levels of p16, p19, and p21. TNS1 and TNS3 also have a significant effect on cell migration. Transfecting with siRNA TNS3 significantly reduced Oct4, Nanog, and Sox-2 levels. Conversely, when TNS4 was silenced, Oct4 and Sox-2 levels significantly increase. TNS1 and TNS3 promote osteogenic and adipogenic differentiation, whereas TNS4 inhibits adipogenic differentiation of TMSCs. TNS3 is involved in the control of focal adhesions by regulating integrin. Thus, TNS enables TMSCs to possess a higher proliferative capacity and differentiation potential than other MSCs. Notably, TNS3 plays a vital role in TMSC biology by regulating ITGβ1 activity.
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13
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Nizioł M, Zińczuk J, Zaręba K, Guzińska-Ustymowicz K, Pryczynicz A. Increased tensin 4 expression is related to the histological type of gastric cancer. World J Clin Oncol 2021; 12:1202-1214. [PMID: 35070739 PMCID: PMC8716987 DOI: 10.5306/wjco.v12.i12.1202] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 06/29/2021] [Accepted: 11/18/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Gastric cancer (GC) is one of the most common malignant tumors worldwide. Tensin 4 (TNS4) is an adhesive protein belonging to the tensin family. This protein is located in focal adhesion sites. The TNS4 gene is considered an oncogene in numerous cancers. This protein plays an important role in adhesion, migration and proliferation of cells.
AIM To evaluate expression of TNS4 protein in GC tissues and analysis of the clinical and histopathological parameters as well as the overall survival rate of patients.
METHODS The expression of TNS4 was assessed in 89 patients using immunohistochemistry.
RESULTS Positive expression of TNS4 was observed in 49 of 89 patients (55.06%). Higher TNS4 expression was more common in GC tumors with a diameter ≥ 5 cm (P = 0.040). We demonstrated that an increase in TNS4 expression was more frequent in tumors of the histological type without mucinous components than in tumors from mucosal cancers (P = 0.023). Furthermore, TNS4 expression was higher in moderately differentiated tumors than in poorly differentiated and non-differentiated tumors (P = 0.002). Increased TNS4 expression was also noted in the intestinal type of GC according to Lauren’s classification (P = 0.020). No statistically significant correlation was found between the expression of TNS4 and the overall survival rate of patients.
CONCLUSION TNS4 expression was significantly higher in tumors with a diameter ≥ 5 cm of the moderately differentiated intestinal type (according to Lauren’s classification) of GC without a mucinous component. Therefore, increased TNS4 expression is related to the histological type of GC with a better prognosis.
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Affiliation(s)
- Marcin Nizioł
- Department of General Pathomorphology, Medical University of Bialystok, Białystok 15-089, Poland
| | - Justyna Zińczuk
- Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Bialystok 15-089, Poland
| | - Konrad Zaręba
- The Second Clinical Department of General and Gastroenterological Surgery, Medical University of Bialystok, Białystok 15-089, Poland
| | | | - Anna Pryczynicz
- Department of General Pathomorphology, Medical University of Bialystok, Białystok 15-089, Poland
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14
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Lu X, Zhou B, Cao M, Shao Q, Pan Y, Zhao T. CTEN Inhibits Tumor Angiogenesis and Growth by Targeting VEGFA Through Down-Regulation of β-Catenin in Breast Cancer. Technol Cancer Res Treat 2021; 20:15330338211045506. [PMID: 34817293 PMCID: PMC8661028 DOI: 10.1177/15330338211045506] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
C-terminal tensin-like (CTEN) belongs to the tensin gene family, which encodes
proteins that localize to focal adhesions and modulate integrin function.
Accumulating studies have reported that CTEN expression can be upregulated or
downregulated in different types of cancers, suggesting that CTEN has both
oncogenic and tumor suppressor functions. In this study, by analyzing the
expression level of CTEN in the human breast cancer (BRCA) samples from the
clinically annotated genomic database, The Cancer Genome Atlas, we found that
CTEN was downregulated in different BRCA subclasses, including luminal, human
epidermal growth factor receptor 2 positive and triple-negative BRCA.
Consistently, the protein level of CTEN was also reduced in BRCA based on the
Proteomic Tumor Analysis Consortium. In contrast, vascular endothelial growth
factor A (VEGFA), a signal protein that stimulates the formation of blood
vessels, was upregulated in BRCA. CTEN overexpression in human umbilical vein
endothelial cells and MCF7 significantly suppressed the expression of VEGFA,
inhibited cell proliferation, migration, and tube formation in vitro.
Mechanistically, CTEN bind to casitas B-lineage lymphoma (c-Cbl), an E3
ubiquitin-protein ligase, and decreased the β-catenin expression. In turn, the
downregulation of β-catenin reduced the expression of VEGFA. Rescuing β-catenin
expression effectively ameliorated the effect of CTEN overexpression in cell
proliferation, migration, and tube formation. In conclusion, CTEN inhibited
tumor angiogenesis by targeting VEGFA through c-Cbl-mediated down-regulation of
β-catenin and may serve as a tumor suppressor in BRCA.
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Affiliation(s)
- Xiangdong Lu
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Bin Zhou
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Minmin Cao
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Qin Shao
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Yukai Pan
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
| | - Tao Zhao
- Jiangyin People's Hospital, Jiangyin, Jiangsu Province, 214400, P.R. China
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15
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EphA2 signaling within integrin adhesions regulates fibrillar adhesion elongation and fibronectin deposition. Matrix Biol 2021; 103-104:1-21. [PMID: 34537369 DOI: 10.1016/j.matbio.2021.09.001] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Revised: 09/01/2021] [Accepted: 09/09/2021] [Indexed: 12/28/2022]
Abstract
The multifunctional glycoprotein fibronectin influences several crucial cellular processes and contributes to multiple pathologies. While a link exists between fibronectin-associated pathologies and the receptor tyrosine kinase EphA2, the mechanism by which EphA2 promotes fibronectin matrix remodeling remains unknown. We previously demonstrated that EphA2 deletion reduces smooth muscle fibronectin deposition and blunts fibronectin deposition in atherosclerosis without influencing fibronectin expression. We now show that EphA2 expression is required for contractility-dependent elongation of tensin- and α5β1 integrin-rich fibrillar adhesions that drive fibronectin fibrillogenesis. Mechanistically, EphA2 localizes to integrin adhesions where focal adhesion kinase mediates ligand-independent Y772 phosphorylation, and mutation of this site significantly blunts fibrillar adhesion length. EphA2 deficiency decreases smooth muscle cell contractility by enhancing p190RhoGAP activation and reducing RhoA activity, whereas stimulating RhoA signaling in EphA2 deficient cells rescues fibrillar adhesion elongation. Together, these data identify EphA2 as a novel regulator of fibrillar adhesion elongation and provide the first data identifying a role for EphA2 signaling in integrin adhesions.
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16
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Mattei AM, Smailys JD, Hepworth EMW, Hinton SD. The Roles of Pseudophosphatases in Disease. Int J Mol Sci 2021; 22:ijms22136924. [PMID: 34203203 PMCID: PMC8269279 DOI: 10.3390/ijms22136924] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Revised: 06/10/2021] [Accepted: 06/24/2021] [Indexed: 01/07/2023] Open
Abstract
The pseudophosphatases, atypical members of the protein tyrosine phosphatase family, have emerged as bona fide signaling regulators within the past two decades. Their roles as regulators have led to a renaissance of the pseudophosphatase and pseudoenyme fields, catapulting interest from a mere curiosity to intriguing and relevant proteins to investigate. Pseudophosphatases make up approximately fourteen percent of the phosphatase family, and are conserved throughout evolution. Pseudophosphatases, along with pseudokinases, are important players in physiology and pathophysiology. These atypical members of the protein tyrosine phosphatase and protein tyrosine kinase superfamily, respectively, are rendered catalytically inactive through mutations within their catalytic active signature motif and/or other important domains required for catalysis. This new interest in the pursuit of the relevant functions of these proteins has resulted in an elucidation of their roles in signaling cascades and diseases. There is a rapid accumulation of knowledge of diseases linked to their dysregulation, such as neuropathies and various cancers. This review analyzes the involvement of pseudophosphatases in diseases, highlighting the function of various role(s) of pseudophosphatases involvement in pathologies, and thus providing a platform to strongly consider them as key therapeutic drug targets.
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17
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Walton NI, Zhang X, Soltis AR, Starr J, Dalgard CL, Wilkerson MD, Conrad D, Pollard HB. Tensin 1 (TNS1) is a modifier gene for low body mass index (BMI) in homozygous [F508del]CFTR patients. Physiol Rep 2021; 9:e14886. [PMID: 34086412 PMCID: PMC8176904 DOI: 10.14814/phy2.14886] [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: 04/08/2021] [Accepted: 05/02/2021] [Indexed: 11/24/2022] Open
Abstract
Cystic fibrosis (CF) is a life‐limiting autosomal recessive genetic disease caused by variants in the CFTR gene, most commonly by the [F508del] variant. Although CF is a classical Mendelian disease, genetic variants in several modifier genes have been associated with variation of the clinical phenotype for pulmonary and gastrointestinal function and urogenital development. We hypothesized that whole genome sequencing of a well‐phenotyped CF populations might identify novel variants in known, or hitherto unknown, modifier genes. Whole genome sequencing was performed on the Illumina HiSeq X platform for 98 clinically diagnosed cystic fibrosis patient samples from the Adult CF Clinic at the University of California San Diego (UCSD). We compared protein‐coding, non‐silent variants genome wide between CFTR [F508del] homozygotes vs CFTR compound heterozygotes. Based on a single variant score test, we found 3 SNPs in common variants (MAF >5%) that occurred at significantly different rates between homozygous [F508del]CFTR and compound heterozygous [F508del]CFTR patients. The 3 SNPs were all located in one gene on chromosome 2: Tensin 1 (TNS1: rs3796028; rs2571445: and rs918949). We observed significantly lower BMIs in homozygous [F508del]CFTR patients who were also homozygous for Tensin 1 rs918949 (T/T) (p = 0.023) or rs2571445 (G/G) (p = 0.02) variants. The Tensin 1 gene is thus a potential modifier gene for low BMI in CF patients homozygous for the [F508del]CFTR variant.
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Affiliation(s)
- Nathan I Walton
- The Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Consortium for Health and Military Performance, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
| | - Xijun Zhang
- The Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
| | - Anthony R Soltis
- The Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
| | - Joshua Starr
- The Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA
| | - Clifton L Dalgard
- The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Matthew D Wilkerson
- The Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, USA.,The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
| | - Douglas Conrad
- Department of Medicine, University of California, San Diego, CA, USA
| | - Harvey B Pollard
- The Collaborative Health Initiative Research Program, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Consortium for Health and Military Performance, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,The American Genome Center, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.,Department of Anatomy, Physiology, and Genetics, Uniformed Services University of the Health Sciences, Bethesda, MD, USA
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18
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Shi Y, Xiang Z, Yang H, Khan S, Li R, Zhou S, Ullah S, Zhang J, Liu B. Pharmacological targeting of TNS3 with histone deacetylase inhibitor as a therapeutic strategy in esophageal squamous cell carcinoma. Aging (Albany NY) 2021; 13:15336-15352. [PMID: 34047714 PMCID: PMC8221360 DOI: 10.18632/aging.203091] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Accepted: 03/06/2021] [Indexed: 01/19/2023]
Abstract
Histone acetylation which regulates about 2-10% of genes has been demonstrated to be involved in tumorigenesis of esophageal squamous cell carcinoma (ESCC). In this study, we investigated the treatment response of ESCC to selective histone deacetylase inhibitor (HDACi) LMK-235 and potential biomarker predicting the treatment sensitivity. We identified tensin-3 (TNS3) which was highly over-expressed in ESCC as one of the down-regulated genes in response to LMK-235 treatment. TNS3 was found positively correlated with the tumor malignancy and poor prognosis in the patients. Silencing TNS3 significantly inhibited ESCC cell proliferation both in vitro and in vivo, sensitizing the treatment response to LMK-235. Our findings provide an insight into understanding the oncogenic role of TNS3 in ESCC and its clinical application for HDAC targeted therapy of ESCC.
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Affiliation(s)
- Yang Shi
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Zheng Xiang
- Department of Pathology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou 450003, China
| | - Huiyu Yang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Suliman Khan
- Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou 450000, China
| | - Ruizhe Li
- Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
| | - Siran Zhou
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Saif Ullah
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Jiyu Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Bingrong Liu
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou 450052, China
- State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou University, Zhengzhou 450052, China
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19
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Nizioł M, Zińczuk J, Zaręba K, Guzińska-Ustymowicz K, Pryczynicz A. Immunohistochemical Analysis of the Expression of Adhesion Proteins: TNS1, TNS2 and TNS3 in Correlation with Clinicopathological Parameters in Gastric Cancer. Biomolecules 2021; 11:640. [PMID: 33926026 PMCID: PMC8146480 DOI: 10.3390/biom11050640] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 04/13/2021] [Accepted: 04/22/2021] [Indexed: 12/24/2022] Open
Abstract
Tensins belong to the group of adhesion proteins that are involved in cell adhesion and migration, actin cytoskeleton maintenance and intercellular communication. TNS1, TNS2 and TNS3 proteins expression was evaluated in 90 patients with gastric cancer by immunohistochemistry method. TNS1 was more frequently present in non-differentiated tumors compared to poorly and moderately differentiated tumors (p = 0.016). TNS1 was also more often observed in metastatic tumors compared to those without distant metastases (p = 0.001). TNS2 was more common in moderately differentiated tumors than in poorly or non-differentiated ones (p = 0.041). TNS2 expression was also more frequently present in tumors with peritumoral inflammation (p = 0.041) and with concomitant H. pylori infection (p = 0.023). In contrast, TNS3 protein was more prevalent in moderately than in poorly and non-differentiated tumors (p = 0.023). No significant relationship was found between tensins' expression and the overall survival rate of patients. TNS1 protein expression is associated with a poor-prognosis type of GC. Higher expression of TNS2 is accompanied by peritumoral inflammation and H. pylori infection, which favor the development of GC of a better prognosis, similarly to higher TNS3 protein expression.
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Affiliation(s)
- Marcin Nizioł
- Department of General Pathomorphology, Medical University of Białystok, Kilińskiego 1, 15-089 Białystok, Poland; (M.N.); (K.G.-U.)
| | - Justyna Zińczuk
- Department of Clinical Laboratory Diagnostics, Medical University of Białystok, Kilińskiego 1, 15-089 Białystok, Poland;
| | - Konrad Zaręba
- 2nd Clinical Department of General and Gastroenterological Surgery, Medical University of Białystok, Kilińskiego 1, 15-089 Białystok, Poland;
| | - Katarzyna Guzińska-Ustymowicz
- Department of General Pathomorphology, Medical University of Białystok, Kilińskiego 1, 15-089 Białystok, Poland; (M.N.); (K.G.-U.)
| | - Anna Pryczynicz
- Department of General Pathomorphology, Medical University of Białystok, Kilińskiego 1, 15-089 Białystok, Poland; (M.N.); (K.G.-U.)
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20
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Tumor suppressor gene DLC1: Its modifications, interactive molecules, and potential prospects for clinical cancer application. Int J Biol Macromol 2021; 182:264-275. [PMID: 33836193 DOI: 10.1016/j.ijbiomac.2021.04.022] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2021] [Revised: 04/02/2021] [Accepted: 04/04/2021] [Indexed: 12/12/2022]
Abstract
Deleted in liver cancer 1 (DLC1) is a recognized tumor suppressor gene that negatively regulates Rho family proteins by hydrolyzing the active GTP-bound state to its inactive GDP-bound state. Active Rho proteins play a positive role in tumorigenesis. Numerous in vitro and in vivo experiments have shown that DLC1 is downregulated or inactivated in various solid tumors, which may be due to the following five reasons: genomic deletion, epigenetic modification and ubiquitin-dependent proteasomal degradation may cause DLC1 underexpression; phosphorylation at the post-translation level may cause DLC1 inactivation; and failure to localize at focal adhesions (FAs) may prevent DLC1 from exerting full activity. All of the causes could be attributed to molecular binding. Experimental evidence suggests that direct or indirect targeting of DLC1 is feasible for cancer treatment. Therefore, elucidating the interaction of DLC1 with its binding partners might provide novel targeted therapies for cancer. In this review, we summarized the binding partners of DLC1 at both the gene and protein levels and expounded a variety of anticancer drugs targeting DLC1 to provide information about DLC1 as a cancer diagnostic indicator or therapeutic target.
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21
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Liao YC, Lo SH. Tensins - emerging insights into their domain functions, biological roles and disease relevance. J Cell Sci 2021; 134:jcs254029. [PMID: 33597154 PMCID: PMC10660079 DOI: 10.1242/jcs.254029] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Tensins are a family of focal adhesion proteins consisting of four members in mammals (TNS1, TNS2, TNS3 and TNS4). Their multiple domains and activities contribute to the molecular linkage between the extracellular matrix and cytoskeletal networks, as well as mediating signal transduction pathways, leading to a variety of physiological processes, including cell proliferation, attachment, migration and mechanical sensing in a cell. Tensins are required for maintaining normal tissue structures and functions, especially in the kidney and heart, as well as in muscle regeneration, in animals. This Review discusses our current understanding of the domain functions and biological roles of tensins in cells and mice, as well as highlighting their relevance to human diseases.
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Affiliation(s)
- Yi-Chun Liao
- Department of Biochemical Science and Technology, National Taiwan University, Taipei 10617, Taiwan
| | - Su Hao Lo
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA 95817, USA
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22
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Boazak EM, King R, Wang J, Chu CM, Toporek AM, Sherwood JM, Overby DR, Geisert EE, Ethier CR. Smarce1 and Tensin 4 Are Putative Modulators of Corneoscleral Stiffness. Front Bioeng Biotechnol 2021; 9:596154. [PMID: 33634081 PMCID: PMC7902041 DOI: 10.3389/fbioe.2021.596154] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Accepted: 01/14/2021] [Indexed: 11/13/2022] Open
Abstract
The biomechanical properties of the cornea and sclera are important in the onset and progression of multiple ocular pathologies and vary substantially between individuals, yet the source of this variation remains unknown. Here we identify genes putatively regulating corneoscleral biomechanical tissue properties by conducting high-fidelity ocular compliance measurements across the BXD recombinant inbred mouse set and performing quantitative trait analysis. We find seven cis-eQTLs and non-synonymous SNPs associating with ocular compliance, and show by RT-qPCR and immunolabeling that only two of the candidate genes, Smarce1 and Tns4, showed significant expression in corneal and scleral tissues. Both have mechanistic potential to influence the development and/or regulation of tissue material properties. This work motivates further study of Smarce1 and Tns4 for their role(s) in ocular pathology involving the corneoscleral envelope as well as the development of novel mouse models of ocular pathophysiology, such as myopia and glaucoma.
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Affiliation(s)
- Elizabeth M Boazak
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, GA, United States
| | - Rebecca King
- Department of Ophthalmology, Emory University, Atlanta, GA, United States
| | - Jiaxing Wang
- Department of Ophthalmology, Emory University, Atlanta, GA, United States
| | - Cassandra M Chu
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, GA, United States
| | - Aaron M Toporek
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, GA, United States
| | - Joseph M Sherwood
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Darryl R Overby
- Department of Bioengineering, Imperial College London, London, United Kingdom
| | - Eldon E Geisert
- Department of Ophthalmology, Emory University, Atlanta, GA, United States
| | - C Ross Ethier
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology, Emory University, Atlanta, GA, United States.,George W. Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, GA, United States
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23
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Choi S, Ferrari G, Tedesco FS. Cellular dynamics of myogenic cell migration: molecular mechanisms and implications for skeletal muscle cell therapies. EMBO Mol Med 2020; 12:e12357. [PMID: 33210465 PMCID: PMC7721365 DOI: 10.15252/emmm.202012357] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 08/02/2020] [Accepted: 08/28/2020] [Indexed: 12/14/2022] Open
Abstract
Directional cell migration is a critical process underlying morphogenesis and post-natal tissue regeneration. During embryonic myogenesis, migration of skeletal myogenic progenitors is essential to generate the anlagen of limbs, diaphragm and tongue, whereas in post-natal skeletal muscles, migration of muscle satellite (stem) cells towards regions of injury is necessary for repair and regeneration of muscle fibres. Additionally, safe and efficient migration of transplanted cells is critical in cell therapies, both allogeneic and autologous. Although various myogenic cell types have been administered intramuscularly or intravascularly, functional restoration has not been achieved yet in patients with degenerative diseases affecting multiple large muscles. One of the key reasons for this negative outcome is the limited migration of donor cells, which hinders the overall cell engraftment potential. Here, we review mechanisms of myogenic stem/progenitor cell migration during skeletal muscle development and post-natal regeneration. Furthermore, strategies utilised to improve migratory capacity of myogenic cells are examined in order to identify potential treatments that may be applied to future transplantation protocols.
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Affiliation(s)
- SungWoo Choi
- Department of Cell and Developmental Biology, University College London, London, UK.,The Francis Crick Institute, London, UK
| | - Giulia Ferrari
- Department of Cell and Developmental Biology, University College London, London, UK
| | - Francesco Saverio Tedesco
- Department of Cell and Developmental Biology, University College London, London, UK.,The Francis Crick Institute, London, UK.,Dubowitz Neuromuscular Centre, Great Ormond Street Institute of Child Health, University College London, London, UK
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Dar KB, Bhat AH, Amin S, Anjum S, Reshi BA, Zargar MA, Masood A, Ganie SA. Exploring Proteomic Drug Targets, Therapeutic Strategies and Protein - Protein Interactions in Cancer: Mechanistic View. Curr Cancer Drug Targets 2020; 19:430-448. [PMID: 30073927 DOI: 10.2174/1568009618666180803104631] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2018] [Revised: 07/17/2018] [Accepted: 07/19/2018] [Indexed: 12/31/2022]
Abstract
Protein-Protein Interactions (PPIs) drive major signalling cascades and play critical role in cell proliferation, apoptosis, angiogenesis and trafficking. Deregulated PPIs are implicated in multiple malignancies and represent the critical targets for treating cancer. Herein, we discuss the key protein-protein interacting domains implicated in cancer notably PDZ, SH2, SH3, LIM, PTB, SAM and PH. These domains are present in numerous enzymes/kinases, growth factors, transcription factors, adaptor proteins, receptors and scaffolding proteins and thus represent essential sites for targeting cancer. This review explores the candidature of various proteins involved in cellular trafficking (small GTPases, molecular motors, matrix-degrading enzymes, integrin), transcription (p53, cMyc), signalling (membrane receptor proteins), angiogenesis (VEGFs) and apoptosis (BCL-2family), which could possibly serve as targets for developing effective anti-cancer regimen. Interactions between Ras/Raf; X-linked inhibitor of apoptosis protein (XIAP)/second mitochondria-derived activator of caspases (Smac/DIABLO); Frizzled (FRZ)/Dishevelled (DVL) protein; beta-catenin/T Cell Factor (TCF) have also been studied as prospective anticancer targets. Efficacy of diverse molecules/ drugs targeting such PPIs although evaluated in various animal models/cell lines, there is an essential need for human-based clinical trials. Therapeutic strategies like the use of biologicals, high throughput screening (HTS) and fragment-based technology could play an imperative role in designing cancer therapeutics. Moreover, bioinformatic/computational strategies based on genome sequence, protein sequence/structure and domain data could serve as competent tools for predicting PPIs. Exploring hot spots in proteomic networks represents another approach for developing targetspecific therapeutics. Overall, this review lays emphasis on a productive amalgamation of proteomics, genomics, biochemistry, and molecular dynamics for successful treatment of cancer.
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Affiliation(s)
- Khalid Bashir Dar
- Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India.,Department of Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Aashiq Hussain Bhat
- Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India.,Department of Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Shajrul Amin
- Department of Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Syed Anjum
- Amity Institute of Biotechnology, Amity University, Rajasthan, India
| | - Bilal Ahmad Reshi
- Department of Biotechnology, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Mohammad Afzal Zargar
- Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Akbar Masood
- Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India
| | - Showkat Ahmad Ganie
- Department of Clinical Biochemistry, School of Biological Sciences, University of Kashmir, Srinagar, India
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Raposo TP, Susanti S, Ilyas M. Investigating TNS4 in the Colorectal Tumor Microenvironment Using 3D Spheroid Models of Invasion. ACTA ACUST UNITED AC 2020; 4:e2000031. [PMID: 32390347 DOI: 10.1002/adbi.202000031] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 04/07/2020] [Accepted: 04/15/2020] [Indexed: 12/30/2022]
Abstract
TNS4 (Tensin 4 or Cten) is a putative oncogene in colorectal cancer (CRC) with a role in regulating cell adhesion, motility, invasion, and epithelial to mesenchymal transition (EMT). The objective is to study the role of TNS4 in CRC using more realistic models of the tumor microenvironment. CRC cells expressing TdTomato protein and shTNS4/shLUC hairpin oligos are grown in 3D spheroids with and without cancer-associated fibroblasts (CAFs). Adhesiveness to collagen I and CAFs is assessed in 2D and cell proliferation, volume, and invasion are assessed in 3D conditions. The role of TNS4 knockdown in gefitinib chemosensitivity and epidermal growth factor receptor (EGFR) and Ras protein levels are also tested. In general, TNS4 knockdown increases cell proliferation in cell lines producing compact spheroids. The addition of CAFs in spheroids supports CRC cell proliferation, whereas CAFs themselves do not proliferate, but increases ECM degradation. TNS4 knockdown reduces adhesiveness and 3D invasion and disrupts EGFR signaling which results in increased sensitivity to Gefitinib. In conclusion, in a 3D spheroid model, TNS4 inhibits cell proliferation and promotes cell invasion into the ECM, possibly by adhesion to the ECM and stromal cells. TNS4 knockdown enhances sensitivity to the EGFR inhibitor gefitinib and may be helpful for Kirsten ras oncogene homolog mutant CRC patients.
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Affiliation(s)
- Teresa P Raposo
- Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.,Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Nottingham Molecular Pathology Node, University of Nottingham, UK
| | - Susanti Susanti
- Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.,Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Nottingham Molecular Pathology Node, University of Nottingham, UK.,Dr. S. Susanti, Deparment of Pharmacology and Clinical Pharmacy, Faculty of Pharmacy, University of Muhammadiyah Purwokerto, Banyumas, Central Java, 53182, Indonesia
| | - Mohammad Ilyas
- Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Queen's Medical Centre, Nottingham, NG7 2UH, UK.,Dr. T. P. Raposo, Dr. S. Susanti, Prof. M. Ilyas, Nottingham Molecular Pathology Node, University of Nottingham, UK
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Cornetti L, Tschirren B. Combining genome-wide association study and F ST -based approaches to identify targets of Borrelia-mediated selection in natural rodent hosts. Mol Ecol 2020; 29:1386-1397. [PMID: 32163646 DOI: 10.1111/mec.15410] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2019] [Revised: 03/02/2020] [Accepted: 03/09/2020] [Indexed: 12/21/2022]
Abstract
Recent advances in high-throughput sequencing technologies provide opportunities to gain novel insights into the genetic basis of phenotypic trait variation. Yet to date, progress in our understanding of genotype-phenotype associations in nonmodel organisms in general and natural vertebrate populations in particular has been hampered by small sample sizes typically available for wildlife populations and a resulting lack of statistical power, as well as a limited ability to control for false-positive signals. Here we propose to combine a genome-wide association study (GWAS) and FST -based approach with population-level replication to partly overcome these limitations. We present a case study in which we used this approach in combination with genotyping-by-sequencing (GBS) single nucleotide polymorphism (SNP) data to identify genomic regions associated with Borrelia afzelii resistance or susceptibility in the natural rodent host of this Lyme disease-causing spirochete, the bank vole (Myodes glareolus). Using this combined approach we identified four consensus SNPs located in exonic regions of the genes Slc26a4, Tns3, Wscd1 and Espnl, which were significantly associated with the voles' Borrelia infectious status within and across populations. Functional links between host responses to bacterial infections and most of these genes have previously been demonstrated in other rodent systems, making them promising new candidates for the study of evolutionary host responses to Borrelia emergence. Our approach is applicable to other systems and may facilitate the identification of genetic variants underlying disease resistance or susceptibility, as well as other ecologically relevant traits, in wildlife populations.
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Affiliation(s)
- Luca Cornetti
- Department of Evolutionary Biology and Environmental Studies, University of Zurich, Zurich, Switzerland.,Zoological Institute, University of Basel, Basel, Switzerland
| | - Barbara Tschirren
- Centre for Ecology and Conservation, University of Exeter, Penryn, UK
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27
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Prazosin inhibits the proliferation and survival of acute myeloid leukaemia cells through down-regulating TNS1. Biomed Pharmacother 2020; 124:109731. [DOI: 10.1016/j.biopha.2019.109731] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Revised: 11/28/2019] [Accepted: 12/04/2019] [Indexed: 02/06/2023] Open
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Gong Z, Hong F, Wang H, Zhang X, Chen J. An eight-mRNA signature outperforms the lncRNA-based signature in predicting prognosis of patients with glioblastoma. BMC MEDICAL GENETICS 2020; 21:56. [PMID: 32188434 PMCID: PMC7081624 DOI: 10.1186/s12881-020-0992-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 03/04/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND The prognosis of the glioblastoma (GBM) is dismal. This study aims to select an optimal RNA signature for prognostic prediction of GBM patients. METHODS For the training set, the long non-coding RNA (lncRNA) and mRNA expression profiles of 151 patients were downloaded from the TCGA. Differentially expressed mRNAs (DEGs) and lncRNAs (DE-lncRNAs) were identified between good prognosis and bad prognosis patients. Optimal prognostic mRNAs and lncRNAs were selected respectively, by using univariate Cox proportional-hazards (PH) regression model and LASSO Cox-PH model. Subsequently, four prognostic scoring models were built based on expression levels or expression status of the selected prognostic lncRNAs or mRNAs, separately. Each prognostic model was applied to the training set and an independent validation set. Function analysis was used to uncover the biological roles of these prognostic DEGs between different risk groups classified by the mRNA-based signature. RESULTS We obtained 261 DEGs and 33 DE-lncRNAs between good prognosis and bad prognosis patients. A panel of eight mRNAs and a combination of ten lncRNAs were determined as predictive RNAs by LASSO Cox-PH model. Among the four prognostic scoring models using the eight-mRNA signature or the ten-lncRNA signature, the one based on the expression levels of the eight mRNAs showed the greatest predictive power. The DEGs between different risk groups using the eight prognostic mRNAs were functionally involved in calcium signaling pathway, neuroactive ligand-receptor interaction pathway, and Wnt signaling pathway. CONCLUSION The eight-mRNA signature has greater prognostic value than the ten-lncRNA-based signature for GBM patients based on bioinformatics analysis.
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Affiliation(s)
- Zhenyu Gong
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, NO. 415 Fengyang Road, Huangpu Distinct, Shanghai, 200003 China
| | - Fan Hong
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, NO. 415 Fengyang Road, Huangpu Distinct, Shanghai, 200003 China
| | - Hongxiang Wang
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, NO. 415 Fengyang Road, Huangpu Distinct, Shanghai, 200003 China
| | - Xu Zhang
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, NO. 415 Fengyang Road, Huangpu Distinct, Shanghai, 200003 China
| | - Juxiang Chen
- Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, NO. 415 Fengyang Road, Huangpu Distinct, Shanghai, 200003 China
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Tensin-3 Regulates Integrin-Mediated Proliferation and Differentiation of Tonsil-Derived Mesenchymal Stem Cells. Cells 2019; 9:cells9010089. [PMID: 31905841 PMCID: PMC7017379 DOI: 10.3390/cells9010089] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2019] [Revised: 12/17/2019] [Accepted: 12/28/2019] [Indexed: 02/08/2023] Open
Abstract
Human palatine tonsils are potential tissue source of multipotent mesenchymal stem cells (MSCs). The proliferation rate of palatine tonsil-derived MSCs (TMSCs) is far higher than that of bone marrow-derived MSCs (BMSCs) or adipose tissue-derived MSCs (ADSCs). In our previous study, we had found through DNA microarray analysis that tensin-3 (TNS3), a type of focal adhesion protein, was more highly expressed in TMSCs than in both BMSCs and ADSCs. Here, the role of TNS3 in TMSCs and its relationship with integrin were investigated. TNS3 expression was significantly elevated in TMSCs than in other cell types. Cell growth curves revealed a significant decrease in the proliferation and migration of TMSCs treated with siRNA for TNS3 (siTNS3). siTNS3 treatment upregulated p16 and p21 levels and downregulated SOX2 expression and focal adhesion kinase, protein kinase B, and c-Jun N-terminal kinase phosphorylation. siTNS3 transfection significantly reduced adipogenic differentiation of TMSCs and slightly decreased osteogenic and chondrogenic differentiation. Furthermore, TNS3 inhibition reduced active integrin beta-1 (ITGβ1) expression, while total ITGβ1 expression was not affected. Inhibition of ITGβ1 expression in TMSCs by siRNA showed similar results observed in TNS3 inhibition. Thus, TNS3 may play an important role in TMSC proliferation and differentiation by regulating active ITGβ1 expression.
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Tensin1 expression and function in chronic obstructive pulmonary disease. Sci Rep 2019; 9:18942. [PMID: 31831813 PMCID: PMC6908681 DOI: 10.1038/s41598-019-55405-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2019] [Accepted: 11/25/2019] [Indexed: 11/18/2022] Open
Abstract
Chronic obstructive pulmonary disease (COPD) constitutes a major cause of morbidity and mortality. Genome wide association studies have shown significant associations between airflow obstruction or COPD with a non-synonymous SNP in the TNS1 gene, which encodes tensin1. However, the expression, cellular distribution and function of tensin1 in human airway tissue and cells are unknown. We therefore examined these characteristics in tissue and cells from controls and people with COPD or asthma. Airway tissue was immunostained for tensin1. Tensin1 expression in cultured human airway smooth muscle cells (HASMCs) was evaluated using qRT-PCR, western blotting and immunofluorescent staining. siRNAs were used to downregulate tensin1 expression. Tensin1 expression was increased in the airway smooth muscle and lamina propria in COPD tissue, but not asthma, when compared to controls. Tensin1 was expressed in HASMCs and upregulated by TGFβ1. TGFβ1 and fibronectin increased the localisation of tensin1 to fibrillar adhesions. Tensin1 and α-smooth muscle actin (αSMA) were strongly co-localised, and tensin1 depletion in HASMCs attenuated both αSMA expression and contraction of collagen gels. In summary, tensin1 expression is increased in COPD airways, and may promote airway obstruction by enhancing the expression of contractile proteins and their localisation to stress fibres in HASMCs.
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Bruns AN, Lo SH. Tensin regulates pharyngeal pumping in Caenorhabditis elegans. Biochem Biophys Res Commun 2019; 522:599-603. [PMID: 31784086 DOI: 10.1016/j.bbrc.2019.11.153] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 11/22/2019] [Indexed: 12/24/2022]
Abstract
Tensin is a focal adhesion molecule that is known to regulate cell adhesion, migration, and proliferation. Although there are four tensin homologs (TNS1, TNS2, TNS3, and CTEN/TNS4) in mammals, only one tensin gene is found in Caenorhabditis elegans. Sequence analysis suggests that Caenorhabditis elegans tensin is slightly closer aligned with human TNS1 than with other human tensins. To establish the role of TNS1 in Caenorhabditis elegans, we have generated TNS1 knockout (KO) worms by CRISPR-Cas9 and homologous recombination directed repair approaches. Lack of TNS1 does not appear to affect the development or gross morphology of the worms. Nonetheless, defecation cycles are significantly longer in TNS1 KO worms. In addition, their pharyngeal pumping rate is markedly faster, which is likely due to a shorter pump duration in the KO worms. These findings indicate that TNS1 is not required for the development and survival of Caenorhabditis elegans but point to a critical role in modulating defecation and pharyngeal pumping rates.
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Affiliation(s)
- Aaron N Bruns
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA, 95817, USA
| | - Su Hao Lo
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA, 95817, USA.
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32
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Wu ZY, Chiu CL, Lo E, Lee YRJ, Yamada S, Lo SH. Hyperactivity of Mek in TNS1 knockouts leads to potential treatments for cystic kidney diseases. Cell Death Dis 2019; 10:871. [PMID: 31740667 PMCID: PMC6861224 DOI: 10.1038/s41419-019-2119-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 09/28/2019] [Accepted: 11/05/2019] [Indexed: 12/29/2022]
Abstract
Cystic kidney disease is the progressive development of multiple fluid-filled cysts that may severely compromise kidney functions and lead to renal failure. TNS1 (tensin-1) knockout mice develop cystic kidneys and die from renal failure. Here, we have established TNS1-knockout MDCK cells and applied 3D culture system to investigate the mechanism leading to cyst formation. Unlike wild-type MDCK cells, which form cysts with a single lumen, TNS1-knockout cysts contain multiple lumens and upregulated Mek/Erk activities. The multiple lumen phenotype and Mek/Erk hyperactivities are rescued by re-expression of wild-type TNS1 but not the TNS1 mutant lacking a fragment essential for its cell–cell junction localization. Furthermore, Mek inhibitor treatments restore the multiple lumens back to single lumen cysts. Mek/Erk hyperactivities are also detected in TNS1-knockout mouse kidneys. Treatment with the Mek inhibitor trametinib significantly reduces the levels of interstitial infiltrates, fibrosis and dilated tubules in TNS1-knockout kidneys. These studies establish a critical role of subcellular localization of TNS1 in suppressing Mek/Erk signaling and maintaining lumenogenesis, and provide potential therapeutic strategies by targeting the Mek/Erk pathway for cystic kidney diseases.
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Affiliation(s)
- Zong-Ye Wu
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA, 95817, USA
| | - Chun-Lung Chiu
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA, 95817, USA
| | - Ethan Lo
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA, 95817, USA
| | - Yuh-Ru Julie Lee
- Department of Plant Biology, University of California-Davis, Davis, CA, 95616, USA
| | - Soichiro Yamada
- Department of Biomedical Engineering, University of California-Davis, Davis, CA, 95616, USA
| | - Su Hao Lo
- Department of Biochemistry and Molecular Medicine, University of California-Davis, Sacramento, CA, 95817, USA.
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Rahmawati E, Yang WV, Tzeng C. Reply to: Adhesion proteins: Suitable therapeutic targets or biomarkers of therapy response for endometriosis? Acta Obstet Gynecol Scand 2019; 98:812. [DOI: 10.1111/aogs.13566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Accepted: 02/04/2019] [Indexed: 11/27/2022]
Affiliation(s)
- Endah Rahmawati
- Graduate Institute of Clinical Medicine College of Medicine Taipei Medical University Taipei Taiwan
- Department of Obstetrics and Gynecology, Faculty of Medicine Public Health and Nursing, Universitas Gadjah Mada Yogyakarta Indonesia
| | - Wei‐Chung V. Yang
- The PhD Program for Translational Medicine College of Medical Science and Technology Taipei Medical University Taipei Taiwan
| | - Chii‐Ruey Tzeng
- Center for Reproductive Medicine Taipei Medical University Hospital Taipei Taiwan
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C. elegans Tensin Promotes Axon Regeneration by Linking the Met-like SVH-2 and Integrin Signaling Pathways. J Neurosci 2019; 39:5662-5672. [PMID: 31109965 DOI: 10.1523/jneurosci.2059-18.2019] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2018] [Revised: 05/07/2019] [Accepted: 05/08/2019] [Indexed: 01/04/2023] Open
Abstract
Axon regeneration is a conserved mechanism induced by axon injury that initiates a neuronal response leading to regrowth of the axon. In Caenorhabditis elegans, the initiation of axon regeneration is regulated by the JNK MAP kinase (MAPK) pathway. We have previously identified a number of genes affecting the JNK pathway using an RNAi-based screen. Analysis of these genes, called the svh genes, has shed new light on the regulation of axon regeneration, revealing the involvement of a signaling cascade consisting of a growth factor SVH-1 and its receptor, the tyrosine kinase SVH-2. Here, we characterize the svh-6/tns-1 gene, which is a homolog of mammalian tensin, and show that it is a positive regulator of axon regeneration in motor neurons. We demonstrate that TNS-1 interacts with tyrosine-autophosphorylated SVH-2 and the integrin β subunit PAT-3 via its SH2 and PTB domains, respectively, to promote axon regeneration. These results suggest that TNS-1 acts as an adaptor to link the SVH-2 and integrin signaling pathways.SIGNIFICANCE STATEMENT The Caenorhabditis elegans JNK MAPK pathway regulates the initiation of axon regeneration. Previously, we showed that a signaling cascade consisting of the HGF-like growth factor SVH-1 and its Met-like receptor tyrosine kinase SVH-2 promotes axon regeneration through activation of the JNK pathway. In this study, we show that the C. elegans tensin, TNS-1, is required for efficient regeneration after axon injury. Phosphorylation of SVH-2 on tyrosine mediates its interaction with the SH2 domain of TNS-1 to positively regulate axon regeneration. Furthermore, TNS-1 interacts via its PTB domain with the integrin β subunit PAT-3. These results suggest that TNS-1 plays a critical role in the regulation of axon regeneration by linking the SVH-2 and integrin signaling pathways.
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Weston PA, Gurusinghe S, Birckhead E, Skoneczny D, Quinn JC, Weston LA. Chemometric analysis of Amaranthus retroflexus in relation to livestock toxicity in southern Australia. PHYTOCHEMISTRY 2019; 161:1-10. [PMID: 30776591 DOI: 10.1016/j.phytochem.2019.01.016] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/10/2018] [Revised: 01/20/2019] [Accepted: 01/25/2019] [Indexed: 06/09/2023]
Abstract
Amaranthus retroflexus L., an introduced invasive weed in southern Australia, has been associated with acute renal failure and/or mortality in a number of livestock species. While its leaves, flowers and stems are generally reported to contain high levels of nitrogen, few studies have fully characterised the chemical composition of A. retroflexus foliage with respect to mammalian toxicity. We performed extensive metabolic profiling of stems, leaves, roots and inflorescence tissues of A. retroflexus collected from three spatially and/or temporally distinct toxicity outbreaks, and report on the 1) composition of primary and secondary metabolites in methanolic extracts of A. retroflexus tissues using HPLC and HPLC-MS QToF and 2) chemometric analysis of A. retroflexus extracts in relation to the associated toxin(s). All tissues of A. retroflexus possessed an abundance of N-containing metabolites, particularly quaternary ammonium compounds which were identified as betaines, two of which (valine betaine and isoleucine betaine) are rarely encountered in plants. Cytotoxicity to murine fibroblasts was highest in extracts of leaf tissue and was associated with a single, a small modified peptide with high similarity to N-acetyl-L-α-aspartyl-L-alanyl-L-α-aspartyl-L-α-glutamyl-O-(carboxymethyl)-L-tyrosyl-L-leucinamide, a synthetic phosphotyrosyl mimic involved in cell signaling processes. One possible mode of action leading to acute renal failure in grazing livestock by a modified peptide such as this is proposed.
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Affiliation(s)
- Paul A Weston
- Graham Centre for Agricultural Innovation (Charles Sturt University and NSW Department of Primary Industries), Wagga Wagga, NSW, 2650, Australia; Charles Sturt University, School of Agricultural and Wine Sciences, Wagga Wagga, NSW, 2678, Australia.
| | - Saliya Gurusinghe
- Graham Centre for Agricultural Innovation (Charles Sturt University and NSW Department of Primary Industries), Wagga Wagga, NSW, 2650, Australia.
| | - Emily Birckhead
- Charles Sturt University, School of Animal and Veterinary Sciences, Wagga Wagga, NSW, 2678, Australia
| | - Dominik Skoneczny
- Graham Centre for Agricultural Innovation (Charles Sturt University and NSW Department of Primary Industries), Wagga Wagga, NSW, 2650, Australia
| | - Jane C Quinn
- Graham Centre for Agricultural Innovation (Charles Sturt University and NSW Department of Primary Industries), Wagga Wagga, NSW, 2650, Australia; Charles Sturt University, School of Animal and Veterinary Sciences, Wagga Wagga, NSW, 2678, Australia
| | - Leslie A Weston
- Graham Centre for Agricultural Innovation (Charles Sturt University and NSW Department of Primary Industries), Wagga Wagga, NSW, 2650, Australia; Charles Sturt University, School of Agricultural and Wine Sciences, Wagga Wagga, NSW, 2678, Australia
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Hong SY, Shih YP, Lo A, Lo SH. Identification of subcellular targeting sequences of Cten reveals its role in cell proliferation. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2019; 1866:450-458. [PMID: 30321615 PMCID: PMC6311424 DOI: 10.1016/j.bbamcr.2018.10.008] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Revised: 08/29/2018] [Accepted: 10/05/2018] [Indexed: 01/26/2023]
Abstract
Spatial and temporal subcellular localization plays critical roles in regulating protein function. Cten (C-terminal tensin like) is a member of the tensin family. Cten recruits signaling molecules, such as DLC1, to focal adhesions, modulates homeostasis of receptor tyrosine kinases, including EGFR and c-Met, and promotes cell migration. These functions are likely controlled by Cten localization at focal adhesions and/or in the cytoplasm. In addition, Cten has been detected in the nucleus by which mechanism is unknown. To this end, we have examined the distribution of Cten in various cell lines, determined primary sequence requirements for its nuclear and focal adhesion localizations, and analyzed potential roles of nuclear Cten. Our results show that a proportion of Cten translocates to nuclei in cancer cell lines and that nuclear exporting of Cten is a CRM1-dependent process. A nuclear localization sequence and a nuclear export sequence are identified within Cten. In addition, like other tensins, Cten contains two independent focal adhesion binding sites. Although further expression of recombinant Cten showed no effect on cancer cell proliferation, silencing of Cten significantly reduced cell growth. Furthermore, expression of Cten mutants either with defective nuclear export sequence or tagged with SV40 nuclear localization sequence promoted cell growth. These results suggest that nuclear Cten contributes to cancer cell proliferation. Our findings identify a molecular mechanism for regulating Cten protein trafficking in mammalian cells and provide new insights into the dynamics of focal adhesion complexes in health and disease.
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Affiliation(s)
- Shiao-Ya Hong
- Department of Biochemistry and Molecular Medicine, California-Davis, Sacramento, CA 95817, USA
| | - Yi-Ping Shih
- Department of Biochemistry and Molecular Medicine, California-Davis, Sacramento, CA 95817, USA
| | - Abigail Lo
- Department of Biochemistry and Molecular Medicine, California-Davis, Sacramento, CA 95817, USA
| | - Su Hao Lo
- Department of Biochemistry and Molecular Medicine, California-Davis, Sacramento, CA 95817, USA.
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Trattnig C, Üçal M, Tam-Amersdorfer C, Bucko A, Zefferer U, Grünbacher G, Absenger-Novak M, Öhlinger KA, Kraitsy K, Hamberger D, Schaefer U, Patz S. MicroRNA-451a overexpression induces accelerated neuronal differentiation of Ntera2/D1 cells and ablation affects neurogenesis in microRNA-451a-/- mice. PLoS One 2018; 13:e0207575. [PMID: 30462722 PMCID: PMC6248975 DOI: 10.1371/journal.pone.0207575] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2017] [Accepted: 11/02/2018] [Indexed: 12/22/2022] Open
Abstract
MiR-451a is best known for its role in erythropoiesis and for its tumour suppressor features. Here we show a role for miR-451a in neuronal differentiation through analysis of endogenous and ectopically expressed or silenced miR-451a in Ntera2/D1 cells during neuronal differentiation. Furthermore, we compared neuronal differentiation in the dentate gyrus of hippocampus of miR-451a-/- and wild type mice. MiR-451a overexpression in lentiviral transduced Ntera2/D1 cells was associated with a significant shifting of mRNA expression of the developmental markers Nestin, βIII Tubulin, NF200, DCX and MAP2 to earlier developmental time points, compared to control vector transduced cells. In line with this, accelerated neuronal network formation in AB.G.miR-451a transduced cells, as well as an increase in neurite outgrowth both in number and length was observed. MiR-451a targets genes MIF, AKT1, CAB39, YWHAZ, RAB14, TSC1, OSR1, POU3F2, TNS4, PSMB8, CXCL16, CDKN2D and IL6R were, moreover, either constantly downregulated or exhibited shifted expression profiles in AB.G.miR-451a transduced cells. Lentiviral knockdown of endogenous miR-451a expression in Ntera2/D1 cells resulted in decelerated differentiation. Endogenous miR-451a expression was upregulated during development in the hippocampus of wildtype mice. In situ hybridization revealed intensively stained single cells in the subgranular zone and the hilus of the dentate gyrus of wild type mice, while genetic ablation of miR-451a was observed to promote an imbalance between proliferation and neuronal differentiation in neurogenic brain regions, suggested by Ki67 and DCX staining. Taken together, these results provide strong support for a role of miR-451a in neuronal maturation processes in vitro and in vivo.
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Affiliation(s)
- Christa Trattnig
- Research Unit for Experimental Neurotraumatology, Department of Neurosurgery, Medical University, Graz, Austria
| | - Muammer Üçal
- Research Unit for Experimental Neurotraumatology, Department of Neurosurgery, Medical University, Graz, Austria
| | | | - Angela Bucko
- Research Unit for Experimental Neurotraumatology, Department of Neurosurgery, Medical University, Graz, Austria
| | - Ulrike Zefferer
- Research Unit for Experimental Neurotraumatology, Department of Neurosurgery, Medical University, Graz, Austria
| | - Gerda Grünbacher
- Research Unit for Experimental Neurotraumatology, Department of Neurosurgery, Medical University, Graz, Austria
| | | | | | - Klaus Kraitsy
- Research Unit for Experimental Neurotraumatology, Department of Neurosurgery, Medical University, Graz, Austria
| | - Daniel Hamberger
- Research Unit for Experimental Neurotraumatology, Department of Neurosurgery, Medical University, Graz, Austria
| | - Ute Schaefer
- Research Unit for Experimental Neurotraumatology, Department of Neurosurgery, Medical University, Graz, Austria
- * E-mail:
| | - Silke Patz
- Research Unit for Experimental Neurotraumatology, Department of Neurosurgery, Medical University, Graz, Austria
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AXL phosphorylates and up-regulates TNS2 and its implications in IRS-1-associated metabolism in cancer cells. J Biomed Sci 2018; 25:80. [PMID: 30419905 PMCID: PMC6233515 DOI: 10.1186/s12929-018-0465-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 08/15/2018] [Indexed: 12/21/2022] Open
Abstract
Background TNS2 is a focal adhesions protein and a binding partner for many proteins, including the receptor tyrosine kinase Axl. Although TNS2 can bind with Axl, the details of their interactions have not been elucidated. TNS2 is involved in IRS-1 signaling pathway. In this study, we confirmed the relationship between TNS2 expression and the expression of Axl, IRS-1, PDK1 and Glut4 in pancreatic cancer patients. Methods The expression levels of TNS2, Axl, IRS-1, PDK1 and Glut4 in human cancer cells were measured by Western blot and/or IP-Western blot assays. Paired samples of pancreatic cancer and non-cancer tissues were obtained from 33 patients and were used to construct tissue microarrays. The expression levels of these markers in the tissue microarrays were measured by enzyme-linked Immunohistochemistry assay, and the relationships were analyzed by Pearson’s chi-square test and two-tailed t-test analysis. Results We demonstrated for the first time that TNS2 is a phosphorylation substrate of Axl. Moreover, we found a positive relationship between TNS2 expression and the expression of Axl, IRS-1, PDK1 and Glut4 in pancreatic cancer patients. Based on these results, we suggest that Axl modulates glucose metabolism potentially through TNS2 and IRS-1. We hypothesize that there exists a novel mechanism whereby Axl binds to and phosphorylates TNS2, releasing TNS2 from interaction with IRS-1 and resulting in increased stability of IRS-1. The two key enzymes of aerobic glycolysis (Glut4 and PDK1) were found to be up-regulated by Axl/TNS2/IRS-1 cross-talk and may play a critical role in glucose metabolism of cancer cells. Conclusions Our results revealed for the first time that Axl binds to and phosphorylates TNS2 and that Axl/TNS2/IRS-1 cross-talk may potentially play a critical role in glucose metabolism of cancer cells. Electronic supplementary material The online version of this article (10.1186/s12929-018-0465-x) contains supplementary material, which is available to authorized users.
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Rahmawati E, Yang WCV, Lei YP, Maurya PK, Chen HW, Tzeng CR. Gonadotropin-releasing hormone agonist induces downregulation of tensin 1 in women with endometriosis. Acta Obstet Gynecol Scand 2018; 98:222-231. [PMID: 30312486 DOI: 10.1111/aogs.13481] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2018] [Accepted: 10/03/2018] [Indexed: 12/12/2022]
Abstract
INTRODUCTION Many cell migration-related molecules are associated with endometriosis. Tensin 1 (TNS1), which has been implicated in cell migration, may play a role in endometriosis. The study goal was to evaluate the TNS1 expression in endometrial tissue and serum from women with endometriosis treated with gonadotropin-releasing hormone agonist (GnRHa). MATERIAL AND METHODS Tissue and serum samples were collected from women with endometriosis who were treated (n = 29) with GnRHa or untreated (n = 30). TNS1 mRNA was examined using quantitative PCR. TNS1 protein levels in tissue and serum samples were investigated using Western blot, immunohistochemistry and ELISA. Eleven women with endometriosis participated in a follow-up investigation of serum TNS1 before and after GnRHa treatment. RESULTS TNS1 mRNA (P = 0.006) and protein (P = 0.001) were significantly downregulated in endometriotic tissue from women with endometriosis who received GnRHa. Immunolocalization of TNS1 showed strong expression in the epithelial and stromal cells of endometriotic tissue from women untreated with GnRHa, whereas endometriotic tissue from GnRHa-treated women showed low TNS1 expression. Follow-up monitoring of serum TNS1 concentration in 11 women showed an average decrease in concentration of 53%, from 294.9 ± 66.69 to 140.3 ± 55.21 pg/mL, following GnRHa treatment (P = 0.003). CONCLUSIONS GnRHa induces downregulation of TNS1 in tissue and serum in women with endometriosis. These results emphasize the importance TNS1 as a potential therapeutic molecular target for the treatment of endometriosis with GnRHa.
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Affiliation(s)
- Endah Rahmawati
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Obstetrics and Gynecology, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Wei-Chung V Yang
- The PhD Program for Translational Medicine, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yen-Ping Lei
- Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei, Taiwan
| | - Pawan K Maurya
- Department of Biochemistry, Central University of Haryana, Mahendergarh, India.,Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Huei-Wen Chen
- Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Chii-Ruey Tzeng
- Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Department of Obstetrics and Gynecology, College of Medicine, Taipei Medical University, Taipei, Taiwan.,Center for Reproductive Medicine, Department of Obstetrics and Gynecology, Taipei Medical University Hospital, Taipei, Taiwan
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Kim E, Kim DH, Singaram I, Jeong H, Koh A, Lee J, Cho W, Ryu SH. Cellular phosphatase activity of C1-Ten/Tensin2 is controlled by Phosphatidylinositol-3,4,5-triphosphate binding through the C1-Ten/Tensin2 SH2 domain. Cell Signal 2018; 51:130-138. [PMID: 30092354 DOI: 10.1016/j.cellsig.2018.07.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 07/20/2018] [Accepted: 07/26/2018] [Indexed: 12/28/2022]
Abstract
Regulation of tyrosine phosphorylation on insulin receptor substrate-1 (IRS-1) is essential for insulin signaling. The protein tyrosine phosphatase (PTP) C1-Ten/Tensin2 has been implicated in the regulation of IRS-1, but the molecular basis of this dephosphorylation is not fully understood. Here, we demonstrate that the cellular phosphatase activity of C1-Ten/Tensin2 on IRS-1 is mediated by the binding of the C1-Ten/Tensin2 Src-homology 2 (SH2) domain to phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3). We show that the role of C1-Ten/Tensin2 is dependent on insulin-induced phosphoinositide 3-kinase activity. The C1-Ten/Tensin2 SH2 domain showed strong preference and high affinity for PtdIns(3,4,5)P3. Using site-directed mutagenesis, we identified three basic residues in the C1-Ten/Tensin2 SH2 domain that were critical for PtdIns(3,4,5)P3 binding but were not involved in phosphotyrosine binding and PTP activity. Using a PtdIns(3,4,5)P3 binding-deficient mutant, we showed that the specific binding of the C1-Ten/Tensin2 SH2 domain to PtdIns(3,4,5)P3 allowed C1-Ten/Tensin2 to function as a PTP in cells. Collectively, our findings suggest that the interaction between the C1-Ten/Tensin2 SH2 domain and PtdIns(3,4,5)P3 produces a negative feedback loop of insulin signaling through IRS-1.
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Affiliation(s)
- Eui Kim
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, South Korea; Brain Korea 21 PLUS project of Bio-Molecular Function, Pohang University of Science and Technology, Pohang 37673, South Korea
| | - Do-Hyeon Kim
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, South Korea
| | - Indira Singaram
- Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA
| | - Heeyoon Jeong
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, South Korea; Brain Korea 21 PLUS project of Bio-Molecular Function, Pohang University of Science and Technology, Pohang 37673, South Korea
| | - Ara Koh
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, South Korea
| | - Jiyoun Lee
- Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, South Korea; Brain Korea 21 PLUS project of Bio-Molecular Function, Pohang University of Science and Technology, Pohang 37673, South Korea
| | - Wonhwa Cho
- Department of Chemistry, University of Illinois at Chicago, Chicago, IL 60607, USA.
| | - Sung Ho Ryu
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang 37673, South Korea; Department of Life Sciences, Pohang University of Science and Technology, Pohang 37673, South Korea; Brain Korea 21 PLUS project of Bio-Molecular Function, Pohang University of Science and Technology, Pohang 37673, South Korea.
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Abstract
Su Hao Lo provides an introduction to the tensin family of focal adhesion proteins.
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Lu X, Gao J, Zhang Y, Zhao T, Cai H, Zhang T. CTEN induces epithelial-mesenchymal transition (EMT) and metastasis in non small cell lung cancer cells. PLoS One 2018; 13:e0198823. [PMID: 29985912 PMCID: PMC6037349 DOI: 10.1371/journal.pone.0198823] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2018] [Accepted: 05/26/2018] [Indexed: 12/29/2022] Open
Abstract
To explore the effects and mechanism of CTEN (COOH-terminus tensin-like molecule) on EMT, cell migration and invasion of Human lung adenocarcinoma cells. The pCMV-vector, pCMV-CTEN, Control-shRNA, and CTEN-shRNA were transfected into A549 and NCI-H1299 cells by Lipofectamine 2000. Transforming growth factor-β1(TGF-β1)and epithelial-mesenchymal transition (EMT) -related biomarkers were detected by eliseand western blot. The migration and invasion ability of A549 cells and NCI-H1299 were examined by scratch-wound assay and transwell assay respectively. We found compare with control group, the expression of TGF-β and mesenchymal markers in CTEN overexpression group were increased, and the epithelial marker was decreased, which induced the EMT process. Meanwhile, scratch-woundassay showed that the migration efficiency of A549 and NCI-H1299 cells in CTEN overexpression group were higher than that in control group.Transwell assay demonstrated that the number of cells that migrated and invaded through the membrane were obviously more than those in control group.Furthermore, Knockdown of CTEN partially reversed transforming growth factor-β1(TGF-β1)-induced changes in EMT markers. In conclusion, CTEN activated the expression of TGF-β1, thereby prompting EMT in lung adenocareinma cancer cells.
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Affiliation(s)
- Xiangdong Lu
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, P.R.China
| | - Juan Gao
- Department of Obstetrics and Gynecology, Jiangyin Hospital of Traditional Chinese Medicine, Jiangyin, P.R.China
| | - Yao Zhang
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, P.R.China
| | - Tao Zhao
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, P.R.China
| | | | - Tingrong Zhang
- Department of Oncology, The Jiangyin Hospital Affiliated to Medical College of Southeast University, Jiangyin, P.R.China
- * E-mail:
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Sawazaki S, Oshima T, Sakamaki K, Aoyama T, Sato T, Shiozawa M, Yoshikawa T, Rino Y, Imada T, Masuda M. Clinical Significance of Tensin 4 Gene Expression in Patients with Gastric Cancer. ACTA ACUST UNITED AC 2018; 31:1065-1071. [PMID: 29102927 DOI: 10.21873/invivo.11171] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2017] [Revised: 08/14/2017] [Accepted: 08/22/2017] [Indexed: 12/15/2022]
Abstract
BACKGROUND Overall survival remains unsatisfactory in stage II/III gastric cancer, even after curative resection and adjuvant chemotherapy. Tensin 4 (TNS4), a cell adhesion factor, is associated with cancer-cell motility and migration. PATIENTS AND METHODS We examined the clinical significance of TNS4 gene expression in 134 patients with stage II/III gastric cancer who underwent adjuvant chemotherapy with S-1. TNS4 gene expression in surgical specimens was measured by quantitative reverse-transcription polymerase chain reaction (RT-PCR). RESULTS TNS4 gene expression levels were significantly higher in cancer tissue than in adjacent normal mucosa. High TNS4 gene expression was associated with significantly poorer 5-year overall survival than was low expression. On multivariate analysis, TNS4 gene expression was an independent prognostic factor. CONCLUSION Overexpression of the TNS4 gene is a useful independent predictor of outcomes in patients with stage II/III gastric cancer who undergo surgery and receive adjuvant chemotherapy with S-1.
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Affiliation(s)
- Sho Sawazaki
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Takashi Oshima
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Kentaro Sakamaki
- Department of Biostatistics, Yokohama City University Medical Center, Yokohama, Japan
| | - Toru Aoyama
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Tsutomu Sato
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Manabu Shiozawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Takaki Yoshikawa
- Department of Gastrointestinal Surgery, Kanagawa Cancer Center, Yokohama, Japan
| | - Yasushi Rino
- Department of Surgery, Yokohama City University, Yokohama, Japan
| | - Toshio Imada
- Department of Surgery, Saiseikai Yokohama-shi Nanbu Hospital, Yokohama, Japan
| | - Munetaka Masuda
- Department of Surgery, Yokohama City University, Yokohama, Japan
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Down-regulation of tensin2 enhances tumorigenicity and is associated with a variety of cancers. Oncotarget 2018; 7:38143-38153. [PMID: 27203214 PMCID: PMC5122378 DOI: 10.18632/oncotarget.9411] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2016] [Accepted: 04/28/2016] [Indexed: 12/27/2022] Open
Abstract
Tensin family members, including tensin2 (TNS2), are present as major components of the focal adhesions. The N-terminal end of TNS2 contains a C1 region (protein kinase C conserved region 1) that is not found in other tensin members. Three isoforms of TNS2 have been identified with previous reports describing the shortest V3 isoform as lacking the C1 region. Although TNS2 is known to regulate cell proliferation and migration, its role in tumorigenicity is controversial. By gain-of-function overexpression approaches, results supporting either promotion or reduction of cancer cell tumorigenicity were reported. Here we report that the complete V3 isoform also contains the C1 region and describe the expression patterns of the three human TNS2 isoforms. By loss-of-function approaches, we show that silencing of TNS2 up-regulates the activities of Akt, Mek, and IRS1, and increases tumorigenicities in A549 and Hela cells. Using public database analyses we found that TNS2 is down-regulated in head and neck, esophageal, breast, lung, liver, and colon cancer. In addition, patients with low TNS2 expression showed poor relapse-free survival rates for breast and lung cancers. These results strongly suggest a role of tensin2 in suppressing cell transformation and reduction of tumorigenicity.
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Zhou H, Zhang Y, Wu L, Xie W, Li L, Yuan Y, Chen Y, Lin Y, He X. Elevated transgelin/TNS1 expression is a potential biomarker in human colorectal cancer. Oncotarget 2018; 9:1107-1113. [PMID: 29416680 PMCID: PMC5787423 DOI: 10.18632/oncotarget.23275] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2017] [Accepted: 12/04/2017] [Indexed: 11/25/2022] Open
Abstract
Transgelin is an actin-binding protein that regulates cell motility and other important cellular functions. Previous studies have suggested that transgelin expression is associated with cancer development and progression, but its specific role in colorectal cancer (CRC) remains controversial. We analyzed expression of transgelin and its candidate downstream target, tensin 1 (TNS1), in CRC patients using the ONCOMINE, Protein Atlas, and OncoLnc databases. Transgelin and TNS1 mRNA and protein levels were higher in CRC patients and CRC cell lines than in normal tissues and cells. Survival analyses using the OncoLnc database revealed that elevated TAGLN/TNS1 levels were associated with a poor overall survival in CRC patients. Transgelin suppression using siRNA decreased TNS1 expression in CRC cells, demonstrating that transgelin induces the TNS1 expression. Importantly, suppression of transgelin or TNS1 using siRNA decreased proliferation and invasiveness of CRC cells. These results suggest that transgelin/TNS1 signaling promotes CRC cell proliferation and invasion, and that transgelin/TNS1 expression levels could potentially serve as a prognostic and therapeutic target in CRC patients.
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Affiliation(s)
- Huimin Zhou
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yiming Zhang
- Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
| | - Lihao Wu
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Wenrui Xie
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Lan Li
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yu Yuan
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Yu Chen
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
| | - Ying Lin
- Department of Gastroenterology and Hepatology, The Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Xinxiang He
- Department of Gastroenterology and Hepatology, The First Affiliated Hospital, School of Clinical Medicine of Guangdong Pharmaceutical University, Guangzhou, China
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Weidle UH, Dickopf S, Hintermair C, Kollmorgen G, Birzele F, Brinkmann U. The Role of micro RNAs in Breast Cancer Metastasis: Preclinical Validation and Potential Therapeutic Targets. Cancer Genomics Proteomics 2018; 15:17-39. [PMID: 29275360 PMCID: PMC5822183 DOI: 10.21873/cgp.20062] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Revised: 11/05/2017] [Accepted: 11/06/2017] [Indexed: 12/18/2022] Open
Abstract
Despite the approval of several molecular therapies in the last years, breast cancer-associated death ranks as the second highest in women. This is due to metastatic disease, which represents a challenge for treatment. A better understanding of the molecular mechanisms of metastasis is, therefore, of paramount importance. In this review we summarize the role of micro RNAs (miRs) involved in metastasis of breast cancer. We present an overview on metastasis-promoting, -suppressing and context-dependent miRs with both activities. We have categorized the corresponding miRs according to their target classes, interaction with stromal cells or exosomes. The pathways affected by individual miRs are outlined in regard to in vitro properties, activity in metastasis-related in vivo models and clinical significance. Current approaches that may be suitable for therapeutic inhibition or restauration of miR activity are outlined. Finally, we discuss the delivery bottlenecks which present as a major challenge in nucleic acid (miR)-based therapies.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Steffen Dickopf
- Roche Pharma Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
| | | | - Gwendlyn Kollmorgen
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Fabian Birzele
- Roche Pharma Research and Early Development, Pharmaceutical Sciences, Roche Innovation Center Basel, Basel, Switzerland
| | - Ulrich Brinkmann
- Roche Pharma Research and Early Development, Large Molecule Research, Roche Innovation Center Munich, Penzberg, Germany
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Integrated MicroRNA-mRNA Analysis Reveals miR-204 Inhibits Cell Proliferation in Gastric Cancer by Targeting CKS1B, CXCL1 and GPRC5A. Int J Mol Sci 2017; 19:ijms19010087. [PMID: 29283424 PMCID: PMC5796037 DOI: 10.3390/ijms19010087] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2017] [Revised: 12/23/2017] [Accepted: 12/25/2017] [Indexed: 01/07/2023] Open
Abstract
Gastric cancer (GC) is the second most frequent cause of cancer-related deaths worldwide. MicroRNAs are single-stranded RNA molecules of 21–23 nucleotides that regulate target gene expression through specific base-pairing interactions between miRNA and untranslated regions of targeted mRNAs. In this study, we generated a multistep approach for the integrated analysis of miRNA and mRNA expression. First, both miRNA and mRNA expression profiling datasets in gastric cancer from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) identified 79 and 1042 differentially expressed miRNAs and mRNAs, respectively, in gastric cancer. Second, inverse correlations between miRNA and mRNA expression levels identified 3206 miRNA–mRNA pairs combined with 79 dysregulated miRNAs and their 774 target mRNAs predicted by three prediction tools, miRanda, PITA, and RNAhybrid. Additionally, miR-204, which was found to be down-regulated in gastric cancer, was ectopically over-expressed in the AGS gastric cancer cell line and all down-regulated targets were identified by RNA sequencing (RNA-seq) analysis. Over-expression of miR-204 reduced the gastric cancer cell proliferation and suppressed the expression of three targets which were validated by qRT-PCR and luciferase assays. For the first time, we identified that CKS1B, CXCL1, and GPRC5A are putative targets of miR-204 and elucidated that miR-204 acted as potential tumor suppressor and, therefore, are useful as a promising therapeutic target for gastric cancer.
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Mateescu RG, Garrick DJ, Reecy JM. Network Analysis Reveals Putative Genes Affecting Meat Quality in Angus Cattle. Front Genet 2017; 8:171. [PMID: 29163638 PMCID: PMC5681485 DOI: 10.3389/fgene.2017.00171] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2017] [Accepted: 10/23/2017] [Indexed: 11/13/2022] Open
Abstract
Improvements in eating satisfaction will benefit consumers and should increase beef demand which is of interest to the beef industry. Tenderness, juiciness, and flavor are major determinants of the palatability of beef and are often used to reflect eating satisfaction. Carcass qualities are used as indicator traits for meat quality, with higher quality grade carcasses expected to relate to more tender and palatable meat. However, meat quality is a complex concept determined by many component traits making interpretation of genome-wide association studies (GWAS) on any one component challenging to interpret. Recent approaches combining traditional GWAS with gene network interactions theory could be more efficient in dissecting the genetic architecture of complex traits. Phenotypic measures of 23 traits reflecting carcass characteristics, components of meat quality, along with mineral and peptide concentrations were used along with Illumina 54k bovine SNP genotypes to derive an annotated gene network associated with meat quality in 2,110 Angus beef cattle. The efficient mixed model association (EMMAX) approach in combination with a genomic relationship matrix was used to directly estimate the associations between 54k SNP genotypes and each of the 23 component traits. Genomic correlated regions were identified by partial correlations which were further used along with an information theory algorithm to derive gene network clusters. Correlated SNP across 23 component traits were subjected to network scoring and visualization software to identify significant SNP. Significant pathways implicated in the meat quality complex through GO term enrichment analysis included angiogenesis, inflammation, transmembrane transporter activity, and receptor activity. These results suggest that network analysis using partial correlations and annotation of significant SNP can reveal the genetic architecture of complex traits and provide novel information regarding biological mechanisms and genes that lead to complex phenotypes, like meat quality, and the nutritional and healthfulness value of beef. Improvements in genome annotation and knowledge of gene function will contribute to more comprehensive analyses that will advance our ability to dissect the complex architecture of complex traits.
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Affiliation(s)
- Raluca G Mateescu
- Department of Animal Sciences, University of Florida, Gainesville, FL, United States
| | - Dorian J Garrick
- Department of Animal Science, Iowa State University, Ames, IA, United States
| | - James M Reecy
- Department of Animal Science, Iowa State University, Ames, IA, United States
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Lee J, Koh A, Jeong H, Kim E, Ha TS, Saleem MA, Ryu SH. C1-Ten is a PTPase of nephrin, regulating podocyte hypertrophy through mTORC1 activation. Sci Rep 2017; 7:12346. [PMID: 28955049 PMCID: PMC5617844 DOI: 10.1038/s41598-017-12382-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2017] [Accepted: 09/07/2017] [Indexed: 02/06/2023] Open
Abstract
Hypertrophy is a prominent feature of damaged podocytes in diabetic kidney disease (DKD). mTORC1 hyperactivation leads to podocyte hypertrophy, but the detailed mechanism of how mTORC1 activation occurs under pathological conditions is not completely known. Moreover, reduced nephrin tyrosine phosphorylation has been observed in podocytes under pathological conditions, but the molecular mechanism linking nephrin phosphorylation and pathology is unclear so far. In this study, we observed a significant increase in C1-Ten level in diabetic kidney and in high glucose-induced damaged podocytes. C1-Ten acts as a protein tyrosine phosphatase (PTPase) at the nephrin-PI3K binding site and renders PI3K for IRS-1, thereby activating mTORC1. Furthermore, C1-Ten causes podocyte hypertrophy and proteinuria by increasing mTORC1 activity in vitro and in vivo. These findings demonstrate the relationship between nephrin dephosphorylation and the mTORC1 pathway, mediated by C1-Ten PTPase activity. We suggest that C1-Ten contributes to the pathogenesis of DKD by inducing podocyte hypertrophy under high glucose conditions.
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Affiliation(s)
- Jiyoun Lee
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Ara Koh
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Heeyoon Jeong
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Eui Kim
- Division of Integrative Biosciences and Biotechnology, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Tae-Sun Ha
- Department of Pediatrics, College of Medicine, Chungbuk National University, Cheongju, 28644, Republic of Korea
| | - Moin A Saleem
- Academic and Children's Renal Unit, University of Bristol, Learning and Research, Southmead Hospital, Bristol, BS10 5NB, UK
| | - Sung Ho Ryu
- Department of Life Sciences, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea.
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Overexpression of CTEN relates to tumor malignant potential and poor outcomes of adenocarcinoma of the esophagogastric junction. Oncotarget 2017; 8:84112-84122. [PMID: 29137409 PMCID: PMC5663581 DOI: 10.18632/oncotarget.21109] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2017] [Accepted: 09/04/2017] [Indexed: 01/14/2023] Open
Abstract
Background To detect a novel treatment target for adenocarcinoma of the esophagogastric junction (AEG), we tested whether C-terminal tensin-like (CTEN), a member of the tensin gene family and frequently overexpressed in various cancers, acts as a cancer-promoting gene through overexpression in AEG. Materials and Methods We analyzed 5 gastric adenocarcinoma (GC) cell lines and 104 primary AEG tumors curatively resected in our hospital between 2000 and 2010. Results CTEN overexpression was detected in GC cell lines (2/5 cell lines; 40%) and primary AEG tumor samples (35/104 cases; 34%). CTEN knockdown using several specific siRNAs inhibited the proliferation, migration, and invasion of CTEN-overexpressing cells. CTEN overexpression was significantly correlated with more aggressive venous and lymphatic invasion, deeper tumor depth, and higher rates of lymph node metastasis and recurrence. Patients with CTEN-overexpressing tumors had a worse overall rate of survival than those with non-expressing tumors (P < 0.0001, log-rank test) in an expression-dependent manner. CTEN positivity was independently associated with a worse outcome in the multivariate analysis (P = 0.0423, hazard ratio 3.54 [1.04-16.4]). Conclusions CTEN plays a crucial role in tumor cell proliferation, migration, and invasion through its overexpression, which highlights its usefulness as a prognosticator and potential therapeutic target in AEG.
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