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Li J, Wang W, Lin Z, Liu Z, Zhang R, Li R, Zhang J, Zheng Y, Qin D, Wu Y, Liu Y. Vinculin: A new target for the diagnosis and treatment of disease. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2025; 195:157-166. [PMID: 39863082 DOI: 10.1016/j.pbiomolbio.2025.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/28/2024] [Revised: 01/10/2025] [Accepted: 01/12/2025] [Indexed: 01/27/2025]
Abstract
Vinculin, a crucial adhesion plaque protein, plays a significant role in cell morphology and tissue development. Dysregulation of focal adhesion proteins has been linked to numerous diseases, including cardiovascular conditions, gastrointestinal disorders, and cancer. Recent studies increasingly highlight vinculin's involvement in the progression of these diseases; however, a comprehensive review remains lacking. Therefore, an in-depth and timely review is essential to consolidate the latest findings on vinculin's role in disease mechanisms. This study aims to examine how vinculin coordinates a complex network of signaling pathways across various pathological contexts.
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Affiliation(s)
- Jiqiang Li
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China
| | - Weiming Wang
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China
| | - Zipeng Lin
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China
| | - Zhenyu Liu
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China
| | - Ruilin Zhang
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China
| | - Runwen Li
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China
| | - Jie Zhang
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China
| | - Youkun Zheng
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, 646000, Luzhou, China
| | - Dalian Qin
- Department of Pharmacology, School of Pharmacy, Southwest Medical University, 646000, Luzhou, China
| | - Ya Wu
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, 646000, Luzhou, China; Department of General Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China.
| | - Yong Liu
- Department of Vascular Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China; Metabolic Vascular Disease Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China; Key Laboratory of Medical Electrophysiology, Ministry of Education & Medical Electrophysiological Key Laboratory of Sichuan Province, (Collaborative Innovation Center for Prevention of Cardiovascular Diseases) Institute of Cardiovascular Research, Southwest Medical University, 646000, Luzhou, China; Department of General Surgery, The Affiliated Hospital of Southwest Medical University, 646000, Luzhou, China.
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Lyu X, Shi Y, Wang D, Cao X, Guo J, Huang G, Zhou L, Zhang M, Dong Z. Impact of LIN7A silencing on U87 cell invasion and its clinical significance in glioblastoma. Sci Rep 2025; 15:7212. [PMID: 40021783 PMCID: PMC11871311 DOI: 10.1038/s41598-025-91285-5] [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: 08/30/2024] [Accepted: 02/19/2025] [Indexed: 03/03/2025] Open
Abstract
Glioblastoma is highly aggressive and resistant to treatment, making it crucial to understand the regulatory mechanisms underlying its invasion. LIN7A, a polar protein, has been implicated in tumor cell migration and invasion, but its role in glioblastoma remains unclear. This study aimed to manipulate LIN7A gene expression in U87 cells, analyze its impact on invasion, and explore the potential mechanisms through which LIN7A regulates glioblastoma cell invasion. Lentiviral vectors were used to silence the LIN7A gene in U87 cells, selecting the most effective vector. LIN7A gene transcription, protein expression and localization were analyzed using RT-qPCR, Western blotting, and immunofluorescence. U87 cell invasion was assessed via real-time cell analysis and spheroid invasion assay, while MMP-2 and MMP-9 protease activities were measured using zymography. β-catenin protein levels and localization were evaluated through Western blotting and immunofluorescence. Expression of target genes in the β-catenin pathway was also measured. An orthotopic xenograft glioblastoma model in nude mice was established by intracranial implantation of U87 cells, with tumor growth monitored using immunofluorescence analysis of brain slices. The clinical significance of LIN7A expression was confirmed by comparing its levels in core and peripheral invading areas of glioblastoma and analyzing RNASeq data and clinical information from the Clinical Proteomic Tumor Analysis Consortium (CPTAC) GBM cohort. Transfection of U87 cells with a lentiviral vector led to decreased LIN7A levels and altered distribution patterns. Silencing the LIN7A gene increased U87 cell proliferation and invasiveness, reduced clonal formation ability, and enhanced MMP-2 and MMP-9 protease activity. It also resulted in a slight increase in cytoplasmic β-catenin content, although not statistically significant, but a significant increase in nuclear β-catenin accumulation and transcriptional activity of target genes in the pathway. Animal studies showed that LIN7A gene silencing caused U87 cells to transition from clumpy to invasive growth mode. LIN7A expression was significantly lower in the peripheral invading area compared to the core area in clinical samples of glioblastoma. Data mining of the CPTAC-GBM cohort revealed a strong association between LIN7A gene expression and survival time. Silencing LIN7A may promote U87 tumor cell invasion by disrupting intercellular junctions, altering cell polarity, and activating the β-catenin pathway. Further research is warranted to elucidate the role of LIN7A in glioblastoma cell invasion.
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Affiliation(s)
- Xiaojuan Lyu
- Department of Oncology, Wuhan Centre Hospital, Wuhan, 430024, People's Republic of China
| | - Yuxiang Shi
- Department of Pathology, Wuhan Centre Hospital, Wuhan, 430024, People's Republic of China
| | - Daixu Wang
- Department of Neurosurgery, Wuhan Centre Hospital, Wuhan, 430024, People's Republic of China
| | - Xing Cao
- Department of Oncology, Wuhan Centre Hospital, Wuhan, 430024, People's Republic of China
| | - Jipeng Guo
- Department of Oncology, Wuhan Centre Hospital, Wuhan, 430024, People's Republic of China
| | - Guodong Huang
- Department of Oncology, Wuhan Centre Hospital, Wuhan, 430024, People's Republic of China
| | - Lin Zhou
- Department of Histoembryology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Mengxian Zhang
- Department of Oncology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China
| | - Zhen Dong
- Department of Neurosurgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, People's Republic of China.
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West JJ, Golloshi R, Cho CY, Wang Y, Stevenson P, Stein-O’Brien G, Fertig EJ, Ewald AJ. Claudin 7 suppresses invasion and metastasis through repression of a smooth muscle actin program. J Cell Biol 2024; 223:e202311002. [PMID: 39320351 PMCID: PMC11450322 DOI: 10.1083/jcb.202311002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Revised: 07/30/2024] [Accepted: 09/12/2024] [Indexed: 09/26/2024] Open
Abstract
Metastasis initiates when cancer cells escape from the primary tumor, which requires changes to intercellular junctions. Claudins are transmembrane proteins that form the tight junction, and their expression is reduced in aggressive breast tumors. However, claudins' roles during breast cancer metastasis remain unclear. We used gain- and loss-of-function genetics in organoids isolated from murine breast cancer models to establish that Cldn7 suppresses invasion and metastasis. Transcriptomic analysis revealed that Cldn7 knockdown induced smooth muscle actin (SMA)-related genes and a broader mesenchymal phenotype. We validated our results in human cell lines, fresh human tumor tissue, bulk RNA-seq, and public single-cell RNA-seq data. We consistently observed an inverse relationship between Cldn7 expression and expression of SMA-related genes. Furthermore, knockdown and overexpression of SMA-related genes demonstrated that they promote breast cancer invasion. Our data reveal that Cldn7 suppresses breast cancer invasion and metastasis through negative regulation of SMA-related and mesenchymal gene expression.
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Affiliation(s)
- Junior J. West
- Departments of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Giovanis Institute for Translational Cell Biology, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Rosela Golloshi
- Departments of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Giovanis Institute for Translational Cell Biology, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Chae Yun Cho
- Departments of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Yuqian Wang
- Departments of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Giovanis Institute for Translational Cell Biology, Johns Hopkins Medicine, Baltimore, MD, USA
| | - Parker Stevenson
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Genevieve Stein-O’Brien
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
- Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Elana J. Fertig
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
- Department of Applied Mathematics and Statistics, Johns Hopkins University, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
| | - Andrew J. Ewald
- Departments of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, MD, USA
- Giovanis Institute for Translational Cell Biology, Johns Hopkins Medicine, Baltimore, MD, USA
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD, USA
- Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD, USA
- Convergence Institute, Johns Hopkins University, Baltimore, MD, USA
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Muñoz-Medel M, Pinto MP, Goralsky L, Cáceres M, Villarroel-Espíndola F, Manque P, Pinto A, Garcia-Bloj B, de Mayo T, Godoy JA, Garrido M, Retamal IN. Porphyromonas gingivalis, a bridge between oral health and immune evasion in gastric cancer. Front Oncol 2024; 14:1403089. [PMID: 38807771 PMCID: PMC11130407 DOI: 10.3389/fonc.2024.1403089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 05/02/2024] [Indexed: 05/30/2024] Open
Abstract
Porphyromonas gingivalis (P. gingivalis) is a gram-negative oral pathogen associated with chronic periodontitis. Previous studies have linked poor oral health and periodontitis with oral cancer. Severe cases of periodontal disease can result in advanced periodontitis, leading to tissue degradation, tooth loss, and may also correlate with higher gastric cancer (GC) risk. In fact, tooth loss is associated with an elevated risk of cancer. However, the clinical evidence for this association remains inconclusive. Periodontitis is also characterized by chronic inflammation and upregulation of members of the Programmed Death 1/PD1 Ligand 1 (PD1/PDL1) axis that leads to an immunosuppressive state. Given that chronic inflammation and immunosuppression are conditions that facilitate cancer progression and carcinogenesis, we hypothesize that oral P. gingivalis and/or its virulence factors serve as a mechanistic link between oral health and gastric carcinogenesis/GC progression. We also discuss the potential impact of P. gingivalis' virulence factors (gingipains, lipopolysaccharide (LPS), and fimbriae) on inflammation and the response to immune checkpoint inhibitors in GC which are part of the current standard of care for advanced stage patients.
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Affiliation(s)
- Matías Muñoz-Medel
- Precision Oncology Center, School of Medicine, Faculty of Medicine and Health Sciences, Universidad Mayor, Santiago, Chile
| | - Mauricio P. Pinto
- Support Team for Oncological Research and Medicine (STORM), Santiago, Chile
| | - Lauren Goralsky
- Department of Biological Sciences, Columbia University, New York, NY, United States
| | - Mónica Cáceres
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Santiago, Chile
- Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, Universidad de Chile, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | | | - Patricio Manque
- Precision Oncology Center, School of Medicine, Faculty of Medicine and Health Sciences, Universidad Mayor, Santiago, Chile
| | - Andrés Pinto
- Department of Oral and Maxillofacial Medicine and Diagnostic Sciences, Case Western Reserve University School of Dental Medicine, Cleveland, OH, United States
| | - Benjamin Garcia-Bloj
- Precision Oncology Center, School of Medicine, Faculty of Medicine and Health Sciences, Universidad Mayor, Santiago, Chile
| | - Tomas de Mayo
- Precision Oncology Center, School of Medicine, Faculty of Medicine and Health Sciences, Universidad Mayor, Santiago, Chile
| | - Juan A. Godoy
- Precision Oncology Center, School of Medicine, Faculty of Medicine and Health Sciences, Universidad Mayor, Santiago, Chile
| | - Marcelo Garrido
- Precision Oncology Center, School of Medicine, Faculty of Medicine and Health Sciences, Universidad Mayor, Santiago, Chile
| | - Ignacio N. Retamal
- Precision Oncology Center, School of Medicine, Faculty of Medicine and Health Sciences, Universidad Mayor, Santiago, Chile
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Liao C, Cui J, Gao M, Wang B, Ito K, Guo Y, Zhang B. Dual-sgRNA CRISPRa System for Enhanced MK-7 Production and Salmonella Infection Mitigation in Bacillus subtilis natto Applied to Caco-2 Cells. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2024; 72:4301-4316. [PMID: 38344988 DOI: 10.1021/acs.jafc.3c08866] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/29/2024]
Abstract
This study optimized the menaquinone-7 (MK-7) synthetic pathways in Bacillus subtilis (B. subtilis) natto NB205, a strain that originated from natto, to enhance its MK-7 production. Utilizing mutation breeding, we developed NBMK308, a mutant strain that demonstrated a significant 117.23% increase in MK-7 production. A comprehensive transcriptome analysis identified two key genes, ispA and ispE, as being critical in MK-7 synthesis. The dual-sgRNA CRISPRa system was utilized to achieve precise regulation of ispA and ispE in the newly engineered strain, A3E3. This strategic modulation resulted in a significant enhancement of MK-7 production, achieving increases of 20.02% and 201.41% compared to traditional overexpression systems and the original strain NB205, respectively. Furthermore, the fermentation supernatant from A3E3 notably inhibited Salmonella invasion in Caco-2 cells, showcasing its potential for combating such infections. The safety of the dual-sgRNA CRISPRa system was confirmed through cell assays. The utilization of the dual-sgRNA CRISPRa system in this study was crucial for the precise regulation of key genes in MK-7 synthesis, leading to a remarkable increase in production and demonstrating additional therapeutic potential in inhibiting pathogenic infections. This approach effectively combined the advantages of microbial fermentation and biotechnology, addressing health and nutritional challenges.
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Affiliation(s)
- Chaoyong Liao
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, China Agricultural University, Beijing 100091, China
| | - Jian Cui
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, China Agricultural University, Beijing 100091, China
| | - Mingkun Gao
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, China Agricultural University, Beijing 100091, China
| | - Bo Wang
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, China Agricultural University, Beijing 100091, China
| | - Koichi Ito
- Department of Food and Physiological Models, Graduate School of Agricultural and Life Sciences, The University of Tokyo, Ibaraki 113-8654, Japan
| | - Yuming Guo
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, China Agricultural University, Beijing 100091, China
| | - Bingkun Zhang
- State Key Laboratory of Animal Nutrition, Department of Animal Nutrition and Feed Science, College of Animal Science and Technology, China Agricultural University, Beijing 100091, China
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Kamakura S, Hayase J, Kohda A, Iwakiri Y, Chishiki K, Izaki T, Sumimoto H. TMEM25 is a Par3-binding protein that attenuates claudin assembly during tight junction development. EMBO Rep 2024; 25:144-167. [PMID: 38177906 PMCID: PMC10897455 DOI: 10.1038/s44319-023-00018-0] [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: 01/10/2023] [Revised: 11/21/2023] [Accepted: 11/22/2023] [Indexed: 01/06/2024] Open
Abstract
The tight junction (TJ) in epithelial cells is formed by integral membrane proteins and cytoplasmic scaffolding proteins. The former contains the claudin family proteins with four transmembrane segments, while the latter includes Par3, a PDZ domain-containing adaptor that organizes TJ formation. Here we show the single membrane-spanning protein TMEM25 localizes to TJs in epithelial cells and binds to Par3 via a PDZ-mediated interaction with its C-terminal cytoplasmic tail. TJ development during epithelial cell polarization is accelerated by depletion of TMEM25, and delayed by overexpression of TMEM25 but not by that of a C-terminally deleted protein, indicating a regulatory role of TMEM25. TMEM25 associates via its N-terminal extracellular domain with claudin-1 and claudin-2 to suppress their cis- and trans-oligomerizations, both of which participate in TJ strand formation. Furthermore, Par3 attenuates TMEM25-claudin association via binding to TMEM25, implying its ability to affect claudin oligomerization. Thus, the TJ protein TMEM25 appears to negatively regulate claudin assembly in TJ formation, which regulation is modulated by its interaction with Par3.
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Affiliation(s)
- Sachiko Kamakura
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Junya Hayase
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Akira Kohda
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yuko Iwakiri
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Kanako Chishiki
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Tomoko Izaki
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Hideki Sumimoto
- Department of Biochemistry, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan.
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Wang D, Yang Y, Cao Y, Meng M, Wang X, Zhang Z, Fu W, Duan S, Tang L. Histone deacetylase inhibitors inhibit lung adenocarcinoma metastasis via HDAC2/YY1 mediated downregulation of Cdh1. Sci Rep 2023; 13:12069. [PMID: 37495623 PMCID: PMC10372082 DOI: 10.1038/s41598-023-38848-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 07/16/2023] [Indexed: 07/28/2023] Open
Abstract
Metastasis is a leading cause of mortality in patients with lung adenocarcinoma. Histone deacetylases have emerged as promising targets for anti-tumor drugs, with histone deacetylase inhibitors (HDACi) being an active area of research. However, the precise mechanisms by which HDACi inhibits lung cancer metastasis remain incompletely understood. In this study, we employed a range of techniques, including qPCR, immunoblotting, co-immunoprecipitation, chromatin-immunoprecipitation, and cell migration assays, in conjunction with online database analysis, to investigate the role of HDACi and HDAC2/YY1 in the process of lung adenocarcinoma migration. The present study has demonstrated that both trichostatin A (TSA) and sodium butyrate (NaBu) significantly inhibit the invasion and migration of lung cancer cells via Histone deacetylase 2 (HDAC2). Overexpression of HDAC2 promotes lung cancer cell migration, whereas shHDAC2 effectively inhibits it. Further investigation revealed that HDAC2 interacts with YY1 and deacetylates Lysine 27 and Lysine9 of Histone 3, thereby inhibiting Cdh1 transcriptional activity and promoting cell migration. These findings have shed light on a novel functional mechanism of HDAC2/YY1 in lung adenocarcinoma cell migration.
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Affiliation(s)
- Dongmei Wang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou, No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213004, Jiangsu, China
- Changzhou Medical Center of Nanjing Medical University, Changzhou, 213004, Jiangsu, China
| | - Yixiao Yang
- Institute of Burn Research, The First Affiliated Hospital, State Key Lab of Trauma, Burn and Combined Injury, Chongqing Key Laboratory for Disease Proteomics, Third Military Medical University (Army Medical University), Chongqing, 400038, China
| | - Yuxiang Cao
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Meiyao Meng
- Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai, 200241, China
| | - Xiaobo Wang
- Henan Provincial Chest Hospital, Zhengzhou, 450000, Henan, China
| | - Zhengxun Zhang
- Henan Provincial Chest Hospital, Zhengzhou, 450000, Henan, China
| | - Wei Fu
- Henan Provincial Chest Hospital, Zhengzhou, 450000, Henan, China
| | - Shichao Duan
- Henan Provincial People's Hospital, Henan Eye Hospital, Henan Eye Institute, Zhengzhou University People's Hospital, Henan University People's Hospital, Zhengzhou, 450003, Henan, China.
| | - Liming Tang
- Department of Gastrointestinal Surgery, The Affiliated Changzhou, No. 2 People's Hospital of Nanjing Medical University, Changzhou, 213004, Jiangsu, China.
- Changzhou Medical Center of Nanjing Medical University, Changzhou, 213004, Jiangsu, China.
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Doulberis M, Papaefthymiou A, Polyzos SA, Vardaka E, Tzitiridou-Chatzopoulou M, Chatzopoulos D, Koffas A, Papadopoulos V, Kyrailidi F, Kountouras J. Local and systemic autoimmune manifestations linked to hepatitis A infection. Acta Gastroenterol Belg 2023; 86:429-436. [PMID: 37814559 DOI: 10.51821/86.3.11299] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/11/2023]
Abstract
Hepatitis A virus (HAV) represents a global burdening infectious agent causing in the majority of cases a self-limiting acute icteric syndrome, the outcome is related to the hepatic substrate and the potential pre-existing damage, whereas a plethora of extra-hepatic manifestations has also been reported. Despite the absence of post- HAV chronicity it has been associated with an additional burden on existing chronic liver diseases. Moreover, the induced immune response and the antigenic molecular mimicry are considered as triggering factors of autoimmunity with regional and distal impact. Diseases such as autoimmune hepatitis, Guillain-Barré syndrome, rheumatoid arthritis, Still's syndrome, Henoch-Schönlein purpura, autoimmune hemolytic anemia, antiphospholipid syndrome, systematic lupus erythematosus or cryoglobulinemic vasculitis have been described in patients with HAV infection. Although the exact mechanisms remain unclear, this review aims to accumulate and clarify the pathways related to this linkage.
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Affiliation(s)
- M Doulberis
- Department of Gastroenterology and Hepatology, Medical University Department, Kantonsspital Aarau, Switzerland
- Department of Gastroenterology and Hepatology, University of Zurich, Zurich, Switzerland
- Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - A Papaefthymiou
- Pancreaticobiliary Medicine Unit, University College London Hospitals (UCLH), London, UK
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - S A Polyzos
- First Laboratory of Pharmacology, Aristotle University of Thessaloniki, Thessaloniki, Macedonia, Greece
| | - E Vardaka
- Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Department of Nutritional Sciences and Dietetics, School of Health Sciences, International Hellenic University, Thessaloniki, Macedonia, Greece
| | - M Tzitiridou-Chatzopoulou
- Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
- Department of Midwifery, University of Western Macedonia, Macedonia, Greece
| | - D Chatzopoulos
- Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - A Koffas
- Barts Liver Centre, Centre for Immunobiology, Blizzard Institute, Barts and The London School of Medicine and Dentistry, QMUL, London, UK
| | - V Papadopoulos
- Department of Gastroenterology, University Hospital of Larissa, Larissa, Greece
| | - F Kyrailidi
- Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - J Kountouras
- Department of Internal Medicine, Second Medical Clinic, Ippokration Hospital, Aristotle University of Thessaloniki, Thessaloniki, Greece
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Kim S, Park S, Moon EH, Kim GJ, Choi J. Hypoxia disrupt tight junctions and promote metastasis of oral squamous cell carcinoma via loss of par3. Cancer Cell Int 2023; 23:79. [PMID: 37095487 PMCID: PMC10123966 DOI: 10.1186/s12935-023-02924-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2023] [Accepted: 04/10/2023] [Indexed: 04/26/2023] Open
Abstract
BACKGROUND Oral squamous cell carcinoma (OSCC) is a highly malignant tumor that is frequently associated with lymph node metastasis, resulting in poor prognosis and survival in patients. In the tumor microenvironment, hypoxia plays an important role in regulating cellular responses such as progressive and rapid growth and metastasis. In these processes, tumor cells autonomously undergo diverse transitions and acquire functions. However, hypoxia-induced transition of OSCC and the involvement of hypoxia in OSCC metastasis remain unclear. Therefore, in this study, we aimed to elucidate the mechanism of hypoxia-induced OSCC metastasis and particularly, its impact on tight junctions (TJs). METHODS The expression of hypoxia-inducible factor 1-alpha (HIF-1α) was detected in tumor tissues and adjacent normal tissues from 29 patients with OSCC using reverse transcription quantitative real-time polymerase chain reaction (qRT-PCR), western blotting, and immunohistochemistry (IHC). The migration and invasion abilities of OSCC cell lines treated with small interfering (si)RNA targeting HIF-1α or cultured in hypoxic conditions were analyzed using Transwell assays. The effect of HIF-1α expression on in vivo tumor metastasis of OSCC cells was evaluated using lung metastasis model. RESULTS HIF-1α was overexpressed in patients with OSCC. OSCC metastasis was correlated with HIF-1α expression in OSCC tissues. Hypoxia increased the migration and invasion abilities of OSCC cell lines by regulating the expression and localization of partitioning-defective protein 3 (Par3) and TJs. Furthermore, HIF-1α silencing effectively decreased the invasion and migration abilities of OSCC cell lines and restored TJ expression and localization via Par3. The expression of HIF-1α was positively regulated the OSCC metastasis in vivo. CONCLUSIONS Hypoxia promotes OSCC metastasis by regulating the expression and localization of Par3 and TJ proteins. HIF-1α positively correlates to OSCC metastasis. Lastly, HIF-1α expression could regulate the expression of Par3 and TJs in OSCC. This finding may aid in elucidating the molecular mechanisms of OSCC metastasis and progression and developing new diagnostic and therapeutic approaches for OSCC metastasis.
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Affiliation(s)
- Shihyun Kim
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea
| | - Suyeon Park
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea
| | - Eun-Hye Moon
- Institute of Lee Gil Ya Cancer and Diabetes, Gachon University, Incheon, 21999, Republic of Korea
| | - Gi Jin Kim
- Department of Biomedical Science, CHA University, Seongnam, Gyeonggi-do, 13488, Republic of Korea
| | - Jongho Choi
- Department of Oral Pathology, College of Dentistry, Gangneung-Wonju National University, 7 Jukheon-gil, Gangneung- si, Gangwon-do, 25457, Republic of Korea.
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10
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Guo X, Gu Y, Guo C, Pei L, Hao C. LINC01146/F11R facilitates growth and metastasis of prostate cancer under the regulation of TGF-β. J Steroid Biochem Mol Biol 2023; 225:106193. [PMID: 36162632 DOI: 10.1016/j.jsbmb.2022.106193] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 02/01/2023]
Abstract
The effect of long intergenic non-protein coding RNAs (lncRNAs) was verified in prostate cancer (PCa), but the mechanism of LINC01146 in PCa is unclear. Bioinformatics was applied to analyze LINC01146 expression in PCa and predict target genes of LINC01146, followed by the verification of qRT-PCR, RNA pull-down and co-immunoprecipitation (Co-IP). The correlation between LINC01146 expression and clinicopathological characteristics was investigated. The location of LINC01146 in PCa cells was detected by fluorescence in situ hybridization (FISH). After interference with LINC01146 or/and F11 receptor (F11R) or treated with transforming growth factor beta 1 (TGF-β1), the function of LINC01146 in PCa in vitro or in vivo was determined by CCK-8, colony formation, flow cytometry, scratch test, transwell assay, xenograft experiment and western blot. LINC01146 and F11R were over-expressed in PCa and positively correlated with poor prognosis. LINC01146 located in the cytoplasm and combined with F11R. LINC01146 overexpression impeded apoptosis, facilitated viability, proliferation, migration and invasion in PCa cells in vitro, promoted tumor growth in vivo, downregulated E-cadherin, Bax and Cleaved caspase-3, and upregulated N-cadherin, Vimentin and PCNA, but LINC01146 silencing did the opposite. F11R was positively regulated by LINC01146 and F11R depletion negated the effect of LINC01146 overexpression on malignant phenotypes of PCa cells. The expression of LINC01146 and F11R was regulated by TGF-β1. The promoting role of TGF-β1 in migration, invasion and F11R in PCa cells was reversed by LINC01146 silencing. LINC01146 upregulated F11R to facilitate malignant phenotypes of PCa cells, which was regulated by TGF-β.
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Affiliation(s)
- Xiaohua Guo
- Department of Urology, Second Hospital of Shanxi Medical University, China.
| | - Yong Gu
- Department of Urology, Second Hospital of Shanxi Medical University, China
| | - Chao Guo
- Department of Urology, Second Hospital of Shanxi Medical University, China
| | - Liang Pei
- Department of Urology, Second Hospital of Shanxi Medical University, China
| | - Chuan Hao
- Department of Urology, Second Hospital of Shanxi Medical University, China
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11
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Metsiou DN, Deligianni D, Giannopoulou E, Kalofonos H, Koutras A, Athanassiou G. Adhesion strength and anti-tumor agents regulate vinculin of breast cancer cells. Front Oncol 2022; 12:811508. [PMID: 36052248 PMCID: PMC9424896 DOI: 10.3389/fonc.2022.811508] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 07/19/2022] [Indexed: 11/13/2022] Open
Abstract
The onset and progression of cancer are strongly associated with the dissipation of adhesion forces between cancer cells, thus facilitating their incessant attachment and detachment from the extracellular matrix (ECM) to move toward metastasis. During this process, cancer cells undergo mechanical stresses and respond to these stresses with membrane deformation while inducing protrusions to invade the surrounding tissues. Cellular response to mechanical forces is inherently related to the reorganization of the cytoskeleton, the dissipation of cell–cell junctions, and the adhesion to the surrounding ECM. Moreover, the role of focal adhesion proteins, and particularly the role of vinculin in cell attachment and detachment during migration, is critical, indicating the tight cell–ECM junctions, which favor or inhibit the metastatic cascade. The biomechanical analysis of these sequences of events may elucidate the tumor progression and the potential of cancer cells for migration and metastasis. In this work, we focused on the evaluation of the spreading rate and the estimation of the adhesion strength between breast cancer cells and ECM prior to and post-treatment with anti-tumor agents. Specifically, different tamoxifen concentrations were used for ER+ breast cancer cells, while even concentrations of trastuzumab and pertuzumab were used for HER2+ cells. Analysis of cell stiffness indicated an increased elastic Young’s modulus post-treatment in both MCF-7 and SKBR-3 cells. The results showed that the post-treatment spreading rate was significantly decreased in both types of breast cancer, suggesting a lower metastatic potential. Additionally, treated cells required greater adhesion forces to detach from the ECM, thus preventing detachment events of cancer cells from the ECM, and therefore, the probability of cell motility, migration, and metastasis was confined. Furthermore, post-detachment and post-treatment vinculin levels were increased, indicating tighter cell–ECM junctions, hence limiting the probability of cell detachment and, therefore, cell motility and migration.
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Affiliation(s)
- Despoina Nektaria Metsiou
- Laboratory of Biomechanics and Biomedical Engineering, Department of Mechanical Engineering and Aeronautics, University of Patras, Patra, Greece
- *Correspondence: Despoina Nektaria Metsiou, ;
| | - Despina Deligianni
- Laboratory of Biomechanics and Biomedical Engineering, Department of Mechanical Engineering and Aeronautics, University of Patras, Patra, Greece
| | - Efstathia Giannopoulou
- Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patra, Greece
| | - Haralabos Kalofonos
- Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patra, Greece
| | - Angelos Koutras
- Clinical Oncology Laboratory, Division of Oncology, Department of Medicine, University of Patras, Patra, Greece
| | - George Athanassiou
- Laboratory of Biomechanics and Biomedical Engineering, Department of Mechanical Engineering and Aeronautics, University of Patras, Patra, Greece
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12
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Wu J, Luo D, Li S. Ovo Like Zinc Finger 2 (OVOL2) Suppresses Breast Cancer Stem Cell Traits and Correlates with Immune Cells Infiltration. BREAST CANCER: TARGETS AND THERAPY 2022; 14:211-227. [PMID: 35996562 PMCID: PMC9391936 DOI: 10.2147/bctt.s363114] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Accepted: 08/05/2022] [Indexed: 12/24/2022]
Affiliation(s)
- Jiafa Wu
- School of Food and Bioengineering, Henan University of Science and Technology, Luoyang, People’s Republic of China
- Correspondence: Jiafa Wu, School of Food and Bioengineering, Henan University of Science and Technology, Kaiyuan Avenue 263, Luoyang, People’s Republic of China, Email
| | - Dongping Luo
- The First Affiliated Hospital, Henan University of Science and Technology, Luoyang, People’s Republic of China
| | - Shengnan Li
- School of Medicine, Henan Polytechnic University, Jiaozuo, People’s Republic of China
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13
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Tight junction protein CLDN17 serves as a tumor suppressor to reduce the invasion and migration of oral cancer cells by inhibiting epithelial-mesenchymal transition. Arch Oral Biol 2021; 133:105301. [PMID: 34781072 DOI: 10.1016/j.archoralbio.2021.105301] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate claudin-17 (CLDN17) expression in oral cancer and its effect on epithelial-mesenchymal transition (EMT), invasion and migration in oral cancer cells. METHODS The GEO2R tool was used to analyze gene expression in two microarray datasets (GSE74530 and GSE146483) derived from the Gene Expression Omnibus (GEO) database. Gene Expression Profiling Interactive Analysis (GEPIA) verified CLDN17 expression in head and neck squamous cell carcinoma (HNSC) patients. Moreover, oral cancer cells were transfected with CLDN17 overexpression plasmid or CLDN17 shRNA to evaluate cell invasion and migration. Gene and protein expression was detected by qRT-PCR, immunohistochemistry and western blotting. RESULTS CLDN17 was one of the top 200 differentially expressed genes in the GSE74530 and GSE146483 datasets and was downregulated in oral cancer. CLDN17 expression was higher in HNSC tissues, and it was related to TNM staging. In HNSC tumors, CLDN17 expression was positively correlated with CDH1 but negatively related to VIM, SNAIL1, SNAIL2, and TWIST1. Meanwhile, we found that CLDN17 expression was lower in oral cancer tissues; it declined with higher T status, N status, M status and staging, lower differentiation grade, and a worse prognosis. Upregulation of CLDN17 inhibited the invasion and migration of oral cancer cells, with elevated CDH1 and reduced VIM, SNAIL1, SNAIL2, and TWIST1, while CLDN17 downregulation had the opposite effects. CONCLUSION CLDN17 may serve as a tumor suppressor in oral cancer since it could reduce the invasion and migration of cells by inhibiting the EMT process, thus becoming a potential therapeutic target in oral cancer.
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14
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Li Y, Li T, Zhou D, Wei J, Li Z, Li X, Jia S, Ouyang Q, Qi S, Chen Z, Zhang B, Yu J, Jia J, Xu A, Huang J. Role of tight junction-associated MARVEL protein marvelD3 in migration and epithelial-mesenchymal transition of hepatocellular carcinoma. Cell Adh Migr 2021; 15:249-260. [PMID: 34338154 PMCID: PMC8331009 DOI: 10.1080/19336918.2021.1958441] [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] [Indexed: 10/29/2022] Open
Abstract
MarvelD3, a recently identified tight junction membrane protein, could be associated with hepatocellular carcinoma (HCC). We aimed to investigate the role of marvelD3 in Epithelial-Mesenchymal Transition (EMT) and migration of HCC and explore the underlying molecular mechanisms. First, we assessed marvlD3 expression in HCC and normal liver tissues and found loss of marvelD3 expression was significantly correlated with the occurrence and TNM stage of HCC. Second, we detected that marvelD3 was downregulated in HCC cells with transforming growth factor β1 and snail/slug-induced EMT. Finally, we analyzed expression of marvelD3 protein was significantly associated with EMT and the NF-κB signaling pathway. Our study demonstrated that MarvelD3 inhibited EMT and migration of HCC cells along with inhibiting NF-κB signaling pathway.Abbreviations: HCC, Hepatocellular carcinoma; TJ, Tight junction; MARVEL, MAL and related proteins for vesicle trafficking and membrane link; EMT, Epithelial-mesenchymal transition; NF-κB, Nuclear factor kappa B; TAMPs, Tight junction-associated marvel proteins; TGF-β1, Transforming growth factor-β1; MMP9, matrix metallopeptidase 9; RT-PCR, Real-time PCR; IHC, Immunohistochemistry; IF, Immunofluorescence.
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Affiliation(s)
- Yanmeng Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Teng Li
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, People's Republic of China
| | - Donghu Zhou
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jia Wei
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhenkun Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Xiaojin Li
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Siyu Jia
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Qin Ouyang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Saiping Qi
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Zhibin Chen
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Bei Zhang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jing Yu
- Department of Oncology, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jidong Jia
- Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Anjian Xu
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | - Jian Huang
- Experimental Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.,National Clinical Research Center for Digestive Disease, Beijing Friendship Hospital, Capital Medical University, Beijing, China
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15
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Tabariès S, Annis MG, Lazaris A, Petrillo SK, Huxham J, Abdellatif A, Palmieri V, Chabot J, Johnson RM, Van Laere S, Verhoef C, Hachem Y, Yumeen S, Meti N, Omeroglu A, Altinel G, Gao ZH, Yu ASL, Grünhagen DJ, Vermeulen P, Metrakos P, Siegel PM. Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern. Commun Biol 2021; 4:657. [PMID: 34079064 PMCID: PMC8172859 DOI: 10.1038/s42003-021-02189-9] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Accepted: 04/29/2021] [Indexed: 02/07/2023] Open
Abstract
Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases. Tabariès et al. describe that claudin 2 is a promoter of colorectal cancer liver metastasis. Furthermore, high Claudin-2 expression is associated with shorter time to liver-specific recurrence and is a biomarker of replacement type CRC liver metastases.
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Affiliation(s)
- Sébastien Tabariès
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada. .,Departments of Medicine, McGill University, Montréal, QC, Canada.
| | - Matthew G Annis
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada.,Departments of Medicine, McGill University, Montréal, QC, Canada
| | - Anthoula Lazaris
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | | | - Jennifer Huxham
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada.,Departments of Medicine, McGill University, Montréal, QC, Canada
| | - Amri Abdellatif
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | - Vincent Palmieri
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | - Jaclyn Chabot
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | - Radia M Johnson
- Department of Bioinformatics & Computational Biology, Genentech Inc., South San Francisco, CA, USA
| | - Steven Van Laere
- University of Antwerp, Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO), Edegem, Antwerp, Belgium.,Translational Cancer Research Unit, Oncologisch Centrum GZA, Wilrijk, Antwerp, Belgium
| | - Cornelis Verhoef
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Yasmina Hachem
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
| | - Sara Yumeen
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
| | - Nicholas Meti
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada
| | - Atilla Omeroglu
- Department of Pathology, McGill University Health Center, Montréal, QC, Canada
| | - Gulbeyaz Altinel
- Department of Pathology, McGill University Health Center, Montréal, QC, Canada
| | - Zu-Hua Gao
- Department of Pathology, McGill University Health Center, Montréal, QC, Canada
| | - Alan S L Yu
- Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, KS, USA
| | - Dirk J Grünhagen
- Department of Surgical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
| | - Peter Vermeulen
- University of Antwerp, Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO), Edegem, Antwerp, Belgium.,Translational Cancer Research Unit, Oncologisch Centrum GZA, Wilrijk, Antwerp, Belgium
| | - Peter Metrakos
- Department of Surgery, McGill University Health Center, Montréal, QC, Canada
| | - Peter M Siegel
- Goodman Cancer Research Centre, McGill University, Montréal, QC, Canada. .,Departments of Medicine, McGill University, Montréal, QC, Canada.
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16
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Wang SS, Liao X, Liu F, Zhang Q, Qiu JJ, Fu SH. miR-132 mediates cell permeability and migration by targeting occludin in high-glucose -induced ARPE-19 cells. Endocr J 2021; 68:531-541. [PMID: 33563844 DOI: 10.1507/endocrj.ej20-0277] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
This study investigated the effects and mechanisms of miR-132 related to the permeability and mobility of human retinal pigment epithelium ARPE-19 cells in high-glucose (HG) condition. ARPE-19 cells were cultured in normal and HG condition and identified by immunofluorescence staining. Cell viability was assessed by the MTT assay, cell permeability was assessed by the FITC-dextran assay and cell mobility was assessed by the wound healing assay. Different miRNA and mRNA expression levels were determined by quantitative real-time polymerase chain reaction (RT-qPCR). The expression of tight junction-related proteins was determined by Western blot assay and immunofluorescence. The interaction between occludin and miR-132 was confirmed by a dual-luciferase reporter assay. We revealed that HG-treated ARPE-19 cells exhibited significantly increased miR-132 expression, decreased expression of the tight-junction markers including occludin and E-cadherin, and increased cell mobility and permeability. Occludin is a direct target of miR-132, which could regulate cell viability, mobility and permeability under HG condition through the JAK/STAT3 signaling pathway. These are the first data to suggest that miR-132 may contribute to the progression of diabetic retinopathy (DR) and that targeting the effect of miR-132 on occudin and the JAK/STAT3 pathway could represent a novel effective DR-treatment strategy.
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Affiliation(s)
- Shan-Shan Wang
- Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, P. R. China
| | - Xing Liao
- Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, P. R. China
| | - Fei Liu
- Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, P. R. China
| | - Qian Zhang
- Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, P. R. China
| | - Jing-Jing Qiu
- Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, P. R. China
| | - Shu-Hua Fu
- Department of Ophthalmology, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, P. R. China
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17
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Papadaki V, Asada K, Watson JK, Tamura T, Leung A, Hopkins J, Dellett M, Sasai N, Davaapil H, Nik-Zainal S, Longbottom R, Nakakido M, Torii R, Veerakumarasivam A, Kaneko S, Sagoo MS, Murphy G, Mitani A, Tsumoto K, Kelly JD, Hamamoto R, Ohnuma SI. Two Secreted Proteoglycans, Activators of Urothelial Cell-Cell Adhesion, Negatively Contribute to Bladder Cancer Initiation and Progression. Cancers (Basel) 2020; 12:E3362. [PMID: 33202923 PMCID: PMC7697838 DOI: 10.3390/cancers12113362] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 10/30/2020] [Accepted: 11/03/2020] [Indexed: 01/06/2023] Open
Abstract
Osteomodulin (OMD) and proline/arginine-rich end leucine repeat protein (PRELP) are secreted extracellular matrix proteins belonging to the small leucine-rich proteoglycans family. We found that OMD and PRELP were specifically expressed in umbrella cells in bladder epithelia, and their expression levels were dramatically downregulated in all bladder cancers from very early stages and various epithelial cancers. Our in vitro studies including gene expression profiling using bladder cancer cell lines revealed that OMD or PRELP application suppressed the cancer progression by inhibiting TGF-β and EGF pathways, which reversed epithelial-mesenchymal transition (EMT), activated cell-cell adhesion, and inhibited various oncogenic pathways. Furthermore, the overexpression of OMD in bladder cancer cells strongly inhibited the anchorage-independent growth and tumorigenicity in mouse xenograft studies. On the other hand, we found that in the bladder epithelia, the knockout mice of OMD and/or PRELP gene caused partial EMT and a loss of tight junctions of the umbrella cells and resulted in formation of a bladder carcinoma in situ-like structure by spontaneous breakdowns of the umbrella cell layer. Furthermore, the ontological analysis of the expression profiling of an OMD knockout mouse bladder demonstrated very high similarity with those obtained from human bladder cancers. Our data indicate that OMD and PRELP are endogenous inhibitors of cancer initiation and progression by controlling EMT. OMD and/or PRELP may have potential for the treatment of bladder cancer.
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Affiliation(s)
- Vasiliki Papadaki
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
- Institute of Fundamental Biological Research, Biomedical Sciences Research Center “Alexander Fleming”, 16672 Vari, Greece
| | - Ken Asada
- Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (K.A.); (S.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
| | - Julie K. Watson
- The Hutchison/MRC Research Centre, Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; (J.K.W.); (A.V.); (G.M.); (J.D.K.)
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
- Stem Cell Technologies, Building 7100, Cambridge Research Park, Beach Drive, Waterbeach, Cambridge CB25 9TL, UK
| | - Toshiya Tamura
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
- Integrated Biology, Research Division Axcelead Drug Discovery Partners, Inc. 26-1, Muraoka-Higashi 2-chome, Fujisawa, Kanagawa 251-0012, Japan
| | - Alex Leung
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
| | - Jack Hopkins
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
| | - Margaret Dellett
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
- C-TRIC, Altnagelvin Hospital Campus, NI Centre for Stratified Medicine, Glenshane Road, Derry/Londonderry BT47 6SB, UK
| | - Noriaki Sasai
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
- Developmental Biomedical Science, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5, Takayama-cho, Ikoma 630-0192, Japan
| | - Hongorzul Davaapil
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
- Cambridge Biomedical Campus, Jeffrey Cheah Biomedical Centre, Puddicombe Way, Wellcome—MRC Cambridge Stem Cell Institute, Cambridge CB2 0AW, UK
| | - Serena Nik-Zainal
- MRC Cancer Unit University of Cambridge Hutchison/MRC Research Centre, Box 197, Cambridge Biomedical Campus, Cambridge CB2 0XZ, UK;
- Academic Laboratory of Medical Genetics, Box 238, Lv 6 Addenbrooke’s Treatment Centre, Addenbrooke’s Hospital, Cambridge CB2 0QQ, UK
| | - Rebecca Longbottom
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
- Critical Care, University College London Hospital, 3rd floor, 235 Euston Road, London NW1 2PG, UK
| | - Makoto Nakakido
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
- Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;
| | - Ryo Torii
- Department of Mechanical Engineering, University College London, Torrington Place, London WC1E 7JE, UK;
| | - Abhi Veerakumarasivam
- The Hutchison/MRC Research Centre, Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; (J.K.W.); (A.V.); (G.M.); (J.D.K.)
- Department of Biological Sciences, School of Science and Technology, Sunway University, Bandar Sunway, Selangor Darul Ehsan 47500, Malaysia
| | - Syuzo Kaneko
- Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (K.A.); (S.K.)
| | - Mandeep S. Sagoo
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
- Retinoblastoma Service, Royal London Hospital, Whitechapel Road, London E1 1BB, UK
- Ocular Oncology Service, Moorfields Eye Hospital, City Road, London EC1V 2PD, UK
- National Institute for Health Research Biomedical Research Centre at Moorfields Eye Hospital NHS Foundation Trust and UCL Institute of Ophthalmology, City Road, London EC1V 2PD, UK
| | - Gillian Murphy
- The Hutchison/MRC Research Centre, Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; (J.K.W.); (A.V.); (G.M.); (J.D.K.)
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge CB2 0RE, UK
| | - Akihisa Mitani
- Department of Respiratory Medicine, The University of Tokyo Hospital, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan;
| | - Kohei Tsumoto
- Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;
| | - John D. Kelly
- The Hutchison/MRC Research Centre, Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; (J.K.W.); (A.V.); (G.M.); (J.D.K.)
- Division of Surgery and Interventional Science, University College London, 74 Huntley Street, London WC1E 6AU, UK
| | - Ryuji Hamamoto
- Division of Molecular Modification and Cancer Biology, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan; (K.A.); (S.K.)
- Cancer Translational Research Team, RIKEN Center for Advanced Intelligence Project, 1-4-1 Nihonbashi, Chuo-ku, Tokyo 103-0027, Japan
- The Hutchison/MRC Research Centre, Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; (J.K.W.); (A.V.); (G.M.); (J.D.K.)
- Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;
| | - Shin-ichi Ohnuma
- UCL Institute of Ophthalmology, University College London, 11-43 Bath Street, London EC1V 9EL, UK; (V.P.); (T.T.); (A.L.); (J.H.); (M.D.); (N.S.); (H.D.); (R.L.); (M.N.); (M.S.S.)
- The Hutchison/MRC Research Centre, Department of Oncology, University of Cambridge, Hills Road, Cambridge CB2 2XZ, UK; (J.K.W.); (A.V.); (G.M.); (J.D.K.)
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18
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Yang H, Le QV, Shim G, Oh YK, Shin YK. Molecular engineering of antibodies for site-specific conjugation to lipid polydopamine hybrid nanoparticles. Acta Pharm Sin B 2020; 10:2212-2226. [PMID: 33304787 PMCID: PMC7715496 DOI: 10.1016/j.apsb.2020.07.006] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/15/2020] [Accepted: 06/05/2020] [Indexed: 12/18/2022] Open
Abstract
Conjugation of antibodies to nanoparticles allows specific cancer targeting, but conventional conjugation methods generate heterogeneous conjugations that cannot guarantee the optimal orientation and functionality of the conjugated antibody. Here, a molecular engineering technique was used for site-specific conjugation of antibodies to nanoparticles. We designed an anti-claudin 3 (CLDN3) antibody containing a single cysteine residue, h4G3cys, then linked it to the maleimide group of lipid polydopamine hybrid nanoparticles (LPNs). Because of their negatively charged lipid coating, LPNs showed high colloidal stability and provided a functional surface for site-specific conjugation of h4G3cys. The activity of h4G3cys was tested by measuring the binding of h4G3cys-conjugated LPNs (C-LPNs) to CLDN3-positive tumor cells and assessing its subsequent photothermal effects. C-LPNsspecifically recognized CLDN3-overexpressing T47D breast cancer cells but not CLDN3-negative Hs578T breast cancer cells. High binding of C-LPNs to CLDN3-overexpressing T47D cells resulted in significantly higher temperature generation upon NIR irradiation and potent anticancer photothermal efficacy. Consistent with this, intravenous injection of C-LPNsin a T47D xenograft mouse model followed by NIR irradiation caused remarkable tumor ablation compared with other treatments through high temperature increases. Our results establish an accurate antibody-linking method and demonstrate the possibility of developing therapeutics using antibody-guided nanoparticles.
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Affiliation(s)
- Hobin Yang
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Quoc-Viet Le
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Gayong Shim
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Yu-Kyoung Oh
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
| | - Young Kee Shin
- Laboratory of Molecular Pathology and Cancer Genomics, College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
- Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul 08826, Republic of Korea
- Bio-MAX, Seoul National University, Seoul 08826, Republic of Korea
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19
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Tight Junction-Related CLDN5 and CLDN6 Genes, and Gap Junction-Related GJB6 and GJB7 Genes Are Somatically Mutated in Gastric and Colorectal Cancers. Pathol Oncol Res 2020; 26:1983-1987. [PMID: 32170581 DOI: 10.1007/s12253-020-00806-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2019] [Accepted: 03/08/2020] [Indexed: 12/24/2022]
Abstract
Tight junction and gap junction are major cell junctions that play important roles in cellular communication and structural integrity. Alterations of these junctions are known to be involved in cancer pathogenesis. Claudins and connexins are major tight and gap junction proteins, but genetic alterations of these genes have not been reported in gastric (GC) and colorectal cancers (CRC) with microsatellite instability (MSI). Claudin genes CLDN5 and CKDN6, and connexin genes GJB6 and GJB7 have mononucleotide repeats in the coding sequences that might be mutation targets in the cancers with MSI. We analyzed 79 GCs and 145 CRCs, and found CLDN5 frameshift mutations in 3 (3%) CRCs and 1 (2.9%) GC, CLDN6 frameshift mutations in 6 (6%) CRCs, GJB6 frameshift mutations in 5 (5%) CRCs and GJB7 frameshift mutation in one CRC (1%) with high MSI (MSI-H). We also analyzed intratumoral heterogeneity (ITH) of the frameshift mutations in 16 CRCs and found that CLDN6 and GJB6 frameshift mutations showed regional ITH in 2 (12.5%) and 2 (12.5%) cases, respectively. Our results show that CLDN5, CLDN6, GJB6 and GJB7 genes harbor not only frameshift mutations but also mutational ITH, which together may be features of GC and CRC with MSI-H. Based on the roles of cellular junctions in cancers, frameshift mutations of tight junction and gap junction genes might contribute to tumorigenesis by altering their functions in GC and CRC.
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20
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Pessôa MTC, Valadares JMM, Rocha SC, Silva SC, McDermott JP, Sánchez G, Varotti FP, Scavone C, Ribeiro RIMA, Villar JAFP, Blanco G, Barbosa LA. 21-Benzylidene digoxin decreases proliferation by inhibiting the EGFR/ERK signaling pathway and induces apoptosis in HeLa cells. Steroids 2020; 155:108551. [PMID: 31812624 PMCID: PMC7028499 DOI: 10.1016/j.steroids.2019.108551] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/07/2019] [Revised: 10/30/2019] [Accepted: 12/02/2019] [Indexed: 12/12/2022]
Abstract
Cardiotonic steroids (CTS) are agents traditionally known for their capacity to bind to the Na,K-ATPase (NKA), affecting the ion transport and the contraction of the heart. Natural CTS have been shown to also have effects on cell signaling pathways. With the goal of developing a new CTS derivative, we synthesized a new digoxin derivative, 21-benzylidene digoxin (21-BD). Previously, we have shown that this compound binds to NKA and has cytotoxic actions on cancer, but not on normal cells. Here, we further studied the mechanisms of actions of 21-BD. Working with HeLa cells, we found that 21-BD decreases the basal, as well as the insulin stimulated proliferation. 21-BD reduces phosphorylation of the epidermal growth factor receptor (EGFR) and extracellular-regulated kinase (ERK), which are involved in pathways that stimulate cell proliferation. In addition, 21-BD promotes apoptosis, which is mediated by the translocation of Bax from the cytosol to mitochondria and the release of mitochondrial cytochrome c to the cytosol. 21-BD also activated caspases-8, -9 and -3, and induced the cleavage of poly (ADP-ribose) polymerase-1 (PARP-1). Altogether, these results show that the new compound that we have synthesized exerts cytotoxic actions on HeLa cells by inhibition of cell proliferation and the activation of both the extrinsic and intrinsic apoptotic pathways. These results support the relevance of the cardiotonic steroid scaffold as modulators of cell signaling pathways and potential agents for their use in cancer.
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Affiliation(s)
- Marco Túlio C Pessôa
- Laboratório de Bioquímica Celular, Universidade Federal de São João del-Rei (UFSJ) Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - Jéssica M M Valadares
- Laboratório de Bioquímica Celular, Universidade Federal de São João del-Rei (UFSJ) Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - Sayonarah C Rocha
- Laboratório de Bioquímica Celular, Universidade Federal de São João del-Rei (UFSJ) Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - Simone C Silva
- Laboratório de Síntese Orgânica e Nanoestruturas, Universidade Federal de São João del-Rei (UFSJ) Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - Jeff P McDermott
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center (KUMC), Kansas City, KS, USA
| | - Gladis Sánchez
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center (KUMC), Kansas City, KS, USA
| | - Fernando P Varotti
- Núcleo de Pesquisa em Química Biológica (NQBio), Universidade Federal de São João del-Rei (UFSJ) Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - Cristóforo Scavone
- Laboratório de Neurofarmacologia Molecular, Departamento de Farmacologia, Instituto de Ciências Biomédicas, Universidade de São Paulo (USP), São Paulo, SP, Brazil
| | - Rosy I M A Ribeiro
- Laboratório de Patologia Experimental, Universidade Federal de São João del-Rei (UFSJ) Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - José A F P Villar
- Laboratório de Síntese Orgânica e Nanoestruturas, Universidade Federal de São João del-Rei (UFSJ) Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil
| | - Gustavo Blanco
- Department of Molecular and Integrative Physiology, University of Kansas Medical Center (KUMC), Kansas City, KS, USA
| | - Leandro A Barbosa
- Laboratório de Bioquímica Celular, Universidade Federal de São João del-Rei (UFSJ) Campus Centro-Oeste Dona Lindu, Divinópolis, MG, Brazil.
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21
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Singh AP, Mia MB, Saxena RK. Acid-functionalized single-walled carbon nanotubes alter epithelial tight junctions and enhance paracellular permeability. J Biosci 2020. [DOI: 10.1007/s12038-020-9989-9] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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22
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Tyrosine-Based Signals Regulate the Assembly of Daple⋅PARD3 Complex at Cell-Cell Junctions. iScience 2020; 23:100859. [PMID: 32058970 PMCID: PMC7005484 DOI: 10.1016/j.isci.2020.100859] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Revised: 11/27/2019] [Accepted: 01/16/2020] [Indexed: 01/06/2023] Open
Abstract
Polarized distribution of organelles and molecules inside a cell is vital for a range of cellular processes and its loss is frequently encountered in disease. Polarization during planar cell migration is a special condition in which cellular orientation is triggered by cell-cell contact. We demonstrate that the protein Daple (CCDC88C) is a component of cell junctions in epithelial cells which serves like a cellular “compass” for establishing and maintaining contact-triggered planar polarity. Furthermore, these processes may be mediated through interaction with the polarity regulator PARD3. This interaction, mediated by Daple's PDZ-binding motif (PBM) and the third PDZ domain of PARD3, is fine-tuned by tyrosine phosphorylation on Daple's PBM by receptor and non-receptor tyrosine kinases, such as Src. Hypophosphorylation strengthens the interaction, whereas hyperphosphorylation disrupts it, thereby revealing an unexpected role of Daple as a platform for signal integration and gradient sensing for tyrosine-based signals within the planar cell polarity pathway.
Daple localizes to cell junction, regulates planar cell migration Localization requires Daple's C-terminal PDZ-binding motif (PBM) The PBM binds a PDZ module of the polarity determinant PARD3 The Daple⋅PARD3 interaction is regulated by tyrosine-based signals
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23
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Salehi P, Tafvizi F, Kamyab Hesari K. Low Expression of Occludin in the Melanoma Patient. IRANIAN JOURNAL OF PATHOLOGY 2019; 14:272-278. [PMID: 31754355 PMCID: PMC6824771 DOI: 10.30699/ijp.2019.85213.1801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/22/2018] [Accepted: 01/12/2019] [Indexed: 12/22/2022]
Abstract
BACKGROUND & OBJECTIVE Malignant melanoma is the fatal cutaneous neoplasm which is curable by the early diagnosis. The expression of occludin protein which is an integral membrane protein is altered in an epithelial-to-mesenchymal transition. Although, recent studies provide sufficient evidence supporting the functional importance of occludin in cancer, the prognostic significance of occludin expression levels in melanoma remains obscure. The aim of this study was to determine occludin expression level and its correlation with clinicopathological features of the patients with melanoma. METHODS The occludin mRNA level was compared between paraffin-embedded tissues of 40 patients with melanoma and 10 subjects with normal skin. The quality and quantity of the RNA was determined and occludin expression level was measured using Real-time PCR and ∆∆CT computational technique. RESULTS The occludin mRNA level reduced five-fold in the melanoma patients compared to the control group (P=0.000). No significant difference was observed between male and female cases (P=0.533). No significant correlation was observed between occludin mRNA level, mitotic count (P=0.252), and Breslow levels (P=0.171). CONCLUSION We can conclude that down-regulation of occludin expression in the patients with melanoma is a hallmark of cancer progression and it might be used as a prognostic factor. No significant correlation was found between occludin gene expression and clinicopathological characteristics including Clark level, Breslow staging, mitotic count, age and gender (P<0.05).
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Affiliation(s)
- Pouri Salehi
- Department of Biology, Parand Branch, Islamic Azad University, Parand, Iran
| | - Farzaneh Tafvizi
- Department of Biology, Parand Branch, Islamic Azad University, Parand, Iran
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24
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Malik S, Zafar Paracha R, Khalid M, Nisar M, Siddiqa A, Hussain Z, Nawaz R, Ali A, Ahmad J. MicroRNAs and their target mRNAs as potential biomarkers among smokers and non-smokers with lung adenocarcinoma. IET Syst Biol 2019; 13:69-76. [PMID: 33444474 PMCID: PMC8687273 DOI: 10.1049/iet-syb.2018.5040] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 07/17/2018] [Accepted: 08/06/2018] [Indexed: 01/09/2023] Open
Abstract
Lung adenocarcinoma is one of the major causes of mortality. Current methods of diagnosis can be improved through identification of disease specific biomarkers. MicroRNAs are small non-coding regulators of gene expression, which can be potential biomarkers in various diseases. Thus, the main objective of this study was to gain mechanistic insights into genetic abnormalities occurring in lung adenocarcinoma by implementing an integrative analysis of miRNAs and mRNAs expression profiles in the case of both smokers and non-smokers. Differential expression was analysed by comparing publicly available lung adenocarcinoma samples with controls. Furthermore, weighted gene co-expression network analysis is performed which revealed mRNAs and miRNAs significantly correlated with lung adenocarcinoma. Moreover, an integrative analysis resulted in identification of several miRNA-mRNA pairs which were significantly dysregulated in non-smokers with lung adenocarcinoma. Also two pairs (miR-133b/Protein Kinase C Zeta (PRKCZ) and miR-557/STEAP3) were found specifically dysregulated in smokers. Pathway analysis further revealed their role in important signalling pathways including cell cycle. This analysis has not only increased the authors' understanding about lung adenocarcinoma but also proposed potential biomarkers. However, further wet laboratory studies are required for the validation of these potential biomarkers which can be used to diagnose lung adenocarcinoma.
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Affiliation(s)
- Sumaria Malik
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Rehan Zafar Paracha
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Maryam Khalid
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Maryum Nisar
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Amnah Siddiqa
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Zamir Hussain
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
| | - Raheel Nawaz
- School of ComputingMathematics and Digital Technology, Manchester Metropolitan UniversityGM459 Geoffrey Manton BuildingManchesterEngland
| | - Amjad Ali
- Atta‐ur‐Rahman School of Applied Biosciences – ASABNational University of Sciences and Technology (NUST)Sector H‐ 12IslamabadPakistan
| | - Jamil Ahmad
- Research Center For Modeling & Simulation (RCMS)National University of Sciences and Technology (NUST)Sector H‐12IslamabadPakistan
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25
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Orlandella FM, Mariniello RM, Iervolino PLC, Auletta L, De Stefano AE, Ugolini C, Greco A, Mirabelli P, Pane K, Franzese M, Denaro M, Basolo F, Salvatore G. Junctional adhesion molecule-A is down-regulated in anaplastic thyroid carcinomas and reduces cancer cell aggressiveness by modulating p53 and GSK3 α/β pathways. Mol Carcinog 2019; 58:1181-1193. [PMID: 30834573 DOI: 10.1002/mc.23001] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2018] [Revised: 01/23/2019] [Accepted: 02/18/2019] [Indexed: 01/27/2023]
Abstract
Junctional adhesion molecule A (JAM-A) is a transmembrane protein that contributes to different biological process, including the epithelial to mesenchymal transition (EMT). Through an EMT profiler array, we explored the molecular players associated with human thyroid cancer progression and identified JAM-A as one of the genes mostly deregulated. The quantitative real-time polymerase chain reaction and immunohistochemistry analyses showed that downregulation of JAM-A occurred in anaplastic thyroid carcinoma (ATC) compared with normal thyroid (NT) and papillary thyroid carcinoma (PTC) tissues and correlated with extrathyroid infiltration, tumor size, and ATC histotype. In ATC cell lines, JAM-A restoration suppressed malignant hallmarks of transformation including cell proliferation, motility, and transendothelial migration. Accordingly, knockdown of JAM-A enhanced thyroid cancer cell proliferation and motility in PTC cells. Through the proteome profiler human phospho-kinase array, we demonstrated that higher expression of JAM-A was associated with a significant increased level of phosphorylation of p53 and GSK3 α/β proteins. In conclusion, our findings highlight a novel role of JAM-A in thyroid cancer progression and suggest that JAM-A restoration could have potential clinical relevance in thyroid cancer treatment.
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Affiliation(s)
| | - Raffaela Mariarosaria Mariniello
- Dipartimento di Scienze Motorie e del Benessere, Università "Parthenope", Napoli, Italy.,CEINGE-Biotecnologie Avanzate S.c.a.r.l., Napoli, Italy
| | | | | | | | - Clara Ugolini
- Dipartimento di Area Medica, Azienda Ospedaliero Universitaria pisana, Pisa, Italy
| | - Adelaide Greco
- Dipartimento di Scienze Biomediche Avanzate, Università Federico II, Napoli, Italy.,Istituto di Biostrutture e Bioimmagini, CNR, Napoli, Italy
| | | | | | | | - Maria Denaro
- Dipartimento di Patologia Chirugica, Medica, Molecolare e dell'Area Critica dell' Università di Pisa, Pisa, Italy
| | - Fulvio Basolo
- Dipartimento di Patologia Chirugica, Medica, Molecolare e dell'Area Critica dell' Università di Pisa, Pisa, Italy
| | - Giuliana Salvatore
- IRCCS SDN, Napoli, Italy.,Dipartimento di Scienze Motorie e del Benessere, Università "Parthenope", Napoli, Italy
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26
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Tabariès S, McNulty A, Ouellet V, Annis MG, Dessureault M, Vinette M, Hachem Y, Lavoie B, Omeroglu A, Simon HG, Walsh LA, Kimbung S, Hedenfalk I, Siegel PM. Afadin cooperates with Claudin-2 to promote breast cancer metastasis. Genes Dev 2019; 33:180-193. [PMID: 30692208 PMCID: PMC6362814 DOI: 10.1101/gad.319194.118] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2018] [Accepted: 11/19/2018] [Indexed: 01/04/2023]
Abstract
Tabariès et al. show that signaling downstream from a Claudin-2/Afadin complex enables the efficient formation of breast cancer metastases. Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that the PDZ-binding motif of Claudin-2 is necessary for anchorage-independent growth of cancer cells and is required for liver metastasis. Several PDZ domain-containing proteins were identified that interact with the PDZ-binding motif of Claudin-2 in liver metastatic breast cancer cells, including Afadin, Arhgap21, Pdlim2, Pdlim7, Rims2, Scrib, and ZO-1. We specifically examined the role of Afadin as a potential Claudin-2-interacting partner that promotes breast cancer liver metastasis. Afadin associates with Claudin-2, an interaction that requires the PDZ-binding motif of Claudin-2. Loss of Afadin also impairs the ability of breast cancer cells to form colonies in soft agar and metastasize to the lungs or liver. Immunohistochemical analysis of Claudin-2 and/or Afadin expression in 206 metastatic breast cancer tumors revealed that high levels of both Claudin-2 and Afadin in primary tumors were associated with poor disease-specific survival, relapse-free survival, lung-specific relapse, and liver-specific relapse. Our findings indicate that signaling downstream from a Claudin-2/Afadin complex enables the efficient formation of breast cancer metastases. Moreover, combining Claudin-2 and Afadin as prognostic markers better predicts the potential of breast cancer to metastasize to soft tissues.
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Affiliation(s)
- Sébastien Tabariès
- Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Medicine, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Alexander McNulty
- Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Biochemistry, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Véronique Ouellet
- Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montréal, Québec H2X 0A9, Canada
| | - Matthew G Annis
- Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Medicine, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Mireille Dessureault
- Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Medicine, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Maude Vinette
- Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Medicine, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Yasmina Hachem
- Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Biochemistry, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Brennan Lavoie
- Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Medicine, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Atilla Omeroglu
- Department of Pathology, McGill University Health Centre, Montréal, Québec H4A 3J1, Canada
| | - Hans-Georg Simon
- Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60614, USA.,Stanley Manne Children's Research Institute, Chicago, Illinois 60614, USA
| | - Logan A Walsh
- Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Human Genetics, McGill University, Montréal, Québec H3A 1A3, Canada
| | - Siker Kimbung
- Division of Oncology, Department of Clinical Sciences, Lund University, Lund SE 221 00, Sweden
| | - Ingrid Hedenfalk
- Division of Oncology, Department of Clinical Sciences, Lund University, Lund SE 221 00, Sweden
| | - Peter M Siegel
- Goodman Cancer Research Centre, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Medicine, McGill University, Montréal, Québec H3A 1A3, Canada.,Department of Biochemistry, McGill University, Montréal, Québec H3A 1A3, Canada
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27
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Wang HF, Ran R, Liu Y, Hui Y, Zeng B, Chen D, Weitz DA, Zhao CX. Tumor-Vasculature-on-a-Chip for Investigating Nanoparticle Extravasation and Tumor Accumulation. ACS NANO 2018; 12:11600-11609. [PMID: 30380832 DOI: 10.1021/acsnano.8b06846] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/17/2023]
Abstract
Nanoparticle tumor accumulation relies on a key mechanism, the enhanced permeability and retention (EPR) effect, but it remains challenging to decipher the exact impact of the EPR effect. Animal models in combination with imaging modalities are useful, but it is impossible to delineate the roles of multiple biological barriers involved in nanoparticle tumor accumulation. Here we report a microfluidic tumor-vasculature-on-a-chip (TVOC) mimicking two key biological barriers, namely, tumor leaky vasculature and 3D tumor tissue with dense extracellular matrix (ECM), to study nanoparticle extravasation through leaky vasculature and the following accumulation in tumor tissues. Intact 3D tumor vasculature was developed with selective permeability of small molecules (20 kDa) but not large ones (70 kDa). The permeability was further tuned by cytokine stimulation, demonstrating the independent control of the leaky tumor vasculature. Combined with tumor spheroids in dense ECM, our TVOC model is capable of predicting nanoparticles' in vivo tumor accumulation, thus providing a powerful platform for nanoparticle evaluation.
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Affiliation(s)
- Hao-Fei Wang
- Australian Institute for Bioengineering and Nanotechnology , The University of Queensland , St Lucia , QLD 4072 , Australia
| | - Rui Ran
- Australian Institute for Bioengineering and Nanotechnology , The University of Queensland , St Lucia , QLD 4072 , Australia
| | - Yun Liu
- Australian Institute for Bioengineering and Nanotechnology , The University of Queensland , St Lucia , QLD 4072 , Australia
| | - Yue Hui
- Australian Institute for Bioengineering and Nanotechnology , The University of Queensland , St Lucia , QLD 4072 , Australia
| | - Bijun Zeng
- Diamantina Institute , The University of Queensland , St Lucia , QLD 4072 , Australia
| | - Dong Chen
- State Key Laboratory of Fluid Power and Mechatronic Systems , Zhejiang University , Zheda Road, No. 38 , Hangzhou , 310027 , People's Republic of China
- Institute of Process Equipment, College of Energy Engineering , Zhejiang University , Zheda Road, No. 38 , Hangzhou , 310027 , People's Republic of China
| | - David A Weitz
- John A. Paulson School of Engineering and Applied Sciences and Department of Physics , Harvard University , Cambridge , Massachusetts 02138 , United States
| | - Chun-Xia Zhao
- Australian Institute for Bioengineering and Nanotechnology , The University of Queensland , St Lucia , QLD 4072 , Australia
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Dietary cholesterol promotes steatohepatitis related hepatocellular carcinoma through dysregulated metabolism and calcium signaling. Nat Commun 2018; 9:4490. [PMID: 30367044 PMCID: PMC6203711 DOI: 10.1038/s41467-018-06931-6] [Citation(s) in RCA: 144] [Impact Index Per Article: 20.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 10/01/2018] [Indexed: 01/03/2023] Open
Abstract
The underlining mechanisms of dietary cholesterol and nonalcoholic steatohepatitis (NASH) in contributing to hepatocellular carcinoma (HCC) remain undefined. Here we demonstrated that high-fat-non-cholesterol-fed mice developed simple steatosis, whilst high-fat-high-cholesterol-fed mice developed NASH. Moreover, dietary cholesterol induced larger and more numerous NASH-HCCs than non-cholesterol-induced steatosis-HCCs in diethylnitrosamine-treated mice. NASH-HCCs displayed significantly more aberrant gene expression-enriched signaling pathways and more non-synonymous somatic mutations than steatosis-HCCs (335 ± 84/sample vs 43 ± 13/sample). Integrated genetic and expressional alterations in NASH-HCCs affected distinct genes pertinent to five pathways: calcium, insulin, cell adhesion, axon guidance and metabolism. Some of the novel aberrant gene expression, mutations and core oncogenic pathways identified in cholesterol-associated NASH-HCCs in mice were confirmed in human NASH-HCCs, which included metabolism-related genes (ALDH18A1, CAD, CHKA, POLD4, PSPH and SQLE) and recurrently mutated genes (RYR1, MTOR, SDK1, CACNA1H and RYR2). These findings add insights into the link of cholesterol to NASH and NASH-HCC and provide potential therapeutic targets.
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HER2 Basolateral versus Circumferential IHC Expression Is Dependent on Polarity and Differentiation of Epithelial Cells in Gastric/GE Adenocarcinoma. PATHOLOGY RESEARCH INTERNATIONAL 2018; 2018:6246493. [PMID: 30140423 PMCID: PMC6081602 DOI: 10.1155/2018/6246493] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 02/15/2018] [Accepted: 06/21/2018] [Indexed: 02/06/2023]
Abstract
Aim Antigenic expression in epithelial cells can be heterogeneous which may pose a problem in immunohistochemical (IHC) analysis of tumor markers, in particular, predictive markers like HER2. Studies have shown that epithelial cells have distinct apical and basolateral domains which are separated by tight junctions. The cell membrane in these two domains has a different composition of macromolecules and hence can have variable antigen expression on immunohistochemistry. In our study, we aimed to investigate this phenomenon of basolateral versus circumferential IHC staining of HER2 in gastric/GE adenocarcinoma. Methods We selected 45 cases of gastric/GE adenocarcinoma and evaluated equal number of specimens (15 each) showing well-differentiated, moderately differentiated, and poorly differentiated morphology. All cases had 3+ HER2 score as per CAP guidelines. HER2-membrane staining pattern in all specimens was analyzed. Results Cases with well-differentiated morphology showed only basolateral or lateral membrane staining in most cases. Poorly differentiated adenocarcinoma samples showed circumferential staining (both basolateral and luminal) in all cases with highly significant p value. Mixed staining pattern was observed in moderately differentiated cases. Diffuse expression of E-cadherin in well-differentiated adenocarcinoma and loss in poorly differentiated tumors were also statistically significant. Conclusion These findings suggest that HER2 in gastric epithelium has a polarized distribution which is maintained by the fence function of tight junctions. With progression to high grade cancer, the glandular structural differentiation in gastric mucosa is lost, along with disruption of tight junctions. This leads to loss of cell polarity and migration of antigens across the membrane.
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30
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Silencing of casein kinase 1 delta reduces migration and metastasis of triple negative breast cancer cells. Oncotarget 2018; 9:30821-30836. [PMID: 30112110 PMCID: PMC6089398 DOI: 10.18632/oncotarget.25738] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Accepted: 06/22/2018] [Indexed: 12/21/2022] Open
Abstract
The casein kinase 1 delta (CSNK1D) is a conserved serine/threonine protein kinase that regulates diverse cellular processes including cell cycle progression, circadian rhythm, and neurite outgrowth. Aberrant expression of CSNK1D is described in several cancer types including breast cancer, where it is amplified in about 30% of triple negative breast (TNBC). Here, we have investigated the function of CSNK1D in triple negative cancer cell migration and metastasis. By using immunohistochemistry and in situ hybridization, we found that CNSK1D is highly expressed in primary tumor cells and in tumor cells invading lymphatic nodes compared to non-metastatic tumors. In vitro, knock-down of CSNK1D expression with specific shRNAs in the breast cancer cell line MDA-MB-231 markedly inhibited cancer cell proliferation, invasion and migration and affected the expression of the tight junction proteins claudin 1, occludin and the junction adhesion molecule A. In vivo, the inactivation of CSNK1D reduced lung metastasis in MDA-MB-231 breast cancer xenografts. Altogether, our results indicate that the downregulation of CSNK1D expression inhibits the proliferation and reduces the migration and the metastasis of breast cancer cells. As numerous inhibitors of CSNK1D are currently under development, this might represent an attractive therapeutic target for the treatment of TNBC.
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31
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Abstract
Functional and genomic heterogeneity of individual cells are central players in a broad spectrum of normal and disease states. Our knowledge about the role of cellular heterogeneity in tissue and organism function remains limited due to analytical challenges one encounters when performing single cell studies in the context of cell-cell interactions. Information based on bulk samples represents ensemble averages over populations of cells, while data generated from isolated single cells do not account for intercellular interactions. We describe a new technology and demonstrate two important advantages over existing technologies: first, it enables multiparameter energy metabolism profiling of small cell populations (<100 cells)—a sample size that is at least an order of magnitude smaller than other, commercially available technologies; second, it can perform simultaneous real-time measurements of oxygen consumption rate (OCR), extracellular acidification rate (ECAR), and mitochondrial membrane potential (MMP)—a capability not offered by any other commercially available technology. Our results revealed substantial diversity in response kinetics of the three analytes in dysplastic human epithelial esophageal cells and suggest the existence of varying cellular energy metabolism profiles and their kinetics among small populations of cells. The technology represents a powerful analytical tool for multiparameter studies of cellular function.
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32
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Tsai HW, Huang MT, Wang PH, Huang BS, Chen YJ, Hsieh SL. Decoy receptor 3 promotes cell adhesion and enhances endometriosis development. J Pathol 2017; 244:189-202. [PMID: 29057478 DOI: 10.1002/path.5000] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2017] [Revised: 09/07/2017] [Accepted: 10/17/2017] [Indexed: 02/06/2023]
Abstract
Endometriosis is a multifactorial inflammatory disease with persistent activation of the nuclear factor-κB (NF-κB) signalling pathway. Aberrant adhesion of endometrium is the essential step in the progression of endometriosis, but the molecular mechanism of ectopic growth of endometrium is still unclear. Decoy receptor 3 (DcR3)/TNFRSF6B, a pleiotropic immunomodulator regulated by oestrogen, is able to activate focal adhesion kinase to promote cell adhesion. We found that DcR3 is upregulated in human ectopic endometrial cells via activation of the Akt-NF-κB signalling pathway, and its expression level correlates positively with that of the adhesion molecules intercellular adhesion molecule 1 (ICAM-1) and homing cell adhesion molecule (HCAM; CD44). In a multivariate regression model, DcR3 expression level was the most significant parameter associated with endometriosis severity. Knockdown of DcR3 not only downregulated the expression of ICAM-1 and HCAM, but also reduced cell adhesion and migration. In vivo investigation further showed that DcR3 promoted the growth and spread of endometrium, whereas knockdown of DcR3 by lentivirus-delivered short hairpin RNA inhibited ectopic adhesion of endometrium and abrogated endometriosis progression. These observations are in support of DcR3 playing a critical role in the pathogenesis of endometriosis, and the inhibition of DcR3 expression being a promising approach for the treatment of endometriosis. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Affiliation(s)
- Hsiao-Wen Tsai
- Department of Obstetrics and Gynaecology, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.,Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan.,School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan
| | | | - Peng-Hui Wang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Obstetrics and Gyneacology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Ben-Shian Huang
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Obstetrics and Gyneacology, Taipei Veterans General Hospital, Taipei, Taiwan
| | - Yi-Jen Chen
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,School of Medicine, National Yang-Ming University, Taipei, Taiwan.,Department of Obstetrics and Gyneacology, Taipei Veterans General Hospital, Taipei, Taiwan.,Cheng-Hsin General Hospital, Taipei, Taiwan
| | - Shie-Liang Hsieh
- Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.,Genomics Research Centre, Academia Sinica, Taipei, Taiwan.,Department of Medical Research and Education, Taipei Veterans General Hospital, Taipei, Taiwan.,Institute for Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan
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Galadari S, Rahman A, Pallichankandy S, Thayyullathil F. Molecular targets and anticancer potential of sanguinarine-a benzophenanthridine alkaloid. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2017; 34:143-153. [PMID: 28899497 DOI: 10.1016/j.phymed.2017.08.006] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2016] [Revised: 07/06/2017] [Accepted: 08/06/2017] [Indexed: 05/03/2023]
Abstract
BACKGROUND Cancer is an enormous global health burden, and should be effectively addressed with better therapeutic strategies. Currently, over 60% of the clinically approved anticancer agents are either directly isolated from natural sources or are modified from natural lead molecules. Sanguinarine (SNG), a quaternary benzophenanthridine alkaloid has gained increasing attention in recent years as a potential anticancer agent. PURPOSE There is a large untapped source of phytochemical-based anticancer agents remaining to be explored. This review article aims to recapitulate different anticancer properties of SNG, and describes some of the molecular targets involved in exerting its effect. It also depicts the pharmacokinetic and toxicological properties of SNG, two parameters important in determining the druggability of a molecule. METHODS Numerous in vivo and in vitro published studies have signified the anticancer properties of SNG. In order to collate and decipher these properties, an extensive literature search was conducted in PubMed, ScienceDirect, and Scopus using keywords followed by the evaluation of the relevant articles where the relevant reports are integrated and analyzed. RESULTS Apart from inducing cell death, SNG inhibits pro-tumorigenic processes such as invasion, angiogenesis, and metastasis in different cancers. Moreover, SNG has been shown to synergistically enhance the sensitivity of several chemotherapeutic agents and is effective against a variety of multi-drug resistant cancers.
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Affiliation(s)
- Sehamuddin Galadari
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island Campus, Abu Dhabi, UAE.
| | - Anees Rahman
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island Campus, Abu Dhabi, UAE.
| | - Siraj Pallichankandy
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island Campus, Abu Dhabi, UAE.
| | - Faisal Thayyullathil
- Cell Death Signaling Laboratory, Division of Science (Biology), Experimental Research Building, New York University Abu Dhabi, PO Box 129188, Saadiyat Island Campus, Abu Dhabi, UAE.
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Chavarría-Velázquez CO, Torres-Martínez AC, Montaño LF, Rendón-Huerta EP. TLR2 activation induced by H. pylori LPS promotes the differential expression of claudin-4, -6, -7 and -9 via either STAT3 and ERK1/2 in AGS cells. Immunobiology 2017; 223:38-48. [PMID: 29031421 DOI: 10.1016/j.imbio.2017.10.016] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2017] [Revised: 06/28/2017] [Accepted: 10/03/2017] [Indexed: 01/14/2023]
Abstract
Gastric carcinogenesis has been associated to H. pylori virulence factors that induce a chronic inflammation process. Lipopolysaccharides play a role in chronic inflammatory responses via TLR2- and TLR4-dependent signaling pathways. Similarly, cellular invasiveness, metastatic potential and prognosis are usually associated to claudin-4, -6, -7 and -9 expression in gastric carcinogenesis. Therefore, the aim of this study was to determine if H. pylori LPS exerts an influence on carcinogenesis-related claudin expression and if it was directly regulated through the TLR2 pathway. Human antrum gastric adenocarcinoma AGS cells exposed or not to H. pylori LPS were used. Polyclonal anti-claudin-4, -6, -7 and -9, anti-TLR2, anti-pERK1/2 as well as rabbit monoclonal anti-pNFκB p65 and mouse monoclonal anti-CdX2 were used. ERK1/2 inhibitor UO126 and STAT3 inhibitor Stattic were also used. Western blot, immunofluorescence and confocal experiments were performed in whole cells as well as total protein, nuclear and cell membrane fractions. The results showed that H. pylori LPS increased the expression of TLR2 in a time dependent bi-phasic manner (<12 and >12h exposure). Immunofluorescence using AGS monolayers corroborated the double phase TLR2 expression mainly on the cell membrane but a detectable signal was also determined in the cytoplasm of the cells. Activation of NFkB was downstream and depended on TLR2 expression as a statistically significant increase in pNFkB, that followed a pattern highly similar to the TLR2 expression was observed on the cell membrane fraction. The increase in TLR2 expression was accompanied by dramatically increased claudin-4 expression in cultures exposed from 30m to 8h to LPS. Increased expression of claudin-6, -7 and -9 also increases in >12h LPS exposure times. The increase in claudins expression was also dependent on NFkB activation. The results also showed an increase in pSTAT3 that followed a bi-phasic pattern that began 30min after stimulation and was compatible with the increase in TLR2 expression. The expression of the claudin-4 related CDX2 transcription factor did not followed the biphasic pattern. The results also showed that claudin-4 expression was STAT3 dependent whereas claudin-6, 7 and 9 expressions was ERK1/2 dependent. Our results suggest that H. pylori LPS induces TLR2 expression in the AGS cells, and that the longer the exposure to LPS, the greater the expression of TLR2 in the cell membrane. Consequently the expression of claudin-4, -6, -7 and -9 also increases.
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Affiliation(s)
| | - Ana C Torres-Martínez
- Laboratorio de Inmunobiología, Depto. Biología Celular y Tisular, Facultad de Medicina, UNAM, Mexico
| | - Luis F Montaño
- Laboratorio de Inmunobiología, Depto. Biología Celular y Tisular, Facultad de Medicina, UNAM, Mexico
| | - Erika P Rendón-Huerta
- Laboratorio de Inmunobiología, Depto. Biología Celular y Tisular, Facultad de Medicina, UNAM, Mexico.
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35
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Peterson TA, Gauran IIM, Park J, Park D, Kann MG. Oncodomains: A protein domain-centric framework for analyzing rare variants in tumor samples. PLoS Comput Biol 2017; 13:e1005428. [PMID: 28426665 PMCID: PMC5398485 DOI: 10.1371/journal.pcbi.1005428] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Accepted: 02/28/2017] [Indexed: 12/28/2022] Open
Abstract
The fight against cancer is hindered by its highly heterogeneous nature. Genome-wide sequencing studies have shown that individual malignancies contain many mutations that range from those commonly found in tumor genomes to rare somatic variants present only in a small fraction of lesions. Such rare somatic variants dominate the landscape of genomic mutations in cancer, yet efforts to correlate somatic mutations found in one or few individuals with functional roles have been largely unsuccessful. Traditional methods for identifying somatic variants that drive cancer are 'gene-centric' in that they consider only somatic variants within a particular gene and make no comparison to other similar genes in the same family that may play a similar role in cancer. In this work, we present oncodomain hotspots, a new 'domain-centric' method for identifying clusters of somatic mutations across entire gene families using protein domain models. Our analysis confirms that our approach creates a framework for leveraging structural and functional information encapsulated by protein domains into the analysis of somatic variants in cancer, enabling the assessment of even rare somatic variants by comparison to similar genes. Our results reveal a vast landscape of somatic variants that act at the level of domain families altering pathways known to be involved with cancer such as protein phosphorylation, signaling, gene regulation, and cell metabolism. Due to oncodomain hotspots' unique ability to assess rare variants, we expect our method to become an important tool for the analysis of sequenced tumor genomes, complementing existing methods.
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Affiliation(s)
- Thomas A. Peterson
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
- University of California, San Francisco, Institute for Computational Health Science, San Francisco, California, United States of America
| | - Iris Ivy M. Gauran
- Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
| | - Junyong Park
- Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
| | - DoHwan Park
- Department of Mathematics and Statistics, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
| | - Maricel G. Kann
- Department of Biological Sciences, University of Maryland, Baltimore County, Baltimore, Maryland, United States of America
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36
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Torres-Martínez AC, Gallardo-Vera JF, Lara-Holguin AN, Montaño LF, Rendón-Huerta EP. Claudin-6 enhances cell invasiveness through claudin-1 in AGS human adenocarcinoma gastric cancer cells. Exp Cell Res 2016; 350:226-235. [PMID: 27914788 DOI: 10.1016/j.yexcr.2016.11.025] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Revised: 10/28/2016] [Accepted: 11/29/2016] [Indexed: 10/20/2022]
Abstract
Claudins participate in tissue barrier function. The loss of this barrier is associated to metalloproteases-related extracellular matrix and basal membranes degradation. Claudin-1 is a pro-MMP-2 activator and claudin-6 transfected AGS (AGS-Cld6) cells are highly invasive. Our aim was to determine if claudin-6 was direct or indirectly associated with MMP-2 activation and cell invasiveness. Cytofluorometry, cell fractioning, immunoprecipitation, gelatin-zymography, cell migration and invasiveness assays were performed, claudin-2, -6, -7 and -9 transfected AGS cells, anti-MMP-2, -9 and -14, anti-claudins specific antibodies and claudin-1 small interfering RNA were used. The results showed a significant (p<0.001) overexpression of claudin-1 in AGS-Cld6 cell membranes. A strong MMP-2 activity was identified in culture supernatants of AGS-Cld6. Claudin-1 co-localized with MMP-2 and MMP-14; interestingly a significant increase in cell membrane and cytosol MMP-14 expression was detected in AGS-Cld6 cells (p<0.05). Silencing of claudin-1 in AGS-Cld6 cells showed a 60% MMP-2 activity decrease in culture supernatants and a significant decrease (p<0.05) in cell migration and invasiveness. Our results suggest that claudin-6 induces MMP-2 activation through claudin-1 membrane expression, which in turn promotes cell migration and invasiveness.
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Affiliation(s)
- A C Torres-Martínez
- Laboratorio de Inmunobiología, Departmento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Circuito Interior s/n, Ciudad Universitaria, México D.F. 04510, Mexico
| | - J F Gallardo-Vera
- Laboratorio de Inmunobiología, Departmento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Circuito Interior s/n, Ciudad Universitaria, México D.F. 04510, Mexico
| | - A N Lara-Holguin
- Laboratorio de Inmunobiología, Departmento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Circuito Interior s/n, Ciudad Universitaria, México D.F. 04510, Mexico
| | - L F Montaño
- Laboratorio de Inmunobiología, Departmento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Circuito Interior s/n, Ciudad Universitaria, México D.F. 04510, Mexico
| | - E P Rendón-Huerta
- Laboratorio de Inmunobiología, Departmento de Biología Celular y Tisular, Facultad de Medicina, UNAM, Circuito Interior s/n, Ciudad Universitaria, México D.F. 04510, Mexico.
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Abstract
IQGAP1 is a scaffold protein involved in the assembly of adherens junctions. Our work has recently revealed a novel role for IQGAP1 in the regulation of tight junctions (TJ) through differential recruitment of claudins to the nascent TJ. Here, we discuss the potential mechanisms of this regulation, including IQGAP1 effects on CDC42, and IQGAP1 interactions with sorting/trafficking molecules (e.g. Exo70). Given the many roles of IQGAP1 and the large number of interacting partners, we focus our discussion of these functions in the context of junction formation, trafficking, growth factor signaling and cancer. We also propose a potential role for IQGAP1 in regulating epithelial integrity and compartmentalized signaling in epithelia.
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Affiliation(s)
- Barbara E Tanos
- a Division of Cancer Therapeutics, The Institute of Cancer Research , London , UK
| | - Charles Yeaman
- b Department of Anatomy and Cell Biology , The University of Iowa , Iowa City , IA , USA
| | - Enrique Rodriguez-Boulan
- c Department of Ophthalmology , Margaret Dyson Vision Research Institute, Weill Cornell Medical College , New York , NY , USA.,d Department of Cell and Developmental Biology , Weill Cornell Medical College , New York , NY , USA
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38
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Long NP, Lee WJ, Huy NT, Lee SJ, Park JH, Kwon SW. Novel Biomarker Candidates for Colorectal Cancer Metastasis: A Meta-analysis of In Vitro Studies. Cancer Inform 2016; 15:11-7. [PMID: 27688707 PMCID: PMC5034882 DOI: 10.4137/cin.s40301] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2016] [Revised: 08/15/2016] [Accepted: 08/16/2016] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common and lethal cancers. Although numerous studies have evaluated potential biomarkers for early diagnosis, current biomarkers have failed to reach an acceptable level of accuracy for distant metastasis. In this paper, we performed a gene set meta-analysis of in vitro microarray studies and combined the results from this study with previously published proteomic data to validate and suggest prognostic candidates for CRC metastasis. Two microarray data sets included found 21 significant genes. Of these significant genes, ALDOA, IL8 (CXCL8), and PARP4 had strong potential as prognostic candidates. LAMB2, MCM7, CXCL23A, SERPINA3, ABCA3, ALDH3A2, and POLR2I also have potential. Other candidates were more controversial, possibly because of the biologic heterogeneity of tumor cells, which is a major obstacle to predicting metastasis. In conclusion, we demonstrated a meta-analysis approach and successfully suggested ten biomarker candidates for future investigation.
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Affiliation(s)
| | | | - Nguyen Truong Huy
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Seul Ji Lee
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Jeong Hill Park
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
| | - Sung Won Kwon
- College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, Korea
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Suhovskih AV, Kashuba VI, Klein G, Grigorieva EV. Prostate cancer cells specifically reorganize epithelial cell-fibroblast communication through proteoglycan and junction pathways. Cell Adh Migr 2016; 11:39-53. [PMID: 27111714 DOI: 10.1080/19336918.2016.1182292] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/31/2023] Open
Abstract
Microenvironment and stromal fibroblasts are able to inhibit tumor cell proliferation both through secreted signaling molecules and direct cell-cell interactions but molecular mechanisms of these effects remain unclear. In this study, we investigated a role of cell-cell contact-related molecules (protein ECM components, proteoglycans (PGs) and junction-related molecules) in intercellular communications between the human TERT immortalized fibroblasts (BjTERT fibroblasts) and normal (PNT2) or cancer (LNCaP, PC3, DU145) prostate epithelial cells. It was shown that BjTERT-PNT2 cell coculture resulted in significant decrease of both BjTERT and PNT2 proliferation rates and reorganization of transcriptional activity of cell-cell contact-related genes in both cell types. Immunocytochemical staining revealed redistribution of DCN and LUM in PNT2 cells and significant increase of SDC1 at the intercellular contact zones between BjTERT and PNT2 cells, suggesting active involvement of the PGs in cell-cell contacts and contact inhibition of cell proliferation. Unlike to PNT2 cells, PC3 cells did not respond to BjTERT in terms of PGs expression, moderately increased transcriptional activity of junctions-related genes (especially tight junction) and failed to establish PC3-BjTERT contacts. At the same time, PC3 cells significantly down-regulated junctions-related genes (especially focal adhesions and adherens junctions) in BjTERT fibroblasts resulting in visible preference for homotypic PC3-PC3 over heterotypic PC3-BjTERT contacts and autonomous growth of PC3 clones. Taken together, the results demonstrate that an instructing role of fibroblasts to normal prostate epithelial cells is revoked by cancer cells through deregulation of proteoglycans and junction molecules expression and overall disorganization of fibroblast-cancer cell communication.
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Affiliation(s)
- Anastasia V Suhovskih
- a MTC, Karolinska Institute , Stockholm , Sweden.,b Institute of Molecular Biology and Biophysics , Novosibirsk , Russia
| | - Vladimir I Kashuba
- a MTC, Karolinska Institute , Stockholm , Sweden.,c Institute of Molecular Biology and Genetics , Kiev , Ukraine
| | - George Klein
- a MTC, Karolinska Institute , Stockholm , Sweden
| | - Elvira V Grigorieva
- a MTC, Karolinska Institute , Stockholm , Sweden.,b Institute of Molecular Biology and Biophysics , Novosibirsk , Russia
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40
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Shi J, Wei PK. Low-dose interleukin-8 induces the adhesion, migration and invasion of the gastric cancer SGC-7901 cell line. Oncol Lett 2015; 10:2871-2877. [PMID: 26722255 DOI: 10.3892/ol.2015.3641] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 07/07/2015] [Indexed: 12/12/2022] Open
Abstract
Interleukin-8 (IL-8), an important inflammatory cytokine, is strongly associated with gastric cancer development and metastasis. High-dose (>1 ng/ml) IL-8 has been revealed to promote the adhesion, migration and invasion of human gastric cancer SGC-7901 cells in a dose-dependent manner. However, the IL-8 level produced by gastric cells is marginal, at even less than 1 ng/ml. It is unclear whether low-dose IL-8 also induces these capacities. In the present study, the effect of low-dose IL-8 on the adhesion, migration and invasion of the SGC-7901 cell line and the underlying molecular mechanism with regard to cluster of differentiation 44 (CD44) were investigated. The SGC-7901 cells were exposed to various concentrations of IL-8 (0, 0.2, 0.5, 0.8 and 1 ng/ml) in vitro. The adhesion of the SGC-7901 cells to fibronectin, an extracellular matrix component, was then detected by cell counting kit 8 assay. Migration and invasion abilities were evaluated by wound scratch and Transwell chamber assays. In addition, protein and mRNA levels of CD44 were measured using immunofluorescence and western blotting, and quantitative polymerase chain reaction, respectively, in cells cultured for 72 h. Following the exposure of the SGC-7901 cells to the various low doses of IL-8, the cell adhesion, migration and invasion capacities were promoted by IL-8, but not in a significant dose-dependent manner. Low-dose IL-8 upregulated the protein and mRNA expression of CD44. In conclusion, low-dose IL-8 potently induces the adhesion, migration and invasion of SGC-7901 cells, and the regulation of CD44 expression is one of the potential molecular mechanisms involved.
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Affiliation(s)
- Jun Shi
- Department of Traditional Chinese Medicine, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
| | - Pin-Kang Wei
- Department of Traditional Chinese Medicine, Shanghai Changzheng Hospital, The Second Military Medical University, Shanghai 200003, P.R. China
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41
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Tabariès S, Annis MG, Hsu BE, Tam CE, Savage P, Park M, Siegel PM. Lyn modulates Claudin-2 expression and is a therapeutic target for breast cancer liver metastasis. Oncotarget 2015; 6:9476-87. [PMID: 25823815 PMCID: PMC4496232 DOI: 10.18632/oncotarget.3269] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2015] [Accepted: 01/31/2015] [Indexed: 12/30/2022] Open
Abstract
Claudin-2 enhances breast cancer liver metastasis and promotes the development of colorectal cancers. The objective of our current study is to define the regulatory mechanisms controlling Claudin-2 expression in breast cancer cells. We evaluated the effect of several Src Family Kinase (SFK) inhibitors or knockdown of individual SFK members on Claudin-2 expression in breast cancer cells. We also assessed the potential effects of pan-SFK and SFK-selective inhibitors on the formation of breast cancer liver metastases. This study reveals that pan inhibition of SFK signaling pathways significantly elevated Claudin-2 expression levels in breast cancer cells. In addition, our data demonstrate that pan-SFK inhibitors can enhance breast cancer metastasis to the liver. Knockdown of individual SFK members reveals that loss of Yes or Fyn induces Claudin-2 expression; whereas, diminished Lyn levels impairs Claudin-2 expression in breast cancer cells. The Lyn-selective kinase inhibitor, Bafetinib (INNO-406), acts to reduce Claudin-2 expression and suppress breast cancer liver metastasis. Our findings may have major clinical implications and advise against the treatment of breast cancer patients with broad-acting SFK inhibitors and support the use of Lyn-specific inhibitors.
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MESH Headings
- Animals
- Apoptosis/drug effects
- Carcinoma/genetics
- Carcinoma/prevention & control
- Carcinoma/secondary
- Cell Line, Tumor
- Claudins/biosynthesis
- Claudins/genetics
- Dasatinib/pharmacology
- Dasatinib/therapeutic use
- Female
- Gene Expression Regulation, Neoplastic/drug effects
- Humans
- Liver Neoplasms/prevention & control
- Liver Neoplasms/secondary
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/pathology
- Mice
- Mice, Inbred BALB C
- Mice, Inbred NOD
- Mice, SCID
- Molecular Targeted Therapy
- Neoplasm Proteins/antagonists & inhibitors
- Neoplasm Proteins/biosynthesis
- Neoplasm Proteins/genetics
- Neoplasm Proteins/physiology
- Promoter Regions, Genetic
- Protein Kinase Inhibitors/pharmacology
- Protein Kinase Inhibitors/therapeutic use
- Proto-Oncogene Proteins c-fos/physiology
- Pyrimidines/pharmacology
- Pyrimidines/therapeutic use
- RNA Interference
- RNA, Messenger/biosynthesis
- RNA, Messenger/genetics
- RNA, Neoplasm/biosynthesis
- RNA, Neoplasm/genetics
- Signal Transduction
- Transcription Factor AP-1/physiology
- Transcription, Genetic
- Triple Negative Breast Neoplasms/genetics
- Triple Negative Breast Neoplasms/pathology
- src-Family Kinases/antagonists & inhibitors
- src-Family Kinases/physiology
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Affiliation(s)
- Sébastien Tabariès
- Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3
| | - Matthew G. Annis
- Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3
| | - Brian E. Hsu
- Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3
| | - Christine E. Tam
- Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3
| | - Paul Savage
- Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3
| | - Morag Park
- Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Oncology, McGill University, Montréal, Québec, Canada, H3A 1A3
| | - Peter M. Siegel
- Goodman Cancer Research Centre, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Medicine, McGill University, Montréal, Québec, Canada, H3A 1A3
- Department of Biochemistry, McGill University, Montréal, Québec, Canada, H3A 1A3
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Rousseau A, Tomasetto C, Alpy F. [TRAF4, a multifaceted protein involved in carcinoma progression]. Biol Aujourdhui 2015; 208:299-310. [PMID: 25840457 DOI: 10.1051/jbio/2014026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2014] [Indexed: 06/04/2023]
Abstract
Eukaryotic epithelial cells form a sheet of contiguous cells, called epithelium, by means of the establishment of well-developed junctional complexes. These junctional complexes ensure the cell cohesion in the tissue and separate the plasma membrane into an apical and a basolateral compartment. This apicobasal polarity, which is crucial for both the architecture and the function of epithelia, is mainly maintained by tight junctions (TJS). Indeed, TJS weakening or loss disrupts the integrity of the epithelium, a process participating to the formation and progression of carcinomas. It has recently been shown that TRAF4, a protein dynamically localized in TJS and commonly overexpressed in carcinomas, plays a variety of functions in tumor progression. Here, we review recent data implicating TRAF4 in carcinogenesis. First, the conserved TRAF proteins family will be presented, and then the molecular mechanism addressing TRAF4 to TJS which involves lipid binding by the TRAF domain will be described. The various roles of TRAF4 in carcinogenesis will be discussed. Finally, we will highlight the ability of all TRAF proteins to bind lipids and discuss its potential functional relevance.
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Affiliation(s)
- Adrien Rousseau
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génomique Fonctionnelle et Cancer, 1 rue Laurent Fries, 67404 Illkirch, France - Institut National de la Santé et de la Recherche Médicale (INSERM), U 964, 67404 Illkirch, France - Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France - Université de Strasbourg, 67404 Illkirch, France
| | - Catherine Tomasetto
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génomique Fonctionnelle et Cancer, 1 rue Laurent Fries, 67404 Illkirch, France - Institut National de la Santé et de la Recherche Médicale (INSERM), U 964, 67404 Illkirch, France - Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France - Université de Strasbourg, 67404 Illkirch, France
| | - Fabien Alpy
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Département de Génomique Fonctionnelle et Cancer, 1 rue Laurent Fries, 67404 Illkirch, France - Institut National de la Santé et de la Recherche Médicale (INSERM), U 964, 67404 Illkirch, France - Centre National de la Recherche Scientifique (CNRS), UMR 7104, 67404 Illkirch, France - Université de Strasbourg, 67404 Illkirch, France
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Shi J, Wei PK. Xiaotan Sanjie decoction inhibits interleukin-8-induced metastatic potency in gastric cancer. World J Gastroenterol 2015; 21:1479-87. [PMID: 25663767 PMCID: PMC4316090 DOI: 10.3748/wjg.v21.i5.1479] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2014] [Revised: 09/09/2014] [Accepted: 10/15/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To investigate the interaction between Xiaotan Sanjie (XTSJ) decoction and interleukin-8 (IL-8) and its effect on adhesion, migration and invasion of SGC-7901 gastric cancer cells. METHODS SGC-7901 gastric cancer cells were exposed to serum containing XTSJ decoction and/or IL-8 (1 ng/mL). SGC-7901 cell adhesion to fibronectin, an extracellular matrix component, was detected using the Cell Counting Kit-8. Migration and invasion abilities of SGC-7901 cells were detected by scratch wound and Transwell chamber assays. Then, protein (immunofluorescence and Western blot) and mRNA levels (quantitative polymerase chain reaction) of cluster of differentiation 44 (CD44), a cell adhesion molecule, were measured in 72-h-cultured SGC-7901 cells. RESULTS Cell adhesion was promoted by IL-8 (P = 0.001), but was inhibited by XTSJ decoction (P = 0.0001). Similarly, IL-8 promoted SGC-7901 cell invasion (P = 0.003), and XTSJ decoction inhibited cell invasion (P = 0.001). IL-8 induced SGC-7901 cell migration, but this was inhibited by XTSJ decoction. IL-8 up-regulated CD44 protein (P = 0.028) and mRNA expression (P = 0.002), whereas XTSJ decoction inhibited CD44 protein expression (P = 0.0001), but not mRNA expression (P = 0.275). An interaction between XTSJ decoction and IL-8 was confirmed in the invasion (P = 0.001) and CD44 mRNA expression of SGC-7901 cells (P = 0.010), but not in cell adhesion (P = 0.051). CONCLUSION XTSJ decoction may inhibit adhesion, migration and invasion of gastric cancer cells, which is partly associated with down-regulation of IL-8.
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Tanos BE, Perez Bay AE, Salvarezza S, Vivanco I, Mellinghoff I, Osman M, Sacks DB, Rodriguez-Boulan E. IQGAP1 controls tight junction formation through differential regulation of claudin recruitment. J Cell Sci 2015; 128:853-62. [PMID: 25588839 DOI: 10.1242/jcs.118703] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
IQGAP1 is a scaffolding protein previously implicated in adherens junction formation. However, its role in the establishment or maintenance of tight junctions (TJs) has not been explored. We hypothesized that IQGAP1 could regulate TJ formation by modulating the expression and/or localization of junctional proteins, and we systematically tested this hypothesis in the model Madin-Darby canine kidney (MDCK) cell line. We find that IQGAP1 silencing enhances a transient increase in transepithelial electrical resistance (TER) observed during the early stages of TJ formation (Cereijido et al., 1978). Quantitative microscopy and biochemical experiments suggest that this effect of IQGAP1 on TJ assembly is accounted for by reduced expression and TJ recruitment of claudin 2, and increased TJ recruitment of claudin 4. Furthermore, we show that IQGAP1 also regulates TJ formation through its interactor CDC42, because IQGAP1 knockdown increases the activity of the CDC42 effector JNK and dominant-negative CDC42 prevents the increase in TER caused by IQGAP1 silencing. Hence, we provide evidence that IQGAP1 modulates TJ formation by a twofold mechanism: (1) controlling the expression and recruitment of claudin 2 and recruitment of claudin 4 to the TJ, and (2) transient inhibition of the CDC42-JNK pathway.
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Affiliation(s)
- Barbara E Tanos
- Department of Ophthalmology, Margaret Dyson Vision Research Institute, Weill Cornell Medical College, New York, NY 10065, USA
| | - Andres E Perez Bay
- Department of Ophthalmology, Margaret Dyson Vision Research Institute, Weill Cornell Medical College, New York, NY 10065, USA
| | - Susana Salvarezza
- Department of Ophthalmology, Margaret Dyson Vision Research Institute, Weill Cornell Medical College, New York, NY 10065, USA
| | - Igor Vivanco
- Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
| | - Ingo Mellinghoff
- Human Oncology & Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA Department of Pharmacology, Weill Cornell Medical College, New York, NY 10065, USA Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
| | - Mahasin Osman
- Department of Molecular Pharmacology, Physiology and Biotechnology, Division of Biology and Medicine, Alpert School of Medicine, Brown University, Providence, RI 02912, USA
| | - David B Sacks
- Department of Laboratory Medicine, National Institutes of Health, Bethesda, MD 20892, USA
| | - Enrique Rodriguez-Boulan
- Department of Ophthalmology, Margaret Dyson Vision Research Institute, Weill Cornell Medical College, New York, NY 10065, USA Department of Cell and Developmental Biology, Weill Cornell Medical College, New York, NY 10065, USA
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45
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Flores AR, Rêma A, Carvalho F, Lopes G, Faustino A, Dias Pereira P. Clinicopathological significance of immunoexpression of claudin-1 and claudin-7 in feline mammary carcinomas. J Comp Pathol 2014; 151:339-46. [PMID: 25246182 DOI: 10.1016/j.jcpa.2014.07.006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Revised: 07/21/2014] [Accepted: 07/28/2014] [Indexed: 01/16/2023]
Abstract
Claudins (CLDNs) are tight junction proteins that have a role in regulating cell adhesion and polarity, paracellular permeability, proliferation and differentiation. Several immunohistochemical studies have shown reduced expression of CLDN-1 and CLDN-7 in human and canine mammary carcinomas, suggesting that these proteins may participate in mammary carcinogenesis, invasion and metastasis. The present study characterizes expression of CLDN-1 and CLDN-7 in feline mammary carcinomas (n = 52) and their metastases (n = 29). There was an inverse association between CLDN-7 expression and histological grade of tumour. Reduced expression of CLDN-7 was significantly associated with decreased tubule formation, high proliferative activity and metastasis. No significant associations were found between CLDN-1 expression and any of these features. Evaluation of expression of CLDN-7, but not CLDN-1, may therefore provide prognostic information, assisting in the diagnosis of a subgroup of aggressive feline mammary carcinomas that share some features with the recently described 'claudin-low' subgroup of human breast cancer.
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Affiliation(s)
- A Rute Flores
- Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira N°228, 4050-313 Porto, Portugal
| | - A Rêma
- Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira N°228, 4050-313 Porto, Portugal
| | - F Carvalho
- Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira N°228, 4050-313 Porto, Portugal
| | - G Lopes
- Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira N°228, 4050-313 Porto, Portugal
| | - A Faustino
- Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira N°228, 4050-313 Porto, Portugal
| | - P Dias Pereira
- Instituto de Ciências Biomédicas de Abel Salazar, University of Porto, Rua Jorge Viterbo Ferreira N°228, 4050-313 Porto, Portugal.
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Planells-Ferrer L, Urresti J, Soriano A, Reix S, Murphy DM, Ferreres JC, Borràs F, Gallego S, Stallings RL, Moubarak RS, Segura MF, Comella JX. MYCN repression of Lifeguard/FAIM2 enhances neuroblastoma aggressiveness. Cell Death Dis 2014; 5:e1401. [PMID: 25188511 PMCID: PMC4540192 DOI: 10.1038/cddis.2014.356] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2014] [Revised: 07/15/2014] [Accepted: 07/22/2014] [Indexed: 01/20/2023]
Abstract
Neuroblastoma (NBL) is the most common solid tumor in infants and accounts for 15% of all pediatric cancer deaths. Several risk factors predict NBL outcome: age at the time of diagnosis, stage, chromosome alterations and MYCN (V-Myc Avian Myelocytomatosis Viral Oncogene Neuroblastoma-Derived Homolog) amplification, which characterizes the subset of the most aggressive NBLs with an overall survival below 30%. MYCN-amplified tumors develop exceptional chemoresistance and metastatic capacity. These properties have been linked to defects in the apoptotic machinery, either by silencing components of the extrinsic apoptotic pathway (e.g. caspase-8) or by overexpression of antiapoptotic regulators (e.g. Bcl-2, Mcl-1 or FLIP). Very little is known on the implication of death receptors and their antagonists in NBL. In this work, the expression levels of several death receptor antagonists were analyzed in multiple human NBL data sets. We report that Lifeguard (LFG/FAIM2 (Fas apoptosis inhibitory molecule 2)/NMP35) is downregulated in the most aggressive and undifferentiated tumors. Intringuingly, although LFG has been initially characterized as an antiapoptotic protein, we have found a new association with NBL differentiation. Moreover, LFG repression resulted in reduced cell adhesion, increased sphere growth and enhanced migration, thus conferring a higher metastatic capacity to NBL cells. Furthermore, LFG expression was found to be directly repressed by MYCN at the transcriptional level. Our data, which support a new functional role for a hitherto undiscovered MYCN target, provide a new link between MYCN overexpression and increased NBL metastatic properties.
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Affiliation(s)
- L Planells-Ferrer
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J Urresti
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - A Soriano
- Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - S Reix
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - D M Murphy
- Molecular and Cellular Therapeutics, Royal College of Surgeons and National Children's Research Centre Our Lady's Children's Hospital, Dublin, Ireland
| | - J C Ferreres
- Hospital Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - F Borràs
- Hospital Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - S Gallego
- 1] Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain [2] Hospital Vall d'Hebron, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - R L Stallings
- Molecular and Cellular Therapeutics, Royal College of Surgeons and National Children's Research Centre Our Lady's Children's Hospital, Dublin, Ireland
| | - R S Moubarak
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - M F Segura
- Laboratory of Translational Research in Pediatric Cancer, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
| | - J X Comella
- Cell Signaling and Apoptosis Group, Vall d'Hebron Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain
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Drug repositioning discovery for early- and late-stage non-small-cell lung cancer. BIOMED RESEARCH INTERNATIONAL 2014; 2014:193817. [PMID: 25210704 PMCID: PMC4156989 DOI: 10.1155/2014/193817] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/10/2014] [Revised: 07/07/2014] [Accepted: 07/12/2014] [Indexed: 12/30/2022]
Abstract
Drug repositioning is a popular approach in the pharmaceutical industry for identifying potential new uses for existing drugs and accelerating the development time. Non-small-cell lung cancer (NSCLC) is one of the leading causes of death worldwide. To reduce the biological heterogeneity effects among different individuals, both normal and cancer tissues were taken from the same patient, hence allowing pairwise testing. By comparing early- and late-stage cancer patients, we can identify stage-specific NSCLC genes. Differentially expressed genes are clustered separately to form up- and downregulated communities that are used as queries to perform enrichment analysis. The results suggest that pathways for early- and late-stage cancers are different. Sets of up- and downregulated genes were submitted to the cMap web resource to identify potential drugs. To achieve high confidence drug prediction, multiple microarray experimental results were merged by performing meta-analysis. The results of a few drug findings are supported by MTT assay or clonogenic assay data. In conclusion, we have been able to assess the potential existing drugs to identify novel anticancer drugs, which may be helpful in drug repositioning discovery for NSCLC.
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48
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Pal D, Basu A. The unique protein kinase Cη: implications for breast cancer (review). Int J Oncol 2014; 45:493-8. [PMID: 24841225 DOI: 10.3892/ijo.2014.2443] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2014] [Accepted: 02/18/2014] [Indexed: 11/05/2022] Open
Abstract
Deregulation of key signal transduction pathways that govern important cellular processes leads to cancer. The development of effective therapeutics for cancer warrants a comprehensive understanding of the signaling pathways that are deregulated in cancer. The protein kinase C (PKC) family has served as an attractive target for cancer therapy for decades owing to its crucial roles in several cellular processes. PKCη is a novel member of the PKC family that plays critical roles in various cellular processes such as growth, proliferation, differentiation and cell death. The regulation of PKCη appears to be unique compared to other PKC isozymes, and there are conflicting reports regarding its role in cancer. This review focuses on the unique aspects of PKCη in terms of its structure, regulation and subcellular distribution and speculates on how these features could account for its distinct functions. We have also discussed the functional implications of PKCη in cancer with particular emphasis on breast cancer.
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Affiliation(s)
- Deepanwita Pal
- Department of Molecular and Medical Genetics, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA
| | - Alakananda Basu
- Department of Molecular and Medical Genetics, University of North Texas Health Science Center and Institute for Cancer Research, Fort Worth, TX 76107, USA
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49
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Tumor Restrictions to Oncolytic Virus. Biomedicines 2014; 2:163-194. [PMID: 28548066 PMCID: PMC5423468 DOI: 10.3390/biomedicines2020163] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 03/17/2014] [Accepted: 03/28/2014] [Indexed: 02/06/2023] Open
Abstract
Oncolytic virotherapy has advanced since the days of its conception but therapeutic efficacy in the clinics does not seem to reach the same level as in animal models. One reason is premature oncolytic virus clearance in humans, which is a reasonable assumption considering the immune-stimulating nature of the oncolytic agents. However, several studies are beginning to reveal layers of restriction to oncolytic virotherapy that are present before an adaptive neutralizing immune response. Some of these barriers are present constitutively halting infection before it even begins, whereas others are raised by minute cues triggered by virus infection. Indeed, we and others have noticed that delivering viruses to tumors may not be the biggest obstacle to successful therapy, but instead the physical make-up of the tumor and its capacity to mount antiviral defenses seem to be the most important efficacy determinants. In this review, we summarize the constitutive and innate barriers to oncolytic virotherapy and discuss strategies to overcome them.
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50
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Somorácz A, Korompay A, Törzsök P, Patonai A, Erdélyi-Belle B, Lotz G, Schaff Z, Kiss A. Tricellulin expression and its prognostic significance in primary liver carcinomas. Pathol Oncol Res 2014; 20:755-64. [PMID: 24652413 DOI: 10.1007/s12253-014-9758-x] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2013] [Accepted: 02/25/2014] [Indexed: 01/30/2023]
Abstract
Numerous data suggest that altered expression of tight junction proteins such as occludin and claudins plays important role in carcinogenesis. However, little is known about tricellulin, a transmembrane tight junction protein concentrated where three epithelial cells meet. We aimed to characterize tricellulin expression in normal and cirrhotic liver in comparison to primary hepatic neoplasms. Tricellulin expression of 20 control livers, 12 cirrhotic livers, 32 hepatocellular carcinomas (HCC), and 20 intrahepatic cholangiocarcinomas (iCCC) was investigated by immunohistochemistry and Western blotting. Co-localization of tricellulin with claudin-1, -4, and MRP2 was studied using double immunofluorescence. Scattered tricellulin immunopositivity was restricted to biliary pole of hepatocytes confirmed by co-localization with MRP2. Moreover, spotted-like reaction was observed between bile duct epithelial cells. In 40 % of HCCs marked tricellulin overexpression was measured regardless of tumor grades. In iCCCs, however, tricellulin expression decreased parallel with dedifferentiation. In HCCs high tricellulin expression, in iCCCs low tricellulin expression correlated with poor prognosis. Co-localization with MRP2 might substantiate that tricellulin plays role in blood-biliary barrier. Overexpressed tricellulin in a subset of HCCs correlated with unfavorable prognosis. Similar to ductal pancreatic adenocarcinoma, higher grades of iCCCs were associated with decreased tricellulin expression correlating with poor prognosis.
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Affiliation(s)
- Aron Somorácz
- 2nd Department of Pathology, Semmelweis University, Budapest, Hungary
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