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Wu S, Gao J, Han Y, Zhang W, Li X, Kong D, Wang H, Zuo L. Balancing act: The dual role of claudin-2 in disease. Ann N Y Acad Sci 2025; 1546:75-89. [PMID: 40101185 DOI: 10.1111/nyas.15311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/20/2025]
Abstract
Claudin-2 (CLDN2), a tight junction protein, is predominantly found in leaky epithelial cell layers where it plays a pivotal role in forming paracellular pores necessary for the efficient transport of cations and water. Its abundance is intricately regulated by upstream signals, modulating its synthesis, transport, and localization to adapt to diverse environmental changes. Aberrant expression levels of CLDN2 are observed in numerous pathological conditions including cancer, inflammation, immune disorders, fibrosis, and kidney and biliary stones. Recent advances have uncovered the mechanisms by which the loss or restoration of CLDN2 affects functions such as epithelial barrier, cell proliferation, renewal, migration, invasion, and tissue regeneration. This exerts a dual-directional influence on the pathogenesis, perpetuation, and progression of diseases, indicating the potential to both accelerate and decelerate the course of disease evolution. Here, we discuss these nuanced bidirectional regulatory effects mediated by CLDN2, and how it may contribute to the progression or regression of disease when it becomes unbalanced.
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Affiliation(s)
- Shanshan Wu
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
| | - Jia Gao
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Yiran Han
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Wenzhe Zhang
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Xue Li
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- The First College of Clinical Medicine, Anhui Medical University, Hefei, China
| | - Derun Kong
- Department of Gastroenterology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Hua Wang
- Inflammation and Immune-Mediated Diseases Laboratory of Anhui Province, Anhui Medical University, Hefei, China
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Li Zuo
- Innovation and Entrepreneurship Laboratory for College Students, Anhui Medical University, Hefei, China
- Laboratory of Molecular Biology, Department of Biochemistry, School of Basic Medical Science, Anhui Medical University, Hefei, China
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Jin Y, Liu H, Wang Y, Zhang R, Wang Q, Wang Y, Cui H, Wang X, Bian Y. Pathogenesis and treatment of colitis-associated colorectal cancer: Insights from Traditional Chinese Medicine. JOURNAL OF ETHNOPHARMACOLOGY 2025; 338:119096. [PMID: 39532222 DOI: 10.1016/j.jep.2024.119096] [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: 06/18/2024] [Revised: 10/11/2024] [Accepted: 11/09/2024] [Indexed: 11/16/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Inflammatory Bowel Disease (IBD) is an inflammatory intestinal disease, and with prolonged illness duration, the annual risk of IBD progressing to colitis-associated colorectal cancer (CAC) gradually increases. In recent years, there has been a noticeable trend towards the application of traditional Chinese medicine (TCM) in the treatment of CAC. AIM OF THIS REVIEW This comprehensive review summarizes the pathogenesis of CAC and details the therapeutic benefits of TCM in treating CAC, including various TCM prescriptions and ingredients, establishing the theoretical foundation for the application of TCM in CAC treatment. METHODS We assessed literature published before March 24, 2024, from several databases, including Web of Science, PubMed, Scopus and Google Scholar. The keywords used include "traditional Chinese medicine", "traditional Chinese medicine prescriptions", "traditional Chinese medicine ingredients", "herbal medicine", "colitis-associated colorectal cancer", "inflammatory bowel disease", "colorectal cancer" and "colitis-cancer transformation". We conducted a comprehensive collection and collation of pertinent scientific articles from various databases, focusing on the efficacy of TCM in the prevention and treatment of "colitis-cancer transformation". RESULTS This paper provides a concise summary and thorough analysis of twenty-eight prescriptions and ingredients of TCM for the prevention and treatment of CAC, based on existing experimental and clinical research. There are positive signs that TCM can effectively prevent and treat the "colitis-cancer transformation" through repairing the intestinal mucosal barrier, correcting intestinal flora imbalance, and regulating intestinal immune responses. CONCLUSION TCM possesses comprehensive regulatory advantages that are multifaceted, multilevel, and multitarget. It has a definite curative effect in the prevention and treatment of CAC. It is essential to enhance the clinical efficacy of TCM in the prevention and treatment of CAC based on syndrome differentiation and treatment, with the assistance of modern medicine.
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Affiliation(s)
- Yutong Jin
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Haizhao Liu
- Department of Integrated Traditional Chinese and Western Medicine, Tianjin First Central Hospital, Nankai University, Tianjin, 300192, China
| | - Yuhui Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Ruixuan Zhang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China
| | - Qiaochu Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300073, China
| | - Yao Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China; School of Basic Medical Sciences, Heilongjiang University of Chinese Medicine, Harbin, 150040, China
| | - Huantian Cui
- First School of Clinical Medicine, Yunnan University of Chinese Medicine, Kunming, 650500, China.
| | - Xiangling Wang
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
| | - Yuhong Bian
- School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 301617, China.
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Das A, Giri S, Dey P. Cell-cell junctional proteins in cancer. Adv Clin Chem 2024; 125:93-142. [PMID: 39988409 DOI: 10.1016/bs.acc.2024.11.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/25/2025]
Abstract
A hallmark change during carcinogenesis is disruption or dysregulation of cell-cell junctions. It enables a transformed cell to adopt mesenchymal phenotype and acquire higher potential to migrate and invade. This ultimately leads to cancer metastasis. During this process, junctional proteins undergo remarkable changes in terms of their expressional pattern, localization, and activity. De-localized junctional proteins may adopt atypical roles which might act to either suppress tumorigenesis or facilitate cancer development, depending on several factors. In this chapter, the authors attempt to know the expression pattern of junctional proteins in different types of cancer, understand its significance, and gather knowledge about the mechanisms by which they regulate tumorigenesis and cancer development.
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Affiliation(s)
- Aparajita Das
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Sarbani Giri
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India.
| | - Pubali Dey
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
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Kumari L, Yadav R, Kumar Y, Bhatia A. Role of tight junction proteins in shaping the immune milieu of malignancies. Expert Rev Clin Immunol 2024; 20:1305-1321. [PMID: 39126381 DOI: 10.1080/1744666x.2024.2391915] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 08/05/2024] [Accepted: 08/09/2024] [Indexed: 08/12/2024]
Abstract
INTRODUCTION Tight junctions (TJs) and their constituent proteins play pivotal roles in cellular physiology and anatomy by establishing functional boundaries within and between neighboring cells. While the involvement of TJ proteins, such as claudins, in cancer is extensively studied, studies highlighting their interaction with immune system are still meager. Studies indicate that alterations in cytokines and immune cell populations can affect TJ proteins, compromising TJ barrier function and exacerbating pro-inflammatory conditions, potentially leading to epithelial cell malignancy. Disrupted TJs in established tumors may foster a pro-tumor immune microenvironment, facilitating tumor progression, invasion, epithelial-to-mesenchymal transition and metastasis. Although previous literature contains many studies describing the involvement of TJs in pathogenesis of malignancies their role in modulating the immune microenvironment of tumors is just beginning to be unleashed. AREAS COVERED This article for the first time attempts to discern the importance of interaction between TJs and immune microenvironment in malignancies. To achieve the above aim a thorough search of databases like PubMed and Google Scholar was conducted to identify the recent and relevant articles on the topic. EXPERT OPINION Breaking the vicious cycle of dysbiosis/infections/chemical/carcinogen-induced inflammation-TJ remodeling-malignancy-TJ dysregulation-more inflammation can be used as a strategy to complement the effect of immunotherapies in various malignancies.
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Affiliation(s)
- Laxmi Kumari
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Reena Yadav
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
| | - Yashwant Kumar
- Department of Immunopathology, Post Graduate Institute of medical Education and Research, Chandigarh, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Post Graduate Institute of Medical Education & Research, Chandigarh, India
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Tabariès S, Robert A, Marcil A, Ling B, Acchione M, Lippens J, Pagé M, Fortin A, Meury L, Coutu M, Annis MG, Girondel C, Navarre J, Jaramillo M, Moraitis AN, Siegel PM. Anti-Claudin-2 Antibody-Drug Conjugates for the Treatment of Colorectal Cancer Liver Metastasis. Mol Cancer Ther 2024; 23:1459-1470. [PMID: 38902871 DOI: 10.1158/1535-7163.mct-23-0393] [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: 06/22/2023] [Revised: 12/20/2023] [Accepted: 06/13/2024] [Indexed: 06/22/2024]
Abstract
We have previously demonstrated that Claudin-2 is required for colorectal cancer (CRC) liver metastasis. The expression of Claudin-2 in primary CRC is associated with poor survival and highly expressed in liver metastases. Claudin-2 also promotes breast cancer liver metastasis by enabling seeding and cancer cell survival. These observations support Claudin-2 as a potential therapeutic target for managing patients with liver metastases. Antibody-drug conjugates (ADC) are promising antitumor therapeutics, which combine the specific targeting ability of monoclonal antibodies with the potent cell killing activity of cytotoxic drugs. Herein, we report the generation of 28 anti-Claudin-2 antibodies for which the binding specificities, cross-reactivity with claudin family members, and cross-species reactivity were assessed by flow cytometry analysis. Multiple drug conjugates were tested, and PNU was selected for conjugation with anti-Claudin-2 antibodies binding either extracellular loop 1 or 2. Anti-Claudin-2 ADCs were efficiently internalized and were effective at killing Claudin-2-expressing CRC cancer cells in vitro. Importantly, PNU-conjugated-anti-Claudin-2 ADCs impaired the development of replacement-type CRC liver metastases in vivo, using established CRC cell lines and patient-derived xenograft (PDX) models of CRC liver metastases. Results suggest that the development of ADCs targeting Claudin-2 is a promising therapeutic strategy for managing patients with CRC liver-metastatic disease who present replacement-type liver metastases.
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Affiliation(s)
- Sébastien Tabariès
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
| | - Alma Robert
- National Research Council Canada, Montréal, Canada
| | - Anne Marcil
- National Research Council Canada, Montréal, Canada
| | - Binbing Ling
- National Research Council Canada, Ottawa, Canada
| | | | | | - Martine Pagé
- National Research Council Canada, Montréal, Canada
| | - Annie Fortin
- National Research Council Canada, Montréal, Canada
| | - Luc Meury
- National Research Council Canada, Montréal, Canada
| | | | - Matthew G Annis
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
| | - Charlotte Girondel
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
| | - Julie Navarre
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
| | | | | | - Peter M Siegel
- Goodman Cancer Institute, McGill University, Montréal, Canada
- Department of Medicine, McGill University, Montréal, Canada
- Department of Biochemistry, McGill University, Montréal, Canada
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Yu N, Su M, Wang J, Liu Y, Yang J, Zhang J, Wang M. Long-Term Exposure of Fresh and Aged Nano Zinc Oxide Promotes Hepatocellular Carcinoma Malignancy by Up-Regulating Claudin-2. Int J Nanomedicine 2024; 19:9989-10008. [PMID: 39371475 PMCID: PMC11453161 DOI: 10.2147/ijn.s478279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2024] [Accepted: 09/26/2024] [Indexed: 10/08/2024] Open
Abstract
Background Tumor development and progression is a long and complex process influenced by a combination of intrinsic (eg, gene mutation) and extrinsic (eg, environmental pollution) factors. As a detoxification organ, the liver plays an important role in human exposure and response to various environmental pollutants including nanomaterials (NMs). Hepatocellular carcinoma (HCC) is one of the most common malignant tumors and remains a serious threat to human health. Whether NMs promote liver cancer progression remains elusive and assessing long-term exposure to subtoxic doses of nanoparticles (NPs) remains a challenge. In this study, we focused on the promotional effects of nano zinc oxide (nZnO) on the malignant progression of human HCC cells HepG2, especially aged nZnO that has undergone physicochemical transformation. Methods In in vitro experiments, we performed colony forming efficiency, soft agar colony formation, and cell migration/invasion assays on HepG2 cells that had been exposed to a low dose of nZnO (1.5 μg/mL) for 3 or 4 months. In in vivo experiments, we subcutaneously inoculated HepG2 cells that had undergone long-term exposure to nZnO for 4 months into BALB/c athymic nude mice and observed tumor formation. ZnCl2 was administered to determine the role of zinc ions. Results Chronic low-dose exposure to nZnO significantly intensified the malignant progression of HCC cells, whereas aged nZnO may exacerbate the severity of malignant progression. Furthermore, through transcriptome sequencing analysis and in vitro cellular rescue experiments, we demonstrated that the mechanism of nZnO-induced malignant progression of HCC could be linked to the activation of Claudin-2 (CLDN2), one of the components of cellular tight junctions, and the dysregulation of its downstream signaling pathways. Conclusion Long-term exposure of fresh and aged nZnO promotes hepatocellular carcinoma malignancy by up-regulating CLDN2. The implications of this work can be profound for cancer patients, as the use of various nanoproducts and unintentional exposure to environmentally transformed NMs may unknowingly hasten the progression of their cancers.
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Affiliation(s)
- Na Yu
- Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, Hefei, 230032, People’s Republic of China
| | - Mingqin Su
- Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, Hefei, 230032, People’s Republic of China
| | - Juan Wang
- Department of Public Health Inspection and Quarantine, School of Public Health, Anhui Medical University, Hefei, 230032, People’s Republic of China
| | - Yakun Liu
- Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, Hefei, 230032, People’s Republic of China
| | - Jingya Yang
- Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, Hefei, 230032, People’s Republic of China
| | - Jingyi Zhang
- Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, Hefei, 230032, People’s Republic of China
| | - Meimei Wang
- Department of Pathophysiology, School of Basic Medical Science, Anhui Medical University, Hefei, 230032, People’s Republic of China
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AlMarzooqi SK, Almarzooqi F, Sadida HQ, Jerobin J, Ahmed I, Abou-Samra AB, Fakhro KA, Dhawan P, Bhat AA, Al-Shabeeb Akil AS. Deciphering the complex interplay of obesity, epithelial barrier dysfunction, and tight junction remodeling: Unraveling potential therapeutic avenues. Obes Rev 2024; 25:e13766. [PMID: 38745386 DOI: 10.1111/obr.13766] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 03/11/2024] [Accepted: 04/17/2024] [Indexed: 05/16/2024]
Abstract
Obesity stands as a formidable global health challenge, predisposing individuals to a plethora of chronic illnesses such as cardiovascular disease, diabetes, and cancer. A confluence of genetic polymorphisms, suboptimal dietary choices, and sedentary lifestyles significantly contribute to the elevated incidence of obesity. This multifaceted health issue profoundly disrupts homeostatic equilibrium at both organismal and cellular levels, with marked alterations in gut permeability as a salient consequence. The intricate mechanisms underlying these alterations have yet to be fully elucidated. Still, evidence suggests that heightened inflammatory cytokine levels and the remodeling of tight junction (TJ) proteins, particularly claudins, play a pivotal role in the manifestation of epithelial barrier dysfunction in obesity. Strategic targeting of proteins implicated in these pathways and metabolites such as short-chain fatty acids presents a promising intervention for restoring barrier functionality among individuals with obesity. Nonetheless, recognizing the heterogeneity among affected individuals is paramount; personalized medical interventions or dietary regimens tailored to specific genetic backgrounds and allergy profiles may prove indispensable. This comprehensive review delves into the nexus of obesity, tight junction remodeling, and barrier dysfunction, offering a critical appraisal of potential therapeutic interventions.
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Affiliation(s)
- Sara K AlMarzooqi
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
| | - Fajr Almarzooqi
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
| | - Hana Q Sadida
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
| | - Jayakumar Jerobin
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Ikhlak Ahmed
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
| | - Abdul-Badi Abou-Samra
- Qatar Metabolic Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Khalid A Fakhro
- Department of Human Genetics, Sidra Medicine, Doha, Qatar
- College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar
- Department of Genetic Medicine, Weill Cornell Medicine, Doha, Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Ajaz A Bhat
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
| | - Ammira S Al-Shabeeb Akil
- Department of Human Genetics-Precision Medicine in Diabetes, Obesity and Cancer Research Program, Sidra Medicine, Doha, Qatar
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Sayed IM, Vo DT, Alcantara J, Inouye KM, Pranadinata RF, Luo L, Boland CR, Goyal NP, Kuo DJ, Huang SC, Sahoo D, Ghosh P, Das S. Molecular Signatures for Microbe-Associated Colorectal Cancers. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.26.595902. [PMID: 38853996 PMCID: PMC11160670 DOI: 10.1101/2024.05.26.595902] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/11/2024]
Abstract
Background Genetic factors and microbial imbalances play crucial roles in colorectal cancers (CRCs), yet the impact of infections on cancer initiation remains poorly understood. While bioinformatic approaches offer valuable insights, the rising incidence of CRCs creates a pressing need to precisely identify early CRC events. We constructed a network model to identify continuum states during CRC initiation spanning normal colonic tissue to pre-cancer lesions (adenomatous polyps) and examined the influence of microbes and host genetics. Methods A Boolean network was built using a publicly available transcriptomic dataset from healthy and adenoma affected patients to identify an invariant Microbe-Associated Colorectal Cancer Signature (MACS). We focused on Fusobacterium nucleatum ( Fn ), a CRC-associated microbe, as a model bacterium. MACS-associated genes and proteins were validated by RT-qPCR, RNA seq, ELISA, IF and IHCs in tissues and colon-derived organoids from genetically predisposed mice ( CPC-APC Min+/- ) and patients (FAP, Lynch Syndrome, PJS, and JPS). Results The MACS that is upregulated in adenomas consists of four core genes/proteins: CLDN2/Claudin-2 (leakiness), LGR5/leucine-rich repeat-containing receptor (stemness), CEMIP/cell migration-inducing and hyaluronan-binding protein (epithelial-mesenchymal transition) and IL8/Interleukin-8 (inflammation). MACS was induced upon Fn infection, but not in response to infection with other enteric bacteria or probiotics. MACS induction upon Fn infection was higher in CPC-APC Min+/- organoids compared to WT controls. The degree of MACS expression in the patient-derived organoids (PDOs) generally corresponded with the known lifetime risk of CRCs. Conclusions Computational prediction followed by validation in the organoid-based disease model identified the early events in CRC initiation. MACS reveals that the CRC-associated microbes induce a greater risk in the genetically predisposed hosts, suggesting its potential use for risk prediction and targeted cancer prevention.
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Rini DM, Nakamichi Y, Morita T, Inoue H, Mizukami Y, Yamamoto Y, Suzuki T. Xylobiose treatment strengthens intestinal barrier function by regulating claudin 2 and heat shock protein 27 expression in human Caco-2 cells. JOURNAL OF THE SCIENCE OF FOOD AND AGRICULTURE 2024; 104:2518-2525. [PMID: 37938188 DOI: 10.1002/jsfa.13111] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 11/02/2023] [Accepted: 11/08/2023] [Indexed: 11/09/2023]
Abstract
BACKGROUND Xylobiose, a non-digestible disaccharide, largely contributes to the beneficial physiological effects of xylooligosaccharides. However, there is insufficient evidence to assess the direct effect of xylobiose on intestinal barrier function. Here, we investigated the intestinal barrier function in human intestinal Caco-2 cells treated with xylobiose. RESULTS In total, 283 genes were upregulated and 256 genes were downregulated in xylobiose-treated Caco-2 cells relative to the controls. We focused on genes related to intestinal barrier function, such as tight junction (TJ) and heat shock protein (HSP). Xylobiose decreased the expression of the TJ gene Claudin 2 (CLDN2) and increased the expression of the cytoprotective HSP genes HSPB1 and HSPA1A, which encode HSP27 and HSP70, respectively. Immunoblot analysis confirmed that xylobiose suppressed CLDN2 expression and enhanced HSP27 and HSP70 expression. A quantitative reverse transcription-PCR and promoter assays indicated that xylobiose post-transcriptionally regulated CLDN2 and HSPB1 levels. Additionally, selective inhibition of phosphatidyl-3-inositol kinase (PI3K) inhibited xylobiose-mediated CLDN2 expression, whereas HSP27 expression induced by xylobiose was sensitive to the inhibition of PI3K, mitogen-activated protein kinase kinase and Src. CONCLUSION The results of the present study reveal that xylobiose suppresses CLDN2 and increases HSP27 expression in intestinal Caco-2 cells via post-transcriptional regulation, potentially strengthening intestinal barrier integrity; however, these effects seem to occur via different signaling pathways. Our findings may help to assess the physiological role of xylobiose. © 2023 Society of Chemical Industry.
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Affiliation(s)
- Dina Mustika Rini
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
- Department of Food Technology, Faculty of Engineering, Universitas Pembangunan Nasional "Veteran" Jawa Timur, Surabaya, Indonesia
| | - Yusuke Nakamichi
- Research Institute for Sustainable Chemistry, National Institute of Advanced Industrial Science and Technology, Higashi-Hiroshima, Japan
| | - Tomotake Morita
- Research Institute for Sustainable Chemistry, National Institute of Advanced Industrial Science and Technology, Higashi-Hiroshima, Japan
| | - Hiroyuki Inoue
- Research Institute for Sustainable Chemistry, National Institute of Advanced Industrial Science and Technology, Higashi-Hiroshima, Japan
| | - Yoichi Mizukami
- Institute of Gene Research, Yamaguchi University Science Research Center, Ube, Japan
| | - Yoshinari Yamamoto
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
| | - Takuya Suzuki
- Graduate School of Integrated Sciences for Life, Hiroshima University, Higashi-Hiroshima, Japan
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Ahmad R, Kumar B, Thapa I, Tamang RL, Yadav SK, Washington MK, Talmon GA, Yu AS, Bastola DK, Dhawan P, Singh AB. Claudin-2 protects against colitis-associated cancer by promoting colitis-associated mucosal healing. J Clin Invest 2023; 133:e170771. [PMID: 37815870 PMCID: PMC10688979 DOI: 10.1172/jci170771] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2023] [Accepted: 10/05/2023] [Indexed: 10/12/2023] Open
Abstract
Patients with inflammatory bowel disease (IBD) are susceptible to colitis-associated cancer (CAC). Chronic inflammation promotes the risk for CAC. In contrast, mucosal healing predicts improved prognosis in IBD and reduced risk of CAC. However, the molecular integration among colitis, mucosal healing, and CAC remains poorly understood. Claudin-2 (CLDN2) expression is upregulated in IBD; however, its role in CAC is not known. The current study was undertaken to examine the role for CLDN2 in CAC. The AOM/DSS-induced CAC model was used with WT and CLDN2-modified mice. High-throughput expression analyses, murine models of colitis/recovery, chronic colitis, ex vivo crypt culture, and pharmacological manipulations were employed in order to increase our mechanistic understanding. The Cldn2KO mice showed significant inhibition of CAC despite severe colitis compared with WT littermates. Cldn2 loss also resulted in impaired recovery from colitis and increased injury when mice were subjected to intestinal injury by other methods. Mechanistic studies demonstrated a possibly novel role of CLDN2 in promotion of mucosal healing downstream of EGFR signaling and by regulation of Survivin expression. An upregulated CLDN2 expression protected from CAC and associated positively with crypt regeneration and Survivin expression in patients with IBD. We demonstrate a potentially novel role of CLDN2 in promotion of mucosal healing in patients with IBD and thus regulation of vulnerability to colitis severity and CAC, which can be exploited for improved clinical management.
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Affiliation(s)
- Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Balawant Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Ishwor Thapa
- School of Interdisciplinary Informatics, University of Nebraska Omaha, Omaha, Nebraska, USA
| | - Raju Lama Tamang
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Santosh K. Yadav
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Mary K. Washington
- Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - Geoffrey A. Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Alan S. Yu
- Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Dhundy K. Bastola
- School of Interdisciplinary Informatics, University of Nebraska Omaha, Omaha, Nebraska, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA
- VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, Nebraska, USA
- VA Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
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11
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Tao D, Guan B, Li H, Zhou C. Expression patterns of claudins in cancer. Heliyon 2023; 9:e21338. [PMID: 37954388 PMCID: PMC10637965 DOI: 10.1016/j.heliyon.2023.e21338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 10/17/2023] [Accepted: 10/19/2023] [Indexed: 11/14/2023] Open
Abstract
Claudins are four-transmembrane proteins, which were found in tight junctions. They maintain cell barriers and regulate cell differentiation and proliferation. They are involved in maintaining cellular polarity and normal functions. Different claudins show different expression patterns. The expression level and localization of claudins are altered in various cancers. They promote or inhibit proliferation, invasion, and migration of cancer cells through multiple signaling pathways. Therefore, claudins may serve as diagnostic markers, novel therapeutic targets, and prognostic risk factors. The important roles of claudins in cancer aroused our great interest. In the present review, we provide a summary of insights into expression patterns of claudins in cancer, which is more comprehensive and provides new ideas for further research.
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Affiliation(s)
- Daoyu Tao
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Bingxin Guan
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Hui Li
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
| | - Chengjun Zhou
- Department of Pathology, The Second Hospital of Shandong University, Jinan, 250012, Shandong, China
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12
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Alghamdi RA, Al-Zahrani MH. Identification of key claudin genes associated with survival prognosis and diagnosis in colon cancer through integrated bioinformatic analysis. Front Genet 2023; 14:1221815. [PMID: 37799140 PMCID: PMC10550083 DOI: 10.3389/fgene.2023.1221815] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 09/04/2023] [Indexed: 10/07/2023] Open
Abstract
The claudin multigene family is associated with various aberrant physiological and cellular signaling pathways. However, the association of claudins with survival prognosis, signaling pathways, and diagnostic efficacy in colon cancer remains poorly understood. Methods: Through the effective utilization of various bioinformatics methods, including differential gene expression analysis, gene set enrichment analysis protein-protein interaction (PPI) network analysis, survival analysis, single sample gene set enrichment analysis (ssGSEA), mutational variance analysis, and identifying receiver operating characteristic curve of claudins in The Cancer Genome Atlas colon adenocarcinoma (COAD). Results: We found that: CLDN2, CLDN1, CLDN14, CLDN16, CLDN18, CLDN9, CLDN12, and CLDN6 are elevated in COAD. In contrast, the CLDN8, CLDN23, CLDN5, CLDN11, CLDN7, and CLDN15 are downregulated in COAD. By analyzing the public datasets GSE15781 and GSE50760 from NCBI-GEO (https://www.ncbi.nlm.nih.gov/geo/), we have confirmed that CLDN1, CLDN2, and CLDN14 are significantly upregulated and CLDN8 and CLDN23 are significantly downregulated in normal colon, colon adenocarcinoma tumor, and liver metastasis of colon adenocarcinoma tissues from human samples. Various claudins are mutated and found to be associated with diagnostic efficacy in COAD. Conclusion: The claudin gene family is associated with prognosis, immune regulation, signaling pathway regulations, and diagnosis of COAD. These findings may provide new molecular insight into claudins in the treatment of colon cancer.
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Affiliation(s)
- Rana A. Alghamdi
- Department of Chemistry, Science and Arts College, King Abdulaziz University, Rabigh, Saudi Arabia
- Regenerative Medicine Unit, King Fahad Medical Research Centre, King Abdulaziz University, Jeddah, Saudi Arabia
| | - Maryam H. Al-Zahrani
- Biochemistry Department, Faculty of Science, King Abdulaziz University, Jeddah, Saudi Arabia
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13
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Telgenhoff D. Claudin-2 in hyperproliferative migrating keratinocytes and migration inhibition via siRNA knockdown. Anat Histol Embryol 2023; 52:723-731. [PMID: 37147871 DOI: 10.1111/ahe.12929] [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: 11/30/2022] [Revised: 04/07/2023] [Accepted: 04/17/2023] [Indexed: 05/07/2023]
Abstract
Claudin-2 is a tight junction protein found in various tissues including the epidermis of the skin. Intracellular signalling via claudin-2 may have an effect on cell proliferation and migration. While the role of claudin-2 in the epidermis has not been established, here we show an increase in claudin-2 expression in hyperproliferative archival skin samples. To further examine the role of claudin-2 in cell migration we examined its expression in cultured keratinocytes and found it was increased in wound margins in an in vitro scratch test assay. We then used a claudin-2 knockdown assay using small interfering ribonucleic acid (siRNA) with a 77% transfection efficiency and decrease in claudin-2 protein via Western blot analysis to examine cell migration, which was inhibited following claudin-2 knockdown over a 5-day period. Cells transfected with claudin-2 siRNA also showed a decreased size compared to controls and a more diffuse staining pattern. Lastly we examined claudin-2 expression in migrating keratinocytes by Western blot analysis and found a significant decrease in protein staining in scratch-test assay cultures after 4 h, followed by a significant increase in claudin-2 protein after 24 h. Taken together these results indicate a role for claudin-2 signalling in proliferation and cell migration in the epidermis of the skin.
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Affiliation(s)
- Dale Telgenhoff
- Clinical and Diagnostic Sciences, Oakland University, Rochester, Michigan, USA
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14
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Nyimanu D, Behm C, Choudhury S, Yu ASL. The role of claudin-2 in kidney function and dysfunction. Biochem Soc Trans 2023; 51:1437-1445. [PMID: 37387353 DOI: 10.1042/bst20220639] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 06/19/2023] [Accepted: 06/22/2023] [Indexed: 07/01/2023]
Abstract
Claudin-2 is a tight junction protein expressed in leaky epithelia where it forms paracellular pores permeable to cations and water. The paracellular pore formed by claudin-2 is important in energy-efficient cation and water transport in the proximal tubules of the kidneys. Mounting evidence now suggests that claudin-2 may modulate cellular processes often altered in disease, including cellular proliferation. Also, dysregulation of claudin-2 expression has been linked to various diseases, including kidney stone disease and renal cell carcinoma. However, the mechanisms linking altered claudin-2 expression and function to disease are poorly understood and require further investigation. The aim of this review is to discuss the current understanding of the role of claudin-2 in kidney function and dysfunction. We provide a general overview of the claudins and their organization in the tight junction, the expression, and function of claudin-2 in the kidney, and the evolving evidence for its role in kidney disease.
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Affiliation(s)
- Duuamene Nyimanu
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, U.S.A
| | - Christine Behm
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, U.S.A
| | - Sonali Choudhury
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, U.S.A
| | - Alan S L Yu
- The Jared Grantham Kidney Institute, University of Kansas Medical Center, 3901 Rainbow Blvd, Kansas City, KS 66160, U.S.A
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15
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Arabi TZ, Algheryafi LA, Alodah NA, Enabi HMK, Alshehry AA, Ouban A. Aberrant Expression of Claudins in Head and Neck Carcinomas and Their Prognostic and Therapeutic Value: A Narrative Review. Cancers (Basel) 2023; 15:4208. [PMID: 37686483 PMCID: PMC10486703 DOI: 10.3390/cancers15174208] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Revised: 08/03/2023] [Accepted: 08/11/2023] [Indexed: 09/10/2023] Open
Abstract
Head and neck carcinomas have been associated with poor prognosis. Recent studies have highlighted the role of claudins' expression in tumors throughout the body, and their prognostic and therapeutic role. Understanding the role of claudins and how their expression affects the progression of carcinomas in the head and neck region may allow for advances in the prognosis and management of this type of cancer. Several studies have highlighted the aberrant expression of the proteins in carcinomas in this region. Specifically, the overexpression of claudin-1 and downregulation of claudins-4, -7, and -17 have been linked with poor survival in oral squamous cell carcinoma patients. In laryngeal squamous cell carcinoma, increased levels of claudins-1 and reduced levels of claudins-3, -8, and -11 have been linked with poor outcomes. Targeting these proteins has shown promising outcomes as therapeutic in preclinical studies. However, studies remain extremely limited in nasal and hypopharyngeal carcinomas. In this review, we survey the available literature describing the aberrant expression of various claudins in carcinomas in this region, while highlighting their potential prognostic and therapeutic value. Then, we describe some molecular mechanisms involved in the aberrant expression of claudins and how they can be utilized as therapeutic targets.
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Affiliation(s)
- Tarek Ziad Arabi
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | | | - Nora A Alodah
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
| | | | | | - Abderrahman Ouban
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- Department of Pathology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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16
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Ouban A, Arabi TZ. Expression of Claudins in Preneoplastic Conditions of the Gastrointestinal Tract: A Review. Cancers (Basel) 2023; 15:4095. [PMID: 37627123 PMCID: PMC10452390 DOI: 10.3390/cancers15164095] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 08/06/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023] Open
Abstract
Premalignant lesions of the gastrointestinal tract are a group of disorders which act as the harbinger of malignant tumors. They are the ground-zero of neoplastic transformation, and their identification and management offer patients the best opportunity of blocking the progress of cancer. However, diagnoses of some of these conditions are hard to make, and their clinical importance is difficult to assess. Recent reports indicated that several claudin proteins have altered expressions in many cancers, including esophageal, gastric, colon, liver, and pancreatic cancers. The early identification of the aberrant expression of these proteins could lead to the early diagnosis and management of gastrointestinal tumors. Specifically, claudins -1, -2, -3, -4, and -18 are frequently overexpressed in gastrointestinal preneoplastic lesions. These altered expressions have shown clinical value in several tumors, providing diagnostic and prognostic information. In this article, we review the literature on the aberrant expression of claudins in preneoplastic lesions of the gastrointestinal tract. Additionally, we summarize their diagnostic and prognostic implications.
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Affiliation(s)
- Abderrahman Ouban
- Department of Pathology, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
| | - Tarek Ziad Arabi
- College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia;
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17
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Ahmad R, Kumar B, Tamang RL, Talmon GA, Dhawan P, Singh AB. P62/SQSTM1 binds with claudin-2 to target for selective autophagy in stressed intestinal epithelium. Commun Biol 2023; 6:740. [PMID: 37460613 PMCID: PMC10352296 DOI: 10.1038/s42003-023-05116-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2022] [Accepted: 07/07/2023] [Indexed: 07/20/2023] Open
Abstract
Impaired autophagy promotes Inflammatory Bowel Disease (IBD). Claudin-2 is upregulated in IBD however its role in the pathobiology remains uncertain due to its complex regulation, including by autophagy. Irrespective, claudin-2 expression protects mice from DSS colitis. This study was undertaken to examine if an interplay between autophagy and claudin-2 protects from colitis and associated epithelial injury. Crypt culture and intestinal epithelial cells (IECs) are subjected to stress, including starvation or DSS, the chemical that induces colitis in-vivo. Autophagy flux, cell survival, co-immunoprecipitation, proximity ligation assay, and gene mutational studies are performed. These studies reveal that under colitis/stress conditions, claudin-2 undergoes polyubiquitination and P62/SQSTM1-assisted degradation through autophagy. Inhibiting autophagy-mediated claudin-2 degradation promotes cell death and thus suggest that claudin-2 degradation promotes autophagy flux to promote cell survival. Overall, these data inform for the previously undescribed role for claudin-2 in facilitating IECs survival under stress conditions, which can be harnessed for therapeutic advantages.
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Affiliation(s)
- Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Balawant Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Raju Lama Tamang
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
- VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Amar B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA.
- Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
- VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
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18
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Capaldo CT. Claudin Barriers on the Brink: How Conflicting Tissue and Cellular Priorities Drive IBD Pathogenesis. Int J Mol Sci 2023; 24:8562. [PMID: 37239907 PMCID: PMC10218714 DOI: 10.3390/ijms24108562] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Revised: 05/08/2023] [Accepted: 05/09/2023] [Indexed: 05/28/2023] Open
Abstract
Inflammatory bowel diseases (IBDs) are characterized by acute or chronic recurring inflammation of the intestinal mucosa, often with increasing severity over time. Life-long morbidities and diminishing quality of life for IBD patients compel a search for a better understanding of the molecular contributors to disease progression. One unifying feature of IBDs is the failure of the gut to form an effective barrier, a core role for intercellular complexes called tight junctions. In this review, the claudin family of tight junction proteins are discussed as they are a fundamental component of intestinal barriers. Importantly, claudin expression and/or protein localization is altered in IBD, leading to the supposition that intestinal barrier dysfunction exacerbates immune hyperactivity and disease. Claudins are a large family of transmembrane structural proteins that constrain the passage of ions, water, or substances between cells. However, growing evidence suggests non-canonical claudin functions during mucosal homeostasis and healing after injury. Therefore, whether claudins participate in adaptive or pathological IBD responses remains an open question. By reviewing current studies, the possibility is assessed that with claudins, a jack-of-all-trades is master of none. Potentially, a robust claudin barrier and wound restitution involve conflicting biophysical phenomena, exposing barrier vulnerabilities and a tissue-wide frailty during healing in IBD.
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Affiliation(s)
- Christopher T Capaldo
- College of Natural and Computer Sciences, Hawai'i Pacific University, Honolulu, HI 96813, USA
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19
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Horowitz A, Chanez-Paredes SD, Haest X, Turner JR. Paracellular permeability and tight junction regulation in gut health and disease. Nat Rev Gastroenterol Hepatol 2023:10.1038/s41575-023-00766-3. [PMID: 37186118 PMCID: PMC10127193 DOI: 10.1038/s41575-023-00766-3] [Citation(s) in RCA: 255] [Impact Index Per Article: 127.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/03/2023] [Indexed: 05/17/2023]
Abstract
Epithelial tight junctions define the paracellular permeability of the intestinal barrier. Molecules can cross the tight junctions via two distinct size-selective and charge-selective paracellular pathways: the pore pathway and the leak pathway. These can be distinguished by their selectivities and differential regulation by immune cells. However, permeability increases measured in most studies are secondary to epithelial damage, which allows non-selective flux via the unrestricted pathway. Restoration of increased unrestricted pathway permeability requires mucosal healing. By contrast, tight junction barrier loss can be reversed by targeted interventions. Specific approaches are needed to restore pore pathway or leak pathway permeability increases. Recent studies have used preclinical disease models to demonstrate the potential of pore pathway or leak pathway barrier restoration in disease. In this Review, we focus on the two paracellular flux pathways that are dependent on the tight junction. We discuss the latest evidence that highlights tight junction components, structures and regulatory mechanisms, their impact on gut health and disease, and opportunities for therapeutic intervention.
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Affiliation(s)
- Arie Horowitz
- UNIROUEN, INSERM U1245, Normandy Centre for Genomic and Personalized Medicine, Normandie University, Rouen, France
| | - Sandra D Chanez-Paredes
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Xenia Haest
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Jerrold R Turner
- Laboratory of Mucosal Barrier Pathobiology, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
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20
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Lama Tamang R, Juritsch AF, Ahmad R, Salomon JD, Dhawan P, Ramer-Tait AE, Singh AB. The diet-microbiota axis: a key regulator of intestinal permeability in human health and disease. Tissue Barriers 2023; 11:2077069. [PMID: 35603609 PMCID: PMC10161950 DOI: 10.1080/21688370.2022.2077069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Accepted: 05/07/2022] [Indexed: 01/21/2023] Open
Abstract
The intestinal barrier orchestrates selective permeability to nutrients and metabolites while excluding noxious stimuli. Recent scientific advances establishing a causal role for the gut microbiota in human health outcomes have generated a resurgent interest toward intestinal permeability. Considering the well-established role of the gut barrier in protection against foreign antigens, there is mounting evidence for a causal link between gut permeability and the microbiome in regulating human health. However, an understanding of the dynamic host-microbiota interactions that govern intestinal barrier functions remains poorly defined. Furthermore, the system-level mechanisms by which microbiome-targeted therapies, such as probiotics and prebiotics, simultaneously promote intestinal barrier function and host health remain an area of active investigation. This review summarizes the recent advances in understanding the dynamics of intestinal permeability in human health and its integration with gut microbiota. We further summarize mechanisms by which probiotics/prebiotics influence the gut microbiota and intestinal barrier functions.
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Affiliation(s)
- Raju Lama Tamang
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Anthony F. Juritsch
- Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
| | - Jeffrey D. Salomon
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
| | - Amanda E. Ramer-Tait
- Department of Food Science and Technology, University of Nebraska-Lincoln, Lincoln, Nebraska, USA
| | - Amar B. Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska, USA
- Veterans Affairs Nebraska-Western Iowa Health Care System, Omaha, Nebraska, USA
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21
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Houillier P, Lievre L, Hureaux M, Prot-Bertoye C. Mechanisms of paracellular transport of magnesium in intestinal and renal epithelia. Ann N Y Acad Sci 2023; 1521:14-31. [PMID: 36622354 DOI: 10.1111/nyas.14953] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
Magnesium is the fourth most abundant cation in the body. It plays a critical role in many biological processes, including the process of energy release. Paracellular transport of magnesium is mandatory for magnesium homeostasis. In addition to intestinal absorption that occurs in part across the paracellular pathway, magnesium is reabsorbed by the kidney tubule. The bulk of magnesium is reabsorbed through the paracellular pathway in the proximal tubule and the thick ascending limb of the loop of Henle. The finding that rare genetic diseases due to pathogenic variants in genes encoding specific claudins (CLDNs), proteins located at the tight junction that determine the selectivity and the permeability of the paracellular pathway, led to an awareness of their importance in magnesium homeostasis. Familial hypomagnesemia with hypercalciuria and nephrocalcinosis is caused by a loss of function of CLDN16 or CLDN19. Pathogenic CLDN10 variants cause HELIX syndrome, which is associated with a severe renal loss of sodium chloride and hypermagnesemia. The present review summarizes the current knowledge of the mechanisms and factors involved in paracellular magnesium permeability. The review also highlights some of the unresolved questions that need to be addressed.
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Affiliation(s)
- Pascal Houillier
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
- CNRS ERL 8228 - Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Physiologie, Paris, France
- Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Paris, France
- Centre de Référence des Maladies Rares du Calcium et du Phosphate, Paris, France
| | - Loïc Lievre
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
- CNRS ERL 8228 - Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
| | - Marguerite Hureaux
- Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Génétique, Paris, France
- Paris Centre de Recherche Cardio-vasculaire, INSERM, Université Paris Cité, Paris, France
| | - Caroline Prot-Bertoye
- Centre de Recherche des Cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
- CNRS ERL 8228 - Laboratoire de Physiologie Rénale et Tubulopathies, Paris, France
- Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Service de Physiologie, Paris, France
- Centre de Référence des Maladies Rénales Héréditaires de l'Enfant et de l'Adulte (MARHEA), Paris, France
- Centre de Référence des Maladies Rares du Calcium et du Phosphate, Paris, France
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22
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Nehme Z, Roehlen N, Dhawan P, Baumert TF. Tight Junction Protein Signaling and Cancer Biology. Cells 2023; 12:243. [PMID: 36672179 PMCID: PMC9857217 DOI: 10.3390/cells12020243] [Citation(s) in RCA: 32] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/29/2022] [Accepted: 01/02/2023] [Indexed: 01/11/2023] Open
Abstract
Tight junctions (TJs) are intercellular protein complexes that preserve tissue homeostasis and integrity through the control of paracellular permeability and cell polarity. Recent findings have revealed the functional role of TJ proteins outside TJs and beyond their classical cellular functions as selective gatekeepers. This is illustrated by the dysregulation in TJ protein expression levels in response to external and intracellular stimuli, notably during tumorigenesis. A large body of knowledge has uncovered the well-established functional role of TJ proteins in cancer pathogenesis. Mechanistically, TJ proteins act as bidirectional signaling hubs that connect the extracellular compartment to the intracellular compartment. By modulating key signaling pathways, TJ proteins are crucial players in the regulation of cell proliferation, migration, and differentiation, all of which being essential cancer hallmarks crucial for tumor growth and metastasis. TJ proteins also promote the acquisition of stem cell phenotypes in cancer cells. These findings highlight their contribution to carcinogenesis and therapeutic resistance. Moreover, recent preclinical and clinical studies have used TJ proteins as therapeutic targets or prognostic markers. This review summarizes the functional role of TJ proteins in cancer biology and their impact for novel strategies to prevent and treat cancer.
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Affiliation(s)
- Zeina Nehme
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France
| | - Natascha Roehlen
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Freiburg University Medical Center, Faculty of Medicine, University of Freiburg, 79098 Freiburg, Germany
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, 68198 NE, USA
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, 68105 NE, USA
- VA Nebraska-Western Iowa Health Care System, Omaha, 68105-1850 NE, USA
| | - Thomas F. Baumert
- Université de Strasbourg, Inserm, Institut de Recherche sur les Maladies Virales et Hépatiques UMR_S1110, 67000 Strasbourg, France
- Institut Hospitalo-Universitaire (IHU), Pôle Hépato-Digestif, Hôpitaux Universitaires de Strasbourg, 67000 Strasbourg, France
- Institut Universitaire de France, 75006 Paris, France
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23
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Wang DW, Zhang WH, Danil G, Yang K, Hu JK. The role and mechanism of claudins in cancer. Front Oncol 2022; 12:1051497. [PMID: 36620607 PMCID: PMC9818346 DOI: 10.3389/fonc.2022.1051497] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2022] [Accepted: 11/28/2022] [Indexed: 12/24/2022] Open
Abstract
Claudins are a tetraspan membrane protein multigene family that plays a structural and functional role in constructing tight junctions. Claudins perform crucial roles in maintaining cell polarity in epithelial and endothelial cell sheets and controlling paracellular permeability. In the last two decades, increasing evidence indicates that claudin proteins play a major role in controlling paracellular permeability and signaling inside cells. Several types of claudins are dysregulated in various cancers. Depending on where the tumor originated, claudin overexpression or underexpression has been shown to regulate cell proliferation, cell growth, metabolism, metastasis and cell stemness. Epithelial-to-mesenchymal transition is one of the most important functions of claudin proteins in disease progression. However, the exact molecular mechanisms and signaling pathways that explain why claudin proteins are so important to tumorigenesis and progression have not been determined. In addition, claudins are currently being investigated as possible diagnostic and treatment targets. Here, we discuss how claudin-related signaling pathways affect tumorigenesis, tumor progression, and treatment sensitivity.
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Affiliation(s)
- De-Wen Wang
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Wei-Han Zhang
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Galiullin Danil
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China,Central Research Laboratory, Bashkir State Medical University, Ufa, Russia
| | - Kun Yang
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China
| | - Jian-Kun Hu
- Gastric Cancer Center and Laboratory of Gastric Cancer, Department of General Surgery, West China Hospital, Sichuan University, Chengdu, China,State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China,*Correspondence: Jian-Kun Hu,
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Eguchi H, Kimura R, Onuma S, Ito A, Yu Y, Yoshino Y, Matsunaga T, Endo S, Ikari A. Elevation of Anticancer Drug Toxicity by Caffeine in Spheroid Model of Human Lung Adenocarcinoma A549 Cells Mediated by Reduction in Claudin-2 and Nrf2 Expression. Int J Mol Sci 2022; 23:ijms232415447. [PMID: 36555089 PMCID: PMC9779108 DOI: 10.3390/ijms232415447] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 12/02/2022] [Accepted: 12/02/2022] [Indexed: 12/12/2022] Open
Abstract
Claudin-2 (CLDN2), a component of tight junctions, is abnormally expressed in human lung adenocarcinoma tissue. CLDN2 contributes to chemoresistance in human lung adenocarcinoma-derived A549 cells, and it may be a target for cancer therapy. Here, we found that coffee ingredients, namely caffeine and theobromine, decreased the protein level of CLDN2 in human lung adenocarcinoma-derived A549 cells. In contrast, other components, such as theophylline and chlorogenic acid, had no effect. These results indicate that the 7-methyl group in methylxanthines may play a key role in the reduction in CLDN2 expression. The caffeine-induced reduction in the CLDN2 protein was inhibited by chloroquine, a lysosome inhibitor. In a protein-stability assay using cycloheximide, CLDN2 protein levels decreased faster in caffeine-treated cells than in vehicle-treated cells. These results suggest that caffeine accelerates the lysosomal degradation of CLDN2. The accumulation and cytotoxicity of doxorubicin were dose-dependently increased, which was exaggerated by caffeine but not by theophylline in spheroids. Caffeine decreased nuclear factor-erythroid 2-related factor 2 (Nrf2) levels without affecting hypoxia-inducible factor-1α levels. Furthermore, caffeine decreased the expression of Nrf2-targeted genes. The effects of caffeine on CLDN2 expression and anticancer-drug-induced toxicity were also observed in lung adenocarcinoma RERF-LC-MS cells. We suggest that caffeine enhances doxorubicin-induced toxicity in A549 spheroids mediated by the reduction in CLDN2 and Nrf2 expression.
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Affiliation(s)
- Hiroaki Eguchi
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Riho Kimura
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Saki Onuma
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Ayaka Ito
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Yaqing Yu
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Yuta Yoshino
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Toshiyuki Matsunaga
- Laboratory of Bioinformatics, Gifu Pharmaceutical University, Gifu 502-8585, Japan
| | - Satoshi Endo
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
| | - Akira Ikari
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan
- Correspondence: ; Tel./Fax: +81-58-230-8124
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Yadav R, Kumar Y, Dahiya D, Bhatia A. Claudins: The Newly Emerging Targets in Breast Cancer. Clin Breast Cancer 2022; 22:737-752. [PMID: 36175290 DOI: 10.1016/j.clbc.2022.09.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 09/04/2022] [Indexed: 01/25/2023]
Abstract
Claudin-low breast cancers are recently described entities showing low expression of certain claudins and cell adhesion molecules. Claudins constitute the backbone of tight junctions (TJs) formed between 2 cells. Their dysregulation plays a vital role in tumorigenesis. First part of the article focuses on the role of claudins in the TJ organization, their structural-functional characteristics, and post-transcriptional and translational modifications. The latter part of the review attempts to summarize existing knowledge regarding the status of claudins in breast cancer. The article also provides an overview of the effect of claudins on tumor progression, metastasis, stemness, chemotherapy resistance, and their crosstalk with relevant signaling pathways in breast cancer. Claudins can act as 2-edged swords in tumors. Some claudins have either tumor-suppressive/ promoting action, while others work as both in a context-dependent manner. Claudins regulate many important events in breast cancer. However, the intricacies involved in their activity are poorly understood. Post-translational modifications in claudins and their impact on TJ integrity, function, and tumor behavior are still unclear. Although their role in adverse events in breast cancer is recognized, their potential to serve as relevant targets for future therapeutics, especially for difficult-to-treat subtypes of the above malignancy, remains to be explored.
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Affiliation(s)
- Reena Yadav
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Yashwant Kumar
- Department of Immunopathology, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Divya Dahiya
- Department of General Surgery, Postgraduate Institute of Medical Education and Research, Chandigarh, India
| | - Alka Bhatia
- Department of Experimental Medicine and Biotechnology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.
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26
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Giri S, Uehara O, Takada A, Paudel D, Morikawa T, Arakawa T, Nagasawa T, Abiko Y, Furuichi Y. The effect of Porphyromonas gingivalis on the gut microbiome of mice in relation to aging. J Periodontal Res 2022; 57:1256-1266. [PMID: 36251393 DOI: 10.1111/jre.13062] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 09/05/2022] [Accepted: 09/27/2022] [Indexed: 11/27/2022]
Abstract
BACKGROUND AND OBJECTIVE The translocation of oral bacteria, including Porphyromonas gingivalis, to the gut has been shown to alter gut microbiome. However, the effect of P. gingivalis on gut microbiome in relation to aging has not been demonstrated. We hypothesize that P. gingivalis has more detrimental effect on gut environment with increased age. The objective of this study is to investigate the effect of P. gingivalis on gut environment using aged mice. MATERIALS AND METHODS C57BL/6J mice aged 4 weeks (young) or 76 weeks (old) were divided into four groups: control-young, control-old, P. gingivalis-administered young, and P. gingivalis-administered old. P. gingivalis was orally administered thrice weekly for 5 weeks. At 30 days after the last P. gingivalis administration, 16S rRNA sequencing was performed to study the gut microbiome. The mRNA and protein expression of intestinal junctional barrier molecules and the levels of the inflammatory cytokines IL-1β and TNF-α in the serum were evaluated. RESULTS Significant differences in the gut microbiomes between the groups, in terms of taxonomic abundance, bacterial diversity, and predicted metagenome function, were observed. A significant reduction in the alpha diversity and in the abundance of beneficial bacteria, such as Akkermansia and Clostridiaceae, in the P. gingivalis-administered old mice was observed. The mRNA and protein levels of Claudin-1 and Claudin-2 in the intestine were significantly elevated, while E-cadherin was significantly downregulated in the P. gingivalis-administered old mice, as were the serum levels of IL-1β and TNF-α. CONCLUSION The effect of P. gingivalis on the gut environment is more pronounced in old mice than in young mice.
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Affiliation(s)
- Sarita Giri
- Division of Periodontology and Endodontology, Department of Oral Rehabilitation, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Osamu Uehara
- Division of Disease Control and Molecular Epidemiology, Department of Oral Growth and Development, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Ayuko Takada
- Division of Biochemistry, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Durga Paudel
- Advanced Research Promotion Center, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Tetsuro Morikawa
- Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Toshiya Arakawa
- Division of Biochemistry, Department of Oral Biology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Toshiyuki Nagasawa
- Division of Advanced Clinical Education, Department of Integrated Dental Education, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Yoshihiro Abiko
- Division of Oral Medicine and Pathology, Department of Human Biology and Pathophysiology, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan
| | - Yasushi Furuichi
- Division of Periodontology and Endodontology, Department of Oral Rehabilitation, School of Dentistry, Health Sciences University of Hokkaido, Hokkaido, Japan
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Xu QR, Du XH, Huang TT, Zheng YC, Li YL, Huang DY, Dai HQ, Li EM, Fang WK. Role of Cell-Cell Junctions in Oesophageal Squamous Cell Carcinoma. Biomolecules 2022; 12:biom12101378. [PMID: 36291586 PMCID: PMC9599896 DOI: 10.3390/biom12101378] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Revised: 09/20/2022] [Accepted: 09/21/2022] [Indexed: 02/05/2023] Open
Abstract
Cell-cell junctions comprise various structures, including adherens junctions, tight junctions, desmosomes, and gap junctions. They link cells to each other in tissues and regulate tissue homeostasis in critical cellular processes. Recent advances in cell-cell junction research have led to critical discoveries. Cell-cell adhesion components are important for the invasion and metastasis of tumour cells, which are not only related to cell-cell adhesion changes, but they are also involved in critical molecular signal pathways. They are of great significance, especially given that relevant molecular mechanisms are being discovered, there are an increasing number of emerging biomarkers, targeted therapies are becoming a future therapeutic concern, and there is an increased number of therapeutic agents undergoing clinical trials. Oesophageal squamous cell carcinoma (ESCC), the most common histological subtype of oesophageal cancer, is one of the most common cancers to affect epithelial tissue. ESCC progression is accompanied by the abnormal expression or localisation of components at cell-cell junctions. This review will discuss the recent scientific developments related to the molecules at cell-cell junctions and their role in ESCC to offer valuable insights for readers, provide a global view of the relationships between position, construction, and function, and give a reference for future mechanistic studies, diagnoses, and therapeutic developments.
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Affiliation(s)
| | | | | | | | | | | | | | - En-Min Li
- Correspondence: (E.-M.L.); (W.-K.F.)
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Ganapathy AS, Saha K, Suchanec E, Singh V, Verma A, Yochum G, Koltun W, Nighot M, Ma T, Nighot P. AP2M1 mediates autophagy-induced CLDN2 (claudin 2) degradation through endocytosis and interaction with LC3 and reduces intestinal epithelial tight junction permeability. Autophagy 2022; 18:2086-2103. [PMID: 34964704 PMCID: PMC9466623 DOI: 10.1080/15548627.2021.2016233] [Citation(s) in RCA: 51] [Impact Index Per Article: 17.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
The intestinal epithelial tight junctions (TJs) provide barrier against paracellular permeation of lumenal antigens. Defects in TJ barrier such as increased levels of pore-forming TJ protein CLDN2 (claudin-2) is associated with inflammatory bowel disease. We have previously reported that starvation-induced macroautophagy/autophagy enhances the TJ barrier by degrading pore-forming CLDN2. In this study, we examined the molecular mechanism underlying autophagy-induced CLDN2 degradation. CLDN2 degradation was persistent in multiple modes of autophagy induction. Immunolocalization, membrane fractionation, and pharmacological inhibition studies showed increased clathrin-mediated CLDN2 endocytosis upon starvation. Inhibition of clathrin-mediated endocytosis negated autophagy-induced CLDN2 degradation and enhancement of the TJ barrier. The co-immunoprecipitation studies showed increased association of CLDN2 with clathrin and adaptor protein AP2 (AP2A1 and AP2M1 subunits) as well as LC3 and lysosomes upon starvation, signifying the role of clathrin-mediated endocytosis in autophagy-induced CLDN2 degradation. The expression and phosphorylation of AP2M1 was increased upon starvation. In-vitro, in-vivo (mouse colon), and ex-vivo (human colon) inhibition of AP2M1 activation prevented CLDN2 degradation. AP2M1 knockout prevented autophagy-induced CLDN2 degradation via reduced CLDN2-LC3 interaction. Site-directed mutagenesis revealed that AP2M1 binds to CLDN2 tyrosine motifs (YXXФ) (67-70 and 148-151). Increased baseline expression of CLDN2 and TJ permeability along with reduced CLDN2-AP2M1-LC3 interactions in ATG7 knockout cells validated the role of autophagy in modulation of CLDN2 levels. Acute deletion of Atg7 in mice increased CLDN2 levels and the susceptibility to experimental colitis. The autophagy-regulated molecular mechanisms linking CLDN2, AP2M1, and LC3 may provide therapeutic tools against intestinal inflammation.Abbreviations: Amil: amiloride; AP2: adaptor protein complex 2; AP2A1: adaptor related protein complex 2 subunit alpha 1; AP2M1: adaptor related protein complex 2 subunit mu 1; ATG7: autophagy related 7; CAL: calcitriol; Cas9: CRISPR-associated protein 9; Con: control; CPZ: chlorpromazine; DSS: dextran sodium sulfate; EBSS: Earle's balanced salt solution; IBD: inflammatory bowel disease; TER: trans-epithelial resistance; KD: knockdown; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MβCD: Methyl-β-cyclodextrin; MET: metformin; MG132: carbobenzoxy-Leu-Leu-leucinal; MTOR: mechanistic target of rapamycin kinase; NT: non target; RAPA: rapamycin; RES: resveratrol; SMER: small-molecule enhancer 28; SQSTM1: sequestosome 1; ST: starvation; ULK1: unc-51 like autophagy activating kinase 1; WT: wild type.
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Affiliation(s)
| | - Kushal Saha
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Eric Suchanec
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Vikash Singh
- Division of Hematology and Oncology, Department of Pediatrics, Pennsylvania State College of Medicine, Hershey, Pa, USA
| | - Aayush Verma
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Gregory Yochum
- Division of Colon and Rectal Surgery, Department of Surgery, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Walter Koltun
- Division of Colon and Rectal Surgery, Department of Surgery, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Meghali Nighot
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Thomas Ma
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA, USA
| | - Prashant Nighot
- Division of Gastroenterology and Hepatology, Department of Medicine, Pennsylvania State College of Medicine, Hershey, PA, USA,CONTACT Prashant Nighot Department of Medicine, College of Medicine, Penn State University, Hershey, PA17033, USA
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Eguchi H, Kimura R, Matsunaga H, Matsunaga T, Yoshino Y, Endo S, Ikari A. Increase in Anticancer Drug-Induced Toxicity by Fisetin in Lung Adenocarcinoma A549 Spheroid Cells Mediated by the Reduction of Claudin-2 Expression. Int J Mol Sci 2022; 23:ijms23147536. [PMID: 35886884 PMCID: PMC9316057 DOI: 10.3390/ijms23147536] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 11/26/2022] Open
Abstract
Claudin-2 (CLDN2), a component of tight junction, is involved in the reduction of anticancer drug-induced toxicity in spheroids of A549 cells derived from human lung adenocarcinoma. Fisetin, a dietary flavonoid, inhibits cancer cell growth, but its effect on chemosensitivity in spheroids is unknown. Here, we found that fisetin (20 μM) decreases the protein level of CLDN2 to 22.3%. Therefore, the expression mechanisms were investigated by real-time polymerase chain reaction and Western blotting. Spheroids were formed in round-bottom plates, and anticancer drug-induced toxicity was measured by ATP content. Fisetin decreased the phosphorylated-Akt level, and CLDN2 expression was decreased by a phosphatidylinositol 3-kinase (PI3K) inhibitor, suggesting the inhibition of PI3K/Akt signal is involved in the reduction of CLDN2 expression. Hypoxia level, one of the hallmarks of tumor microenvironment, was reduced by fisetin. Although fisetin did not change hypoxia inducible factor-1α level, it decreased the protein level of nuclear factor erythroid 2-related factor 2, a stress response factor, by 25.4% in the spheroids. The toxicity of doxorubicin (20 μM) was enhanced by fisetin from 62.8% to 40.9%, which was rescued by CLDN2 overexpression (51.7%). These results suggest that fisetin can enhance anticancer drug toxicity in A549 spheroids mediated by the reduction of CLDN2 expression.
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Affiliation(s)
- Hiroaki Eguchi
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan; (H.E.); (R.K.); (H.M.); (Y.Y.); (S.E.)
| | - Riho Kimura
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan; (H.E.); (R.K.); (H.M.); (Y.Y.); (S.E.)
| | - Haruka Matsunaga
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan; (H.E.); (R.K.); (H.M.); (Y.Y.); (S.E.)
| | - Toshiyuki Matsunaga
- Education Center of Green Pharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 502-8585, Japan;
| | - Yuta Yoshino
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan; (H.E.); (R.K.); (H.M.); (Y.Y.); (S.E.)
| | - Satoshi Endo
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan; (H.E.); (R.K.); (H.M.); (Y.Y.); (S.E.)
| | - Akira Ikari
- Laboratory of Biochemistry, Department of Biopharmaceutical Sciences, Gifu Pharmaceutical University, Gifu 501-1196, Japan; (H.E.); (R.K.); (H.M.); (Y.Y.); (S.E.)
- Correspondence: ; Tel./Fax: +81-58-230-8124
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30
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Aggarwal H, Pathak P, Gupta SK, Kumar Y, Jagavelu K, Dikshit M. Serum and cecal metabolic profile of the insulin resistant and dyslipidemic p47 phox knockout mice. Free Radic Res 2022; 56:483-497. [PMID: 36251883 DOI: 10.1080/10715762.2022.2133705] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Involvement of NOX-dependent oxidative stress in the pathophysiology of metabolic disorders as well as in the maintenance of metabolic homeostasis has been demonstrated previously. In the present study, the metabolic profile in p47phox-/- and WT mice fed on a chow diet was evaluated to assess the role of metabolites in glucose intolerance and dyslipidemia under altered oxidative stress conditions. p47phox-/- mice displayed glucose intolerance, dyslipidemia, hyperglycemia, insulin resistance (IR), hyperinsulinemia, and altered energy homeostasis without any significant change in gluconeogenesis. The expression of genes involved in lipid synthesis and uptake was enhanced in the liver, adipose tissue, and intestine tissues. Similarly, the expression of genes associated with lipid efflux in the liver and intestine was also enhanced. Enhanced gut permeability, inflammation, and shortening of the gut was evident in p47phox-/- mice. Circulating levels of pyrimidines, phosphatidylglycerol lipids, and 3-methyl-2-oxindole were augmented, while level of purine was reduced in the serum. Moreover, the cecal metabolome was also altered, as was evident with the increase in indole-3-acetamide, N-acetyl galactosamine, glycocholate, and a decrease in hippurate, indoxyl sulfate, and indigestible sugars (raffinose and melezitose). Treatment of p47phox-/- mice with pioglitazone, marginally improved glucose intolerance, and dyslipidemia, with an increase in PUFAs (linoleate, docosahexaenoic acid, and arachidonic acid). Overall, the results obtained in p47phox-/- mice indicate an association of IR and dyslipidemia with altered serum and cecal metabolites (both host and bacterial-derived), implying a critical role of NOX-derived ROS in metabolic homeostasis.
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Affiliation(s)
- Hobby Aggarwal
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India.,Non-Communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Priya Pathak
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India
| | - Sonu Kumar Gupta
- Non-Communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, India
| | - Yashwant Kumar
- Non-Communicable Diseases Division, Translational Health Science and Technology Institute, Faridabad, India
| | | | - Madhu Dikshit
- Pharmacology Division, CSIR-Central Drug Research Institute, Lucknow, India.,Translational Health Science and Technology Institute, Faridabad, India
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Iyer DN, Foo DCC, Lo OSH, Wan TMH, Li X, Sin RWY, Pang RWC, Law WL, Ng L. MiR-509-3p is oncogenic, targets the tumor suppressor PHLPP2, and functions as a novel tumor adjacent normal tissue based prognostic biomarker in colorectal cancer. BMC Cancer 2022; 22:351. [PMID: 35361144 PMCID: PMC8969217 DOI: 10.1186/s12885-021-09075-x] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2021] [Accepted: 11/30/2021] [Indexed: 12/28/2022] Open
Abstract
Background Recently the role of microRNAs has been explored immensely as novel regulators and potential biomarkers in several cancers. MiR-509-3p is one such miRNA that has been observed to show a mixed expression in different cancers, while it’s expression and clinical relevance in colorectal cancer (CRC) has not yet been characterized. Methods We used quantitative PCR to evaluate the expression of miR-509-3p in fresh-frozen CRC tumor tissues and the corresponding tumor-adjacent normal (NAT) tissues from 103 patients. Subsequently, functional studies were performed to further interpret the role of the miRNA in CRC. Results MiR-509-3p was found to be overexpressed in CRC tissues in nearly 80% of cases and was associated with an aggressive disease presentation. Notably, a higher expression of the miRNA promoted cell proliferation, migration, and invasion of CRC cells in in vitro and in vivo models. Mechanistically, we confirmed that miR-509-3p directly binds the 3’UTR of the tumor suppressor PHLPP2 and inhibits its expression. Furthermore, within the previous 103 clinical tissue specimens, we observed an overexpression of miR-509-3p within the NAT tissue of patients associated with a poor disease prognosis. Using multivariate analysis, it was observed that the expression of miR-509-3p within the NAT tissue was an independent predictor of prognosis in CRC. At the cellular level, through indirect coculture experiments, miR-509-3p was observed to regulate the proliferative, migratory, and invasive behavior of normal colon cells. Conclusion MiR-509-3p strongly contributes to the development and progression of CRC and can potentially function as a prognostic biomarker in the disease. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-021-09075-x.
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Affiliation(s)
- Deepak Narayanan Iyer
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Dominic Chi-Chung Foo
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Oswens Siu-Hung Lo
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Timothy Ming-Hun Wan
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Xue Li
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Ryan Wai-Yan Sin
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Roberta Wen-Chi Pang
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Wai-Lun Law
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China
| | - Lui Ng
- Department of Surgery, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
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Vitamin D Receptor Influences Intestinal Barriers in Health and Disease. Cells 2022; 11:cells11071129. [PMID: 35406694 PMCID: PMC8997406 DOI: 10.3390/cells11071129] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2022] [Revised: 03/23/2022] [Accepted: 03/24/2022] [Indexed: 12/12/2022] Open
Abstract
Vitamin D receptor (VDR) executes most of the biological functions of vitamin D. Beyond this, VDR is a transcriptional factor regulating the expression levels of many target genes, such as genes for tight junction proteins claudin-2, -5, -12, and -15. In this review, we discuss the progress of research on VDR that influences intestinal barriers in health and disease. We searched PubMed and Google Scholar using key words vitamin D, VDR, tight junctions, cancer, inflammation, and infection. We summarize the literature and progress reports on VDR regulation of tight junction distribution, cellular functions, and mechanisms (directly or indirectly). We review the impacts of VDR on barriers in various diseases, e.g., colon cancer, infection, inflammatory bowel disease, and chronic inflammatory lung diseases. We also discuss the limits of current studies and future directions. Deeper understanding of the mechanisms by which the VDR signaling regulates intestinal barrier functions allow us to develop efficient and effective therapeutic strategies based on levels of tight junction proteins and vitamin D/VDR statuses for human diseases.
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Yang L, Zhang W, Li M, Dam J, Huang K, Wang Y, Qiu Z, Sun T, Chen P, Zhang Z, Zhang W. Evaluation of the Prognostic Relevance of Differential Claudin Gene Expression Highlights Claudin-4 as Being Suppressed by TGFβ1 Inhibitor in Colorectal Cancer. Front Genet 2022; 13:783016. [PMID: 35281827 PMCID: PMC8907593 DOI: 10.3389/fgene.2022.783016] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Accepted: 01/25/2022] [Indexed: 11/13/2022] Open
Abstract
Background: Claudins (CLDNs) are a family of closely related transmembrane proteins that have been linked to oncogenic transformation and metastasis across a range of cancers, suggesting that they may be valuable diagnostic and/or prognostic biomarkers that can be used to evaluate patient outcomes. However, CLDN expression patterns associated with colorectal cancer (CRC) remain to be defined.Methods: The mRNA levels of 21 different CLDN family genes were assessed across 20 tumor types using the Oncomine database. Correlations between these genes and patient clinical outcomes, immune cell infiltration, clinicopathological staging, lymph node metastasis, and mutational status were analyzed using the GEPIA, UALCAN, Human Protein Atlas, Tumor Immune Estimation Resource, STRING, Genenetwork, cBioportal, and DAVID databases in an effort to clarify the potential functional roles of different CLDN protein in CRC. Molecular docking analyses were used to probe potential interactions between CLDN4 and TGFβ1. Levels of CLDN4 and CLDN11 mRNA expression in clinical CRC patient samples and in the HT29 and HCT116 cell lines were assessed via qPCR. CLDN4 expression levels in these 2 cell lines were additionally assessed following TGFβ1 inhibitor treatment.Results: These analyses revealed that COAD and READ tissues exhibited the upregulation of CLDN1, CLDN2, CLDN3, CLDN4, CLDN7, and CLDN12 as well as the downregulation of CLDN5 and CLDN11 relative to control tissues. Higher CLDN11 and CLDN14 expression as well as lower CLDN23 mRNA levels were associated with poorer overall survival (OS) outcomes. Moreover, CLDN2 and CLDN3 or CLDN11 mRNA levels were significantly associated with lymph node metastatic progression in COAD or READ lower in COAD and READ tissues. A positive correlation between the expression of CLDN11 and predicted macrophage, dendritic cell, and CD4+ T cell infiltration was identified in CRC, with CLDN12 expression further being positively correlated with CD4+ T cell infiltration whereas a negative correlation was observed between such infiltration and the expression of CLDN3 and CLDN15. A positive correlation between CLDN1, CLDN16, and neutrophil infiltration was additionally detected, whereas neutrophil levels were negatively correlated with the expression of CLDN3 and CLDN15. Molecular docking suggested that CLDN4 was able to directly bind via hydrogen bond with TGFβ1. Relative to paracancerous tissues, clinical CRC tumor tissue samples exhibited CLDN4 and CLDN11 upregulation and downregulation, respectively. LY364947 was able to suppress the expression of CLDN4 in both the HT29 and HCT116 cell lines.Conclusion: Together, these results suggest that the expression of different CLDN family genes is closely associated with CRC tumor clinicopathological staging and immune cell infiltration. Moreover, CLDN4 expression is closely associated with TGFβ1 in CRC, suggesting that it and other CLDN family members may represent viable targets for antitumor therapeutic intervention.
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Affiliation(s)
- Linqi Yang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Wenqi Zhang
- Department of Hematology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Meng Li
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Jinxi Dam
- College of Natural Science, Michigan State University, East Lansing, MI, United States
| | - Kai Huang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yihan Wang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Zhicong Qiu
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Tao Sun
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Pingping Chen
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China
- *Correspondence: Wei Zhang, ; Pingping Chen, ; Zhenduo Zhang,
| | - Zhenduo Zhang
- Shijiazhuang People’s Hospital, Shijiazhuang, China
- *Correspondence: Wei Zhang, ; Pingping Chen, ; Zhenduo Zhang,
| | - Wei Zhang
- Department of Pharmacology, Hebei University of Chinese Medicine, Shijiazhuang, China
- *Correspondence: Wei Zhang, ; Pingping Chen, ; Zhenduo Zhang,
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Dissecting the Mechanism of Action of Spiperone-A Candidate for Drug Repurposing for Colorectal Cancer. Cancers (Basel) 2022; 14:cancers14030776. [PMID: 35159043 PMCID: PMC8834219 DOI: 10.3390/cancers14030776] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/25/2022] [Accepted: 01/29/2022] [Indexed: 02/05/2023] Open
Abstract
Simple Summary Despite advances in primary and adjuvant treatments, approximately 50% of colorectal cancer (CRC) patients still die from recurrence and metastatic disease. Thus, alternative and more effective therapeutic approaches are expected to be developed. Drug repurposing is increasing interest in cancer therapy, as it represents a cheaper and faster alternative strategy to de novo drug synthesis. Psychiatric medications are promising as a new generation of antitumor drugs. Here, we demonstrate that spiperone—a licensed drug for the treatment of schizophrenia—induces apoptosis in CRC cells. Our data reveal that spiperone’s cytotoxicity in CRC cells is mediated by phospholipase C activation, intracellular calcium homeostasis dysregulation, and irreversible endoplasmic reticulum stress induction, resulting in lipid metabolism alteration and Golgi apparatus damage. By identifying new targetable pathways in CRC cells, our findings represent a promising starting point for the design of novel therapeutic strategies for CRC. Abstract Approximately 50% of colorectal cancer (CRC) patients still die from recurrence and metastatic disease, highlighting the need for novel therapeutic strategies. Drug repurposing is attracting increasing attention because, compared to traditional de novo drug discovery processes, it may reduce drug development periods and costs. Epidemiological and preclinical evidence support the antitumor activity of antipsychotic drugs. Herein, we dissect the mechanism of action of the typical antipsychotic spiperone in CRC. Spiperone can reduce the clonogenic potential of stem-like CRC cells (CRC-SCs) and induce cell cycle arrest and apoptosis, in both differentiated and CRC-SCs, at clinically relevant concentrations whose toxicity is negligible for non-neoplastic cells. Analysis of intracellular Ca2+ kinetics upon spiperone treatment revealed a massive phospholipase C (PLC)-dependent endoplasmic reticulum (ER) Ca2+ release, resulting in ER Ca2+ homeostasis disruption. RNA sequencing revealed unfolded protein response (UPR) activation, ER stress, and induction of apoptosis, along with IRE1-dependent decay of mRNA (RIDD) activation. Lipidomic analysis showed a significant alteration of lipid profile and, in particular, of sphingolipids. Damage to the Golgi apparatus was also observed. Our data suggest that spiperone can represent an effective drug in the treatment of CRC, and that ER stress induction, along with lipid metabolism alteration, represents effective druggable pathways in CRC.
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Implication of Intestinal Barrier Dysfunction in Gut Dysbiosis and Diseases. Biomedicines 2022; 10:biomedicines10020289. [PMID: 35203499 PMCID: PMC8869546 DOI: 10.3390/biomedicines10020289] [Citation(s) in RCA: 147] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2021] [Revised: 01/21/2022] [Accepted: 01/24/2022] [Indexed: 02/04/2023] Open
Abstract
The intestinal mucosal barrier, also referred to as intestinal barrier, is widely recognized as a critical player in gut homeostasis maintenance as it ensures the complex crosstalk between gut microbes (both commensals and pathogens) and the host immune system. Highly specialized epithelial cells constantly cope with several protective and harmful agents to maintain the multiple physiological functions of the barrier as well as its integrity. However, both genetic defects and environmental factors can break such equilibrium, thus promoting gut dysbiosis, dysregulated immune-inflammatory responses, and even the development of chronic pathological conditions. Here, we review and discuss the molecular and cellular pathways underlying intestinal barrier structural and functional homeostasis, focusing on potential alterations that may undermine this fine balance.
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Kyuno D, Takasawa A, Takasawa K, Ono Y, Aoyama T, Magara K, Nakamori Y, Takemasa I, Osanai M. Claudin-18.2 as a therapeutic target in cancers: cumulative findings from basic research and clinical trials. Tissue Barriers 2022; 10:1967080. [PMID: 34486479 PMCID: PMC8794250 DOI: 10.1080/21688370.2021.1967080] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 08/06/2021] [Accepted: 08/07/2021] [Indexed: 12/25/2022] Open
Abstract
Claudins are major components of tight junctions that maintain cell polarity and intercellular adhesion. The dynamics of claudins in cancer cells have attracted attention as a therapeutic target. During carcinogenesis, claudin expression is generally downregulated; however, overexpression of claudin-18.2 has been observed in several types of cancers. Upregulated and mislocalized claudin-18.2 expression in cancer cells has been suggested as a therapeutic target. Research on claudin-18.2 has revealed its involvement in carcinogenesis. Clinical trials using zolbetuximab, a monoclonal antibody targeting claudin-18.2, for patients with advanced cancer yielded positive results with few high-grade adverse events; thus, it is expected to be a novel and effective therapeutic. Here, we review current insights into the role that claudin-18.2 plays in basic cancer research and clinical applications. A better understanding of these roles will facilitate the development of new treatment strategies for cancer patients with poor prognoses.
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Affiliation(s)
- Daisuke Kyuno
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Japan
| | - Akira Takasawa
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Kumi Takasawa
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Yusuke Ono
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Tomoyuki Aoyama
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Kazufumi Magara
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Yuna Nakamori
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
| | - Ichiro Takemasa
- Department of Surgery, Surgical Oncology and Science, Sapporo Medical University, Sapporo, Japan
| | - Makoto Osanai
- Department of Pathology, Sapporo Medical University, Sapporo, Japan
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Chu YD, Lim SN, Yeh CT, Lin WR. COX5B-Mediated Bioenergetic Alterations Modulate Cell Growth and Anticancer Drug Susceptibility by Orchestrating Claudin-2 Expression in Colorectal Cancers. Biomedicines 2021; 10:60. [PMID: 35052740 PMCID: PMC8772867 DOI: 10.3390/biomedicines10010060] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2021] [Revised: 12/21/2021] [Accepted: 12/27/2021] [Indexed: 11/23/2022] Open
Abstract
Oxidative phosphorylation (OXPHOS) consists of four enzyme complexes and ATP synthase, and is crucial for maintaining physiological tissue and cell growth by supporting the main bioenergy pool. Cytochrome c oxidase (COX) has been implicated as a primary regulatory site of OXPHOS. Recently, COX subunit 5B (COX5B) emerged as a potential biomarker associated with unfavorable prognosis by modulating cell behaviors in specific cancer types. However, its molecular mechanism remains unclear, particularly in colorectal cancers (CRCs). To understand the role of COX5B in CRCs, the expression and postoperative outcome associations using independent in-house patient cohorts were evaluated. A higher COX5B tumor/nontumor expression ratio was associated with unfavorable clinical outcomes (p = 0.001 and 0.011 for overall and disease-free survival, respectively. In cell-based experiments, the silencing of COX5B repressed cell growth and enhanced the susceptibility of CRCs cells to anticancer drugs. Finally, downstream effectors identified by RNA sequencing followed by RT-qPCR and functional compensation experiments revealed that the tight junction protein Claudin-2 (CLDN2) acts downstream of COX5B-mediated bioenergetic alterations in controlling cell growth and the sensitivity to anticancer drugs in CRCs cells. In conclusion, it was found that COX5B promoted cell growth and attenuated anticancer drugs susceptibility in CRCs cells by orchestrating CLDN2 expression, which may contribute to unfavorable postoperative outcomes of patients with CRCs.
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Affiliation(s)
- Yu-De Chu
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
| | - Siew-Na Lim
- Department of Neurology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Chau-Ting Yeh
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Molecular Medicine Research Center, Chang Gung University, Taoyuan 333, Taiwan
- Department of Hepatology and Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
| | - Wey-Ran Lin
- Liver Research Center, Chang Gung Memorial Hospital, Taoyuan 333, Taiwan;
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Hepatology and Gastroenterology, Linkou Chang Gung Memorial Hospital, Taoyuan 333, Taiwan
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Wei M, Zhang Y, Yang X, Ma P, Li Y, Wu Y, Chen X, Deng X, Yang T, Mao X, Qiu L, Meng W, Zhang B, Wang Z, Han J. Claudin-2 promotes colorectal cancer growth and metastasis by suppressing NDRG1 transcription. Clin Transl Med 2021; 11:e667. [PMID: 34965023 PMCID: PMC8715829 DOI: 10.1002/ctm2.667] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Revised: 11/11/2021] [Accepted: 11/17/2021] [Indexed: 02/05/2023] Open
Abstract
Colorectal cancer (CRC) is one of the most common malignant tumours, with multiple driving factors and biological transitions involved in its development. Claudin-2 (CLDN2), a well-defined component of cellular tight junction, has been indicated to associate with CRC progression. However, the function of CLDN2 and the underlying mechanism whereby the downstream signalling transduction is regulated in CRC remains largely unclear. In this study, we demonstrated that CLDN2 is upregulated in CRC samples and associated with poor survival. And CLDN2 depletion significantly promotes N-myc downstream-regulated gene 1 (NDRG1) transcription, leading to termination of the CRC growth and metastasis in vitro and in vivo. Mechanistically, this process promotes CLDN2/ZO1/ZONAB complex dissociation and ZONAB shuttle into nucleus to enrich in the promoter of NDRG1. Thus, this study reveals a novel CLDN2/ZO1/ZONAB-NDRG1 axis in CRC by regulating the expression of EMT-related genes and CDKIs, suggesting CLDN2 may serve as a promising target for CRC treatment.
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Affiliation(s)
- Mingtian Wei
- Department of Gastrointestinal SurgeryFrontiers Science Center for Disease‐related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Yaguang Zhang
- Research Laboratory of Tumors Epigenetics and GenomicsDepartment of General SurgeryFrontiers Science Center for Disease‐related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Xuyang Yang
- Department of Gastrointestinal SurgeryFrontiers Science Center for Disease‐related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Pingfan Ma
- Research Laboratory of Tumors Epigenetics and GenomicsDepartment of General SurgeryFrontiers Science Center for Disease‐related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Yan Li
- Research Laboratory of Tumors Epigenetics and GenomicsDepartment of General SurgeryFrontiers Science Center for Disease‐related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Yangping Wu
- Department of Respiratory and Critical Care MedicineState Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
- Department of Clinical Research ManagementWest China HospitalSichuan UniversityChengduChina
| | - Xiangzheng Chen
- Department of Liver Surgery & Liver Transplantation CenterWest China HospitalSichuan UniversityChengduChina
| | - Xiangbing Deng
- Department of Gastrointestinal SurgeryFrontiers Science Center for Disease‐related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Tinghan Yang
- Department of Gastrointestinal SurgeryFrontiers Science Center for Disease‐related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Xiaobing Mao
- Research Laboratory of Tumors Epigenetics and GenomicsDepartment of General SurgeryFrontiers Science Center for Disease‐related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Lei Qiu
- Research Laboratory of Tumors Epigenetics and GenomicsDepartment of General SurgeryFrontiers Science Center for Disease‐related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Wenjian Meng
- Department of Gastrointestinal SurgeryFrontiers Science Center for Disease‐related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Bo Zhang
- Department of Gastrointestinal SurgeryFrontiers Science Center for Disease‐related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
- Research Laboratory of Tumors Epigenetics and GenomicsDepartment of General SurgeryFrontiers Science Center for Disease‐related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduChina
| | - Ziqiang Wang
- Department of Gastrointestinal SurgeryFrontiers Science Center for Disease‐related Molecular Network and State Key Laboratory of BiotherapyWest China HospitalSichuan UniversityChengduChina
| | - Junhong Han
- Research Laboratory of Tumors Epigenetics and GenomicsDepartment of General SurgeryFrontiers Science Center for Disease‐related Molecular NetworkState Key Laboratory of Biotherapy and Cancer CenterWest China HospitalSichuan UniversityChengduChina
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Čužić S, Antolić M, Ognjenović A, Stupin-Polančec D, Petrinić Grba A, Hrvačić B, Dominis Kramarić M, Musladin S, Požgaj L, Zlatar I, Polančec D, Aralica G, Banić M, Urek M, Mijandrušić Sinčić B, Čubranić A, Glojnarić I, Bosnar M, Eraković Haber V. Claudins: Beyond Tight Junctions in Human IBD and Murine Models. Front Pharmacol 2021; 12:682614. [PMID: 34867313 PMCID: PMC8635807 DOI: 10.3389/fphar.2021.682614] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Accepted: 10/11/2021] [Indexed: 12/11/2022] Open
Abstract
Claudins are transmembrane proteins constituting one of three tight junction protein families. In patients with inflammatory bowel disease (IBD), disease activity–dependent changes in expression of certain claudins have been noted, thus making certain claudin family members potential therapy targets. A study was undertaken with the aim of exploring expression of claudins in human disease and two different animal models of IBD: dextrane sulfate sodium–induced colitis and adoptive transfer model of colitis. The expression of sealing claudin-1, claudin-3, claudin-4, and claudin-8, and pore-forming claudin-2 in humans and rodents has been evaluated by immunohistochemistry and quantitative polymerase chain reaction. Claudins were expressed by epithelial and cells of mesodermal origin and were found to be situated at the membrane, within the cytoplasm, or within the nuclei. Claudin expression by human mononuclear cells isolated from lamina propria has been confirmed by Western blot and flow cytometry. The claudin expression pattern in uninflamed and inflamed colon varied between species and murine strains. In IBD and both animal models, diverse alterations in claudin expression by epithelial and inflammatory cells were recorded. Tissue mRNA levels for each studied claudin reflected changes within cell lineage and, at the same time, mirrored the ratio between various cell types. Based on the results of the study, it can be concluded that 1) claudins are not expressed exclusively by epithelial cells, but by certain types of cells of mesodermal origin as well; 2) changes in the claudin mRNA level should be interpreted in the context of overall tissue alterations; and 3) both IBD animal models that were analyzed can be used for investigating claudins as a therapy target, respecting their similarities and differences highlighted in this study.
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Affiliation(s)
- Snježana Čužić
- Fidelta, Zagreb, Croatia
- *Correspondence: Snježana Čužić, ; Vesna Eraković Haber,
| | | | | | | | | | | | | | | | | | | | | | - Gorana Aralica
- School of Medicine, University Zagreb, Zagreb, Croatia
- Department of Pathology Clinical Hospital Dubrava, Zagreb, Croatia
| | - Marko Banić
- School of Medicine, University Zagreb, Zagreb, Croatia
- Department of Internal Medicine Clinical Hospital Dubrava, Zagreb, Croatia
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
| | - Marija Urek
- School of Medicine, University Zagreb, Zagreb, Croatia
- Department of Pathology Clinical Hospital Dubrava, Zagreb, Croatia
| | - Brankica Mijandrušić Sinčić
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Department of Internal Medicine, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | - Aleksandar Čubranić
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- Department of Internal Medicine, Clinical Hospital Center Rijeka, Rijeka, Croatia
| | | | | | - Vesna Eraković Haber
- Fidelta, Zagreb, Croatia
- Faculty of Medicine, University of Rijeka, Rijeka, Croatia
- *Correspondence: Snježana Čužić, ; Vesna Eraković Haber,
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Kozieł MJ, Ziaja M, Piastowska-Ciesielska AW. Intestinal Barrier, Claudins and Mycotoxins. Toxins (Basel) 2021; 13:758. [PMID: 34822542 PMCID: PMC8622050 DOI: 10.3390/toxins13110758] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 10/20/2021] [Accepted: 10/22/2021] [Indexed: 02/08/2023] Open
Abstract
The intestinal barrier is the main barrier against all of the substances that enter the body. Proper functioning of this barrier guarantees maintained balance in the organism. Mycotoxins are toxic, secondary fungi metabolites, that have a negative impact both on human and animal health. It was postulated that various mycotoxins may affect homeostasis by disturbing the intestinal barrier. Claudins are proteins that are involved in creating tight junctions between epithelial cells. A growing body of evidence underlines their role in molecular response to mycotoxin-induced cytotoxicity. This review summarizes the information connected with claudins, their association with an intestinal barrier, physiological conditions in general, and with gastrointestinal cancers. Moreover, this review also includes information about the changes in claudin expression upon exposition to various mycotoxins.
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41
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Li J. Context-Dependent Roles of Claudins in Tumorigenesis. Front Oncol 2021; 11:676781. [PMID: 34354941 PMCID: PMC8329526 DOI: 10.3389/fonc.2021.676781] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Accepted: 07/05/2021] [Indexed: 12/16/2022] Open
Abstract
The barrier and fence functions of the claudin protein family are fundamental to tissue integrity and human health. Increasing evidence has linked claudins to signal transduction and tumorigenesis. The expression of claudins is frequently dysregulated in the context of neoplastic transformation. Studies have uncovered that claudins engage in nearly all aspects of tumor biology and steps of tumor development, suggesting their promise as targets for treatment or biomarkers for diagnosis and prognosis. However, claudins can be either tumor promoters or tumor suppressors depending on the context, which emphasizes the importance of taking various factors, including organ type, environmental context and genetic confounders, into account when studying the biological functions and targeting of claudins in cancer. This review discusses the complicated roles and intrinsic and extrinsic determinants of the context-specific effects of claudins in cancer.
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Affiliation(s)
- Jian Li
- Department of General Surgery, The Third Hospital of Mianyang, Sichuan Mental Health Center, Mianyang, China
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Bowen CM, Walter L, Borras E, Wu W, Ozcan Z, Chang K, Bommi PV, Taggart MW, Thirumurthi S, Lynch PM, Reyes-Uribe L, Scheet PA, Sinha KM, Vilar E. Combination of Sulindac and Bexarotene for Prevention of Intestinal Carcinogenesis in Familial Adenomatous Polyposis. Cancer Prev Res (Phila) 2021; 14:851-862. [PMID: 34266857 DOI: 10.1158/1940-6207.capr-20-0496] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Revised: 02/23/2021] [Accepted: 05/25/2021] [Indexed: 01/07/2023]
Abstract
Familial adenomatous polyposis (FAP) is a hereditary colorectal cancer syndrome, which results in the development of hundreds of adenomatous polyps carpeting the gastrointestinal tract. NSAIDs have reduced polyp burden in patients with FAP and synthetic rexinoids have demonstrated the ability to modulate cytokine-mediated inflammation and WNT signaling. This study examined the use of the combination of an NSAID (sulindac) and a rexinoid (bexarotene) as a durable approach for reducing FAP colonic polyposis to prevent colorectal cancer development. Whole transcriptomic analysis of colorectal polyps and matched normal mucosa in a cohort of patients with FAP to identify potential targets for prevention in FAP was performed. Drug-dose synergism of sulindac and bexarotene in cell lines and patient-derived organoids was assessed, and the drug combination was tested in two different mouse models. This work explored mRNA as a potential predictive serum biomarker for this combination in FAP. Overall, transcriptomic analysis revealed significant activation of inflammatory and cell proliferation pathways. A synergistic effect of sulindac (300 μmol/L) and bexarotene (40 μmol/L) was observed in FAP colonic organoids with primary targeting of polyp tissue compared with normal mucosa. This combination translated into a significant reduction in polyp development in ApcMin/+ and ApcLoxP/+-Cdx2 mice. Finally, the reported data suggest miRNA-21 could serve as a predictive serum biomarker for polyposis burden in patients with FAP. These findings support the clinical development of the combination of sulindac and bexarotene as a treatment modality for patients with FAP. PREVENTION RELEVANCE: This study identified a novel chemopreventive regimen combining sulindac and bexarotene to reduce polyposis in patients with FAP using in silico tools, ex vivo, and in vivo models. This investigation provides the essential groundwork for moving this drug combination forward into a clinical trial.
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Affiliation(s)
- Charles M Bowen
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Lewins Walter
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Ester Borras
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Wenhui Wu
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Zuhal Ozcan
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kyle Chang
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Prashant V Bommi
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Melissa W Taggart
- Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Selvi Thirumurthi
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Patrick M Lynch
- Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Laura Reyes-Uribe
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Paul A Scheet
- Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Krishna M Sinha
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Eduardo Vilar
- Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston, Texas. .,Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas
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Szeglin BC, Wu C, Marco MR, Park HS, Zhang Z, Zhang B, Garcia-Aguilar J, Beauchamp RD, Chen XS, Smith JJ. A SMAD4-modulated gene profile predicts disease-free survival in stage II and III colorectal cancer. Cancer Rep (Hoboken) 2021; 5:e1423. [PMID: 34114372 PMCID: PMC8789617 DOI: 10.1002/cnr2.1423] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 04/12/2021] [Accepted: 05/04/2021] [Indexed: 02/06/2023] Open
Abstract
Background Colorectal cancer is the second‐leading cause of cancer‐related mortality in the United States and a leading cause of cancer‐related mortality worldwide. Loss of SMAD4, a critical tumor suppressor and the central node of the transforming growth factor‐beta superfamily, is associated with worse outcomes for colorectal cancer patients; however, it is unknown whether an RNA‐based profile associated with SMAD4 expression could be used to better identify high‐risk colorectal cancer patients. Aim Identify a gene expression‐based SMAD4‐modulated profile and test its association with patient outcome. Methods and results Using a discovery dataset of 250 colorectal cancer patients, we analyzed expression of BMP/Wnt target genes for association with SMAD4 expression. Promoters of the BMP/Wnt genes were interrogated for SMAD‐binding elements. Fifteen genes were implicated and three tested for modulation by SMAD4 in patient‐derived colorectal cancer tumoroids. Expression of the 15 genes was used for unsupervised hierarchical clustering of a training dataset and two resulting clusters modeled in a centroid model. This model was applied to an independent validation dataset of stage II and III patients. Disease‐free survival was analyzed by the Kaplan‐Meier method. In vitro analysis of three genes identified in the SMAD4‐modulated profile (JAG1, TCF7, and MYC) revealed modulation by SMAD4 consistent with the trend observed in the profile. In the training dataset (n = 553), the profile was not associated with outcome. However, among stage II and III patients (n = 461), distinct clusters were identified by unsupervised hierarchical clustering that were associated with disease‐free survival (p = .02, log‐rank test). The main model was applied to a validation dataset of stage II/III CRC patients (n = 257) which confirmed the association of clustering with disease‐free survival (p = .013, log‐rank test). Conclusions A SMAD4‐modulated gene expression profile identified high‐risk stage II and III colorectal cancer patients, can predict disease‐free survival, and has prognostic potential for stage II and III colorectal cancer patients.
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Affiliation(s)
- Bryan C Szeglin
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA.,Albert Einstein College of Medicine, Bronx, New York, USA
| | - Chao Wu
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA.,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Michael R Marco
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Hyun Sung Park
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA.,Weill Cornell Medical College, New York, USA
| | - Zeda Zhang
- Gerstner Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, USA
| | - Bing Zhang
- Department of Molecular and Human Genetics and the Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, USA
| | - Julio Garcia-Aguilar
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA
| | - R Daniel Beauchamp
- Section of Surgical Sciences, Vanderbilt University Medical Center, Nashville, Tennessee, USA
| | - X Steven Chen
- Division of Biostatistics, Department of Public Health Sciences, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - J Joshua Smith
- Colorectal Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, USA.,Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, USA
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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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Marincola Smith P, Choksi YA, Markham NO, Hanna DN, Zi J, Weaver CJ, Hamaamen JA, Lewis KB, Yang J, Liu Q, Kaji I, Means AL, Beauchamp RD. Colon epithelial cell TGFβ signaling modulates the expression of tight junction proteins and barrier function in mice. Am J Physiol Gastrointest Liver Physiol 2021; 320:G936-G957. [PMID: 33759564 PMCID: PMC8285585 DOI: 10.1152/ajpgi.00053.2021] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 03/15/2021] [Accepted: 03/19/2021] [Indexed: 01/31/2023]
Abstract
Defective barrier function is a predisposing factor in inflammatory bowel disease (IBD) and colitis-associated cancer (CAC). Although TGFβ signaling defects have been associated with IBD and CAC, few studies have examined the relationship between TGFβ and intestinal barrier function. Here, we examine the role of TGFβ signaling via SMAD4 in modulation of colon barrier function. The Smad4 gene was conditionally deleted in the intestines of adult mice and intestinal permeability assessed using an in vivo 4 kDa FITC-Dextran (FD4) permeability assay. Mouse colon was isolated for gene expression (RNA-sequencing), Western blot, and immunofluorescence analysis. In vitro colon organoid culture was utilized to assess junction-related gene expression by qPCR and transepithelial resistance (TER). In silico analyses of human IBD and colon cancer databases were performed. Mice lacking intestinal expression of Smad4 demonstrate increased colonic permeability to FD4 without gross mucosal damage. mRNA/protein expression analyses demonstrate significant increases in Cldn2/Claudin 2 and Cldn8/Claudin 8, and decreases in Cldn3, Cldn4, and Cldn7/Claudin 7 with intestinal SMAD4 loss in vivo without changes in Claudin protein localization. TGFβ1/BMP2 treatment of polarized SMAD4+ colonoids increases TER. Cldn2, Cldn4, Cldn7, and Cldn8 are regulated by canonical TGFβ signaling, and TGFβ-dependent regulation of these genes is dependent on nascent RNA transcription (Cldn2, Cldn4, Cldn8) but not nascent protein translation (Cldn4, Cldn8). Human IBD/colon cancer specimens demonstrate decreased SMAD4, CLDN4, CLDN7, and CLDN8 and increased CLDN2 compared with healthy controls. Canonical TGFβ signaling modulates the expression of tight junction proteins and barrier function in mouse colon.NEW & NOTEWORTHY We demonstrate that canonical TGFβ family signaling modulates the expression of critical tight junction proteins in colon epithelial cells, and that expression of these tight junction proteins is associated with maintenance of colon epithelial barrier function in mice.
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Affiliation(s)
- Paula Marincola Smith
- Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Graduate Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - Yash A Choksi
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Veterans Affairs Hospital, Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Nicholas O Markham
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - David N Hanna
- Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jinghuan Zi
- Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Connie J Weaver
- Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jalal A Hamaamen
- Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Keeli B Lewis
- Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Jing Yang
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Qi Liu
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Biostatistics, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Izumi Kaji
- Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Anna L Means
- Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Graduate Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
- Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
| | - R Daniel Beauchamp
- Section of Surgical Sciences, Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
- Graduate Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
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Effects of histone deacetylase inhibitors Tricostatin A and Quisinostat on tight junction proteins of human lung adenocarcinoma A549 cells and normal lung epithelial cells. Histochem Cell Biol 2021; 155:637-653. [PMID: 33974136 DOI: 10.1007/s00418-021-01966-1] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/16/2021] [Indexed: 02/08/2023]
Abstract
Histone deacetylase (HDAC) inhibitors have a potential therapeutic role for non-small cell lung cancer (NSCLC). However, more preclinical studies of HDAC inhibitors in NSCLC and normal lung epithelial cells are required to evaluate their antitumor activities and mechanisms. The bicellular tight junction molecule claudin-2 (CLDN-2) is highly expressed in lung adenocarcinoma tissues and increase the proliferation of adenocarcinoma cells. Downregulation of the tricellular tight junction molecule angulin-1/LSR induces malignancy via EGF-dependent CLDN-2 and TGF-β-dependent cellular metabolism in human lung adenocarcinoma cells. In the present study, to investigate the detailed mechanisms of the antitumor activities of HDAC inhibitors in lung adenocarcinoma, human lung adenocarcinoma A549 cells and normal lung epithelial cells were treated with the HDAC inibitors Trichostatin A (TSA) and Quisinostat (JNJ-2648158) with or without TGF-β. Both HDAC inhibitors increased anguin-1/LSR, decrease CLDN-2, promoted G1 arrest and prevented the migration of A549 cells. Furthermore, TSA but not Quisinostat with or without TGF-β induced cellular metabolism indicated as the mitochondrial respiration measured using the oxygen consumption rate. In normal human lung epithelial cells, treatment with TSA and Quisinostat increased expression of LSR and CLDN-2 and decreased that of CLDN-1 with or without TGF-β in 2D culture. Quisinostat but not TSA with TGF-β increased CLDN-7 expression in 2D culture. Both HDAC inhibitors prevented disruption of the epithelial barrier measured as the permeability of FD-4 induced by TGF-β in 2.5D culture. TSA and Quisinostat have potential for use in therapy for lung adenocarcinoma via changes in the expression of angulin-1/LSR and CLDN-2.
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Kumar B, Ahmad R, Giannico GA, Zent R, Talmon GA, Harris RC, Clark PE, Lokeshwar V, Dhawan P, Singh AB. Claudin-2 inhibits renal clear cell carcinoma progression by inhibiting YAP-activation. JOURNAL OF EXPERIMENTAL & CLINICAL CANCER RESEARCH : CR 2021; 40:77. [PMID: 33622361 PMCID: PMC7901196 DOI: 10.1186/s13046-021-01870-5] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/22/2020] [Accepted: 02/08/2021] [Indexed: 12/28/2022]
Abstract
Background Claudin-2 expression is upregulated in multiple cancers and promotes cancer malignancy. Remarkably, the regulation of claudin-2 expression in kidney cell lines contrasts its reported regulation in other organs. However, claudin-2 role in renal clear cell carcinoma (RCC) remains unknown despite its predominant expression in the proximal tubular epithelium (PTE), the site of RCC origin. Methods Publicly available and independent patient databases were examined for claudin-2 association with RCC. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by Mass spectroscopy, immunoprecipitation and mutational studies, and functional evaluations. Results We show that the significant decrease in claudin-2 expression characterized PTE cells and Ex-vivo cultured mouse kidney subjected to dedifferentiation. Inhibition of claudin-2 was enough to induce mesenchymal plasticity and invasive mobility in these models. Further, a progressive loss of claudin-2 expression associated with the RCC progression and poor patient survival. Overexpression of claudin-2 in RCC-derived cancer cells inhibited tumorigenic abilities and xenograft tumor growth. These data supported a novel tumor-suppressive role of claudin-2 in RCC. Mechanistic insights further revealed that claudin-2 associates with YAP-protein and modulates its phosphorylation (S127) and nuclear expression. The tumor suppressive effects of claudin-2 expression were lost upon deletion of its PDZ-binding motif emphasizing the critical role of the PDZ-domain in claudin-2 interaction with YAP in regulating RCC malignancy. Conclusions Our results demonstrate a novel kidney specific tumor suppressive role for claudin-2 protein and further demonstrate that claudin-2 co-operates with the YAP signaling in regulating the RCC malignancy. Supplementary Information The online version contains supplementary material available at 10.1186/s13046-021-01870-5.
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Affiliation(s)
- Balawant Kumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Rizwan Ahmad
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA
| | - Giovanna A Giannico
- Department of Pathology, Microbiology and Immunology, Vanderbilt Medical Center, Nashville, TN, USA
| | - Roy Zent
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN, USA
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Raymond C Harris
- Department of Medicine, Vanderbilt Medical Center, Nashville, TN, USA
| | | | - Vinata Lokeshwar
- Department of Biochemistry and Molecular Biology, Augusta University, Augusta, GA, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA.,Member, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA.,VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA
| | - Amar B Singh
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA. .,Member, Fred and Pamela Buffett Cancer Center, University of Nebraska Medical Center, 985870 Nebraska Medical Center, Omaha, NE, 68198-5870, USA. .,VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA.
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Jauregi-Miguel A. The tight junction and the epithelial barrier in coeliac disease. INTERNATIONAL REVIEW OF CELL AND MOLECULAR BIOLOGY 2020; 358:105-132. [PMID: 33707052 DOI: 10.1016/bs.ircmb.2020.09.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Epithelial barriers are essential to maintain multicellular organisms well compartmentalized and protected from external environment. In the intestine, the epithelial layer orchestrates a dynamic balance between nutrient absorption and prevention of microorganisms, and antigen intrusion. Intestinal barrier function has been shown to be altered in coeliac disease but whether it contributes to the pathogenesis development or if it is merely a phenomenon secondary to the aberrant immune response is still unknown. The tight junction complexes are multiprotein cell-cell adhesions that seal the epithelial intercellular space and regulate the paracellular permeability of ions and solutes. These structures have a fundamental role in epithelial barrier integrity as well as in signaling mechanisms that control epithelial-cell polarization, the formation of apical domains and cellular processes such as cell proliferation, migration, differentiation, and survival. In coeliac disease, the molecular structures and function of tight junctions appear disrupted and are not completely recovered after treatment with gluten-free diet. Moreover, zonulin, the only known physiological regulator of the tight junction permeability, appears augmented in autoimmune conditions associated with TJ dysfunction, including coeliac disease. This chapter will examine recent discoveries about the molecular architecture of tight junctions and their functions. We will discuss how different factors contribute to tight junction disruption and intestinal barrier impairment in coeliac disease. To conclude, new insights into zonulin-driven disruption of tight junction structures and barrier integrity in coeliac disease are presented together with the advancements in novel therapy to treat the barrier defect seen in pathogenesis.
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Affiliation(s)
- Amaia Jauregi-Miguel
- Wallenberg Centre for Molecular Medicine, Linköping University, Linköping, Sweden; Department of Biomedical and Clinical Sciences, Faculty of Health Science, Linköping University, Linköping, Sweden.
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Role of tight junctions in the epithelial-to-mesenchymal transition of cancer cells. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1863:183503. [PMID: 33189716 DOI: 10.1016/j.bbamem.2020.183503] [Citation(s) in RCA: 84] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 10/20/2020] [Accepted: 10/21/2020] [Indexed: 12/15/2022]
Abstract
The epithelial-mesenchymal transition (EMT) is an essential step in cancer progression. Epithelial cells possess several types of cell-cell junctions, and tight junctions are known to play important roles in maintaining the epithelial program. EMT is characterized by a loss of epithelial markers, including E-cadherin and tight junction proteins. Somewhat surprisingly, the evidence is accumulating that upregulated expression of tight junction proteins plays an important role in the EMT of cancer cells. Tight junctions have distinct tissue-specific and cancer-specific regulatory mechanisms, enabling them to play different roles in EMT. Tight junctions and related signaling pathways are attractive targets for cancer treatments; signal transduction inhibitors and monoclonal antibodies for tight junction proteins may be used to suppress EMT, invasion, and metastasis. Here we review the role of bicellular and tricellular tight junction proteins during EMT. Further investigation of regulatory mechanisms of tight junctions during EMT in cancer cells will inform the development of biomarkers for predicting prognosis as well as novel therapies.
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50
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Bednarz-Misa I, Fortuna P, Diakowska D, Jamrozik N, Krzystek-Korpacka M. Distinct Local and Systemic Molecular Signatures in the Esophageal and Gastric Cancers: Possible Therapy Targets and Biomarkers for Gastric Cancer. Int J Mol Sci 2020; 21:ijms21124509. [PMID: 32630408 PMCID: PMC7349922 DOI: 10.3390/ijms21124509] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 06/23/2020] [Accepted: 06/24/2020] [Indexed: 12/24/2022] Open
Abstract
Gastric (GC) and esophageal (EC) cancers are highly lethal. Better understanding of molecular abnormalities is needed for new therapeutic targets and biomarkers to be found. Expression of 18 cancer-related genes in 31 paired normal-tumor samples was quantified by reversely-transcribed quantitative polymerase chain reaction (RTqPCR) and systemic concentration of 27 cytokines/chemokines/growth factors in 195 individuals was determined using Luminex xMAP technology. Only Ki67, CLDN2, and BCLxL were altered in GC while Ki67, CDKN1A, ODC1, SLC2A1, HIF1A, VEGFA, NOS2, CCL2, PTGS2, IL10, IL10Ra, and ACTA2 were changed in EC. The relatively unaltered molecular GC landscape resulted from high expression of BCLxL, CDKN1A, BCL2, Ki67, HIF1A, VEGFA, ACTA2, TJP1, CLDN2, IL7Ra, ODC1, PTGS2, and CCL2 in non-cancerous tissue. The NOS2 expression and IL-4, IL-9, FGF2, and RANTES secretion were higher in cardiac than non-cardiac GC. Four-cytokine panels (interleukin (IL)-1β/IL-1ra/IL-6/RANTES or IL-1β/IL-6/IL-4/IL-13) differentiated GC from benign conditions with 87–89% accuracy. Our results showed increased proliferative, survival, inflammatory and angiogenic capacity in gastric tumor-surrounding tissue, what might contribute to GC aggressiveness and facilitate cancer recurrence. Further studies are needed to determine the CLDN2 and NOS2 suitability as candidate molecular targets in GC and cardiac GC, respectively, and discern the role of CLDN2 or to verify IL-1β/IL-1ra/IL-6/RANTES or IL-1β/IL-6/IL-4/IL-13 usefulness as differential biomarkers.
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Affiliation(s)
- Iwona Bednarz-Misa
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (P.F.); (N.J.)
| | - Paulina Fortuna
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (P.F.); (N.J.)
| | - Dorota Diakowska
- Department of Gastrointestinal and General Surgery, Wroclaw Medical University, 50-368 Wroclaw, Poland;
- Department of Nervous System Diseases, Wroclaw Medical University, 51-618 Wroclaw, Poland
| | - Natalia Jamrozik
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (P.F.); (N.J.)
| | - Małgorzata Krzystek-Korpacka
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (I.B.-M.); (P.F.); (N.J.)
- Correspondence:
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