|
1
|
Ram AK, Vairappan B. Role of zonula occludens in gastrointestinal and liver cancers. World J Clin Cases 2022; 10:3647-3661. [PMID: 35647143 PMCID: PMC9100728 DOI: 10.12998/wjcc.v10.i12.3647] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2021] [Revised: 08/08/2021] [Accepted: 03/04/2022] [Indexed: 02/06/2023] Open
Abstract
A growing body of evidence suggests that tight junction (TJ) proteins play a crucial role in the pathogenesis of various diseases, including gastrointestinal (GI) cancer and hepatocellular carcinoma (HCC). TJ proteins primarily maintain the epithelial and endothelial cells intact together through integral proteins however, recent reports suggest that they also regulate gene expression necessary for cell proliferation, angiogenesis, and metastasis through adapter proteins such as zonula occludens (ZO). ZO proteins are membrane-associated cytosolic scaffolding proteins that modulate cell proliferation by interacting with several transcription factors. Reduced ZO proteins in GI cancer and HCC are correlated with tumor development and poor prognosis. Pubmed has searched for using the keyword ZO and gastric cancer, ZO and cancer, and ZO and HCC for the last ten years to date. This review summarized the role of ZO proteins in cell proliferation and their expression in GI cancer and HCC. Furthermore, therapeutic interventions targeting ZO in GI and liver cancers are reviewed.
Collapse
Affiliation(s)
- Amit Kumar Ram
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
| | - Balasubramaniyan Vairappan
- Liver Diseases Research Lab, Department of Biochemistry, Jawaharlal Institute of Postgraduate Medical Education and Research, Pondicherry 605006, India
| |
Collapse
|
|
2
|
Greco G, Amasheh S, Shen Z, Lu Z, Aschenbach JR. Effects of glucagon-like peptides 1 and 2 and epidermal growth factor on the epithelial barrier of the rumen of adult sheep. J Anim Physiol Anim Nutr (Berl) 2019; 103:1727-1738. [PMID: 31498510 DOI: 10.1111/jpn.13200] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2019] [Revised: 08/10/2019] [Accepted: 08/12/2019] [Indexed: 11/29/2022]
Abstract
Epidermal growth factor (EGF) and glucagon-like peptides (GLP) modulate the tight junctions (TJ) of the intestinal epithelial barrier (EB) of monogastric animals. This work tried to elucidate whether GLP-1, GLP-2 and EGF can affect the EB of the rumen. Ovine ruminal epithelia were incubated in Ussing chambers for 7 hr with 25 or 250 nM of either GLP-1 or GLP-2 on the serosal side, with 2.5 nM of EGF on the serosal side or with 0.25 or 2.5 nM EGF on the mucosal side. No treatment affected tissue conductance. Short-circuit current (Isc ) was affected by time and treatment and their interactions. Only 250 nM of either GLP-1 or GLP-2 decreased Isc in certain periods compared with 25 nM GLP-1 or 0.25 nM mucosally applied EGF; however, not when compared to control epithelia. Fluorescein flux rates (Jfluor ) of ruminal epithelia were affected by treatment, time and time × treatment interaction. The time × treatment interaction was based on an increase in Jfluor between the first and last hour in epithelia incubated with 25 nM GLP-1 or GLP-2 and in epithelia incubated with EGF. After 7 hr incubation, claudin-7 mRNA expression was downregulated in all treatments. Claudin-1 mRNA was upregulated after incubation with 2.5 nM EGF on the serosal side, claudin-4 mRNA was downregulated by 2.5 nM EGF on the mucosal side, and occludin mRNA was increased after incubation with 250 nM GLP-2. The protein abundance of all tested TJ proteins was not influenced by treatment. We conclude that GLP-1, GLP-2, and EGF have no obvious acute effects on the EB of ruminal epithelia under simulated physiological conditions ex vivo. However, by decreasing the mRNA expression of claudin-7 and partly affecting other TJ proteins, they may modulate EB in the longer term or under certain conditions.
Collapse
Affiliation(s)
- Gabriele Greco
- Institute of Veterinary Physiology, Freie Universität Berlin, Berlin, Germany
| | - Salah Amasheh
- Institute of Veterinary Physiology, Freie Universität Berlin, Berlin, Germany
| | - Zanming Shen
- Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural University, Nanjing, China
| | - Zhongyan Lu
- Laboratory of Animal Physiology and Biochemistry, Nanjing Agricultural University, Nanjing, China
| | - Jörg R Aschenbach
- Institute of Veterinary Physiology, Freie Universität Berlin, Berlin, Germany
| |
Collapse
|
|
3
|
Isani M, Illingworth L, Herman E, Schmidt M, Barron L, Bowling J, Elizee M, Bai I, Gayer C, Grishin A, Erwin CR, Ford HR, Warner BW. Soybean-derived recombinant human epidermal growth factor protects against experimental necrotizing enterocolitis. J Pediatr Surg 2018; 53:1203-1207. [PMID: 29636182 DOI: 10.1016/j.jpedsurg.2018.02.084] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2018] [Accepted: 02/27/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Epidermal Growth Factor (EGF) reduces necrotizing enterocolitis (NEC). However, its high cost virtually prohibits clinical use. To reduce cost, soybean expressing human EGF was developed. Here we report effectiveness of soybean-derived EGF in experimental NEC. METHODS Newborn rats were subjected to the NEC-inducing regimen of formula feeding and hypoxia. Formula was supplemented with extract from EGF-expressing or empty soybeans. NEC pathology was determined microscopically. Localization of tight junction proteins JAM-A and ZO-1 was examined by immunofluorescence and levels of mucosal COX-2 and iNOS mRNAs by real time PCR. RESULTS Soybean extract amounts corresponding to 150μg/kg/day EGF caused considerable mortality, whereas those corresponding to 75μg/kg/day EGF were well tolerated. There was no significant difference in NEC scores between animals fed plain formula and formula supplemented with empty soybean extract. Soybean-EGF-supplemented formula at 75μg/kg/day EGF significantly decreased NEC, attenuated dissociation of JAM-A and ZO-1 proteins from tight junctions, and reduced intestinal expression of COX-2 and iNOS mRNAs. CONCLUSION Supplementation with soybean-expressed EGF significantly decreased NEC in the rat model. Soybean-expressed EGF may provide an economical solution for EGF administration and prophylaxis of clinical NEC.
Collapse
MESH Headings
- Animals
- Animals, Newborn
- Cyclooxygenase 2/metabolism
- Disease Models, Animal
- Enterocolitis, Necrotizing/pathology
- Enterocolitis, Necrotizing/prevention & control
- Epidermal Growth Factor/therapeutic use
- Humans
- Infant Formula
- Infant, Newborn
- Infant, Premature
- Infant, Premature, Diseases/pathology
- Infant, Premature, Diseases/prevention & control
- Intestinal Mucosa/metabolism
- Intestines/pathology
- Junctional Adhesion Molecules/metabolism
- Nitric Oxide Synthase Type II/metabolism
- Plant Extracts/therapeutic use
- Protective Agents/therapeutic use
- RNA, Messenger/metabolism
- Rats, Sprague-Dawley
- Recombinant Proteins/therapeutic use
- Glycine max
- Zonula Occludens Proteins/metabolism
Collapse
Affiliation(s)
- Mubina Isani
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Laura Illingworth
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Eliot Herman
- University of Arizona School of Plant Sciences, Tucson, AZ
| | - Monica Schmidt
- University of Arizona School of Plant Sciences, Tucson, AZ
| | - Lauren Barron
- Division of Pediatric Surgery, Washington University, St. Louis, MO
| | - Jordan Bowling
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Melissa Elizee
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Iris Bai
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA
| | - Christopher Gayer
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Anatoly Grishin
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | | | - Henri R Ford
- Division of Pediatric Surgery, Children's Hospital Los Angeles, Los Angeles, CA; Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, CA
| | - Brad W Warner
- Division of Pediatric Surgery, Washington University, St. Louis, MO.
| |
Collapse
|
|
4
|
Sekhar V, Pollicino T, Diaz G, Engle RE, Alayli F, Melis M, Kabat J, Tice A, Pomerenke A, Altan-Bonnet N, Zamboni F, Lusso P, Emerson SU, Farci P. Infection with hepatitis C virus depends on TACSTD2, a regulator of claudin-1 and occludin highly downregulated in hepatocellular carcinoma. PLoS Pathog 2018. [PMID: 29538454 PMCID: PMC5882150 DOI: 10.1371/journal.ppat.1006916] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Entry of hepatitis C virus (HCV) into hepatocytes is a complex process that involves numerous cellular factors, including the scavenger receptor class B type 1 (SR-B1), the tetraspanin CD81, and the tight junction (TJ) proteins claudin-1 (CLDN1) and occludin (OCLN). Despite expression of all known HCV-entry factors, in vitro models based on hepatoma cell lines do not fully reproduce the in vivo susceptibility of liver cells to primary HCV isolates, implying the existence of additional host factors which are critical for HCV entry and/or replication. Likewise, HCV replication is severely impaired within hepatocellular carcinoma (HCC) tissue in vivo, but the mechanisms responsible for this restriction are presently unknown. Here, we identify tumor-associated calcium signal transducer 2 (TACSTD2), one of the most downregulated genes in primary HCC tissue, as a host factor that interacts with CLDN1 and OCLN and regulates their cellular localization. TACSTD2 gene silencing disrupts the typical linear distribution of CLDN1 and OCLN along the cellular membrane in both hepatoma cells and primary human hepatocytes, recapitulating the pattern observed in vivo in primary HCC tissue. Mechanistic studies suggest that TACSTD2 is involved in the phosphorylation of CLDN1 and OCLN, which is required for their proper cellular localization. Silencing of TACSTD2 dramatically inhibits HCV infection with a pan-genotype effect that occurs at the level of viral entry. Our study identifies TACSTD2 as a novel regulator of two major HCV-entry factors, CLDN1 and OCLN, which is strongly downregulated in malignant hepatocytes. These results provide new insights into the complex process of HCV entry into hepatocytes and may assist in the development of more efficient cellular systems for HCV propagation in vitro.
Collapse
Affiliation(s)
- Vandana Sekhar
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Teresa Pollicino
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
- Division of Clinical and Molecular Hepatology, Department of Human Pathology, University of Messina, Messina, Italy
| | - Giacomo Diaz
- Department of Biomedical Sciences, University of Cagliari, Cagliari, Italy
| | - Ronald E. Engle
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Farah Alayli
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Marta Melis
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Juraj Kabat
- Biological Imaging Facility/Research Technologies Branch, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Ashley Tice
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Anna Pomerenke
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Nihal Altan-Bonnet
- Laboratory of Host-Pathogen Dynamics, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Fausto Zamboni
- Liver Transplantation Center, Brotzu Hospital, Cagliari, Italy
| | - Paolo Lusso
- Viral Pathogenesis Section, Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Suzanne U. Emerson
- Molecular Hepatitis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Patrizia Farci
- Hepatic Pathogenesis Section, Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
- * E-mail:
| |
Collapse
|
|
5
|
Zhang L, Feng T, Spicer LJ. The role of tight junction proteins in ovarian follicular development and ovarian cancer. Reproduction 2018; 155:R183-R198. [PMID: 29374086 DOI: 10.1530/rep-17-0503] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2017] [Accepted: 01/26/2018] [Indexed: 01/01/2023]
Abstract
Tight junctions (TJ) are protein structures that control the transport of water, ions and macromolecules across cell layers. Functions of the transmembrane TJ protein, occluding (OCLN) and the cytoplasmic TJ proteins, tight junction protein 1 (TJP1; also known as zona occludens protein-1), cingulin (CGN) and claudins (CLDN) are reviewed, and current evidence of their role in the ovarian function is reviewed. Abundance of OCLN, CLDNs and TJP1 mRNA changed during follicular growth. In vitro treatment with various growth factors known to affect ovarian folliculogenesis indicated that CGN, OCLN and TJP1 are hormonally regulated. The summarized studies indicate that expression of TJ proteins (i.e., OCLN, CLDN, TJP1 and CGN) changes with follicle size in a variety of vertebrate species but whether these changes in TJ proteins are increased or decreased depends on species and cell type. Evidence indicates that autocrine, paracrine and endocrine regulators, such as fibroblast growth factor-9, epidermal growth factor, androgens, tumor necrosis factor-α and glucocorticoids may modulate these TJ proteins. Additional evidence presented indicates that TJ proteins may be involved in ovarian cancer development in addition to normal follicular and luteal development. A model is proposed suggesting that hormonal downregulation of TJ proteins during ovarian follicular development could reduce barrier function (i.e., selective permeability of molecules between theca and granulosa cells) and allow for an increase in the volume of follicular fluid as well as allow additional serum factors into the follicle that may directly impact granulosa cell functions.
Collapse
Affiliation(s)
- Lingna Zhang
- Department of Animal ScienceOklahoma State University, Stillwater, Oklahoma, USA
| | - Tao Feng
- Institute of Animal Husbandry and Veterinary MedicineBeijing Academy of Agriculture and Forestry Sciences, Beijing, China
| | - Leon J Spicer
- Department of Animal ScienceOklahoma State University, Stillwater, Oklahoma, USA
| |
Collapse
|
|
6
|
Zhang L, Schütz LF, Robinson CL, Totty ML, Spicer LJ. Evidence that gene expression of ovarian follicular tight junction proteins is regulated in vivo and in vitro in cattle. J Anim Sci 2017; 95:1313-1324. [PMID: 28380519 DOI: 10.2527/jas.2016.0892] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Tight junctions (TJ) are common paracellular sealing structures that control the transport of water, ions, and macromolecules across cell layers. Because the role of TJ in bovine follicular development is unknown, we investigated the developmental and hormonal regulation of the transmembrane TJ protein, occludin (OCLN), and the cytoplasmic TJ proteins, TJ protein 1 (TJP1) and cingulin (CGN) in bovine granulosa cells (GC) and theca cells (TC). For this purpose, bovine GC and TC were isolated from large (>8 mm) and/or small (1 to 5 mm) follicles and either extracted for real-time PCR (qPCR) or cultured in vitro. The abundances of both and mRNA were greater ( < 0.05) in TC than GC, whereas the mRNA abundance was greater ( < 0.05) in GC than TC. The abundance of mRNA in both GC and TC was greater ( < 0.05) in small follicles compared with large follicles, whereas the GC of large follicles had less ( < 0.05) mRNA abundance than the GC of small follicles. The abundance of mRNA in GC or TC did not differ ( > 0.10) among follicle sizes. In vitro treatment with various growth factors known to affect ovarian folliculogenesis indicated that , , and were hormonally regulated. Fibroblast growth factor 9 (FGF9) decreased ( < 0.05) the and mRNA abundances. Tumor necrosis factor α (TNFα) and vascular endothelial growth factor A (VEGFA) increased ( < 0.05) the mRNA abundance but decreased ( < 0.05) the mRNA abundance. Dexamethasone (DEX) increased ( < 0.05) and mRNA abundances. Epidermal growth factor (EGF) decreased ( < 0.05) and dihydrotestosterone (DHT) increased ( < 0.05) the abundances of , , and mRNA. We propose that the downregulation of OCLN and other TJ proteins during follicular development could reduce barrier function, thereby participating in increasing follicle size by allowing for an increase in the volume of follicular fluid as well as by allowing additional serum factors into the follicular fluid that potentially may directly impact GC functions. The results of the current study indicate the following in cattle: 1) gene expression of TJ proteins (i.e., , , and ) differs between GC and TC and changes with follicle size, and 2) autocrine, paracrine, and endocrine regulators, such as FGF9, EGF, DHT, TNFα, and glucocorticoids, modulate , , and mRNA abundance in TC in vitro.
Collapse
|
|
7
|
Kyuno D, Yamaguchi H, Ito T, Kono T, Kimura Y, Imamura M, Konno T, Hirata K, Sawada N, Kojima T. Targeting tight junctions during epithelial to mesenchymal transition in human pancreatic cancer. World J Gastroenterol 2014; 20:10813-10824. [PMID: 25152584 PMCID: PMC4138461 DOI: 10.3748/wjg.v20.i31.10813] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/24/2013] [Accepted: 05/05/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer continues to be a leading cause of cancer-related death worldwide and there is an urgent need to develop novel diagnostic and therapeutic strategies to reduce the mortality of patients with this disease. In pancreatic cancer, some tight junction proteins, including claudins, are abnormally regulated and therefore are promising molecular targets for diagnosis, prognosis and therapy. Claudin-4 and -18 are overexpressed in human pancreatic cancer and its precursor lesions. Claudin-4 is a high affinity receptor of Clostridium perfringens enterotoxin (CPE). The cytotoxic effects of CPE and monoclonal antibodies against claudin-4 are useful as novel therapeutic tools for pancreatic cancer. Claudin-18 could be a putative marker and therapeutic target with prognostic implications for patients with pancreatic cancer. Claudin-1, -7, tricellulin and marvelD3 are involved in epithelial to mesenchymal transition (EMT) of pancreatic cancer cells and thus might be useful as biomarkers during disease. Protein kinase C is closely related to EMT of pancreatic cancer and regulates tight junctions of normal human pancreatic duct epithelial cells and the cancer cells. This review focuses on the regulation of tight junctions via protein kinase C during EMT in human pancreatic cancer for the purpose of developing new diagnostic and therapeutic modalities for pancreatic cancer.
Collapse
|
|
8
|
Wardill HR, Gibson RJ, Logan RM, Bowen JM. TLR4/PKC-mediated tight junction modulation: a clinical marker of chemotherapy-induced gut toxicity? Int J Cancer 2014; 135:2483-92. [PMID: 24310924 DOI: 10.1002/ijc.28656] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Revised: 11/19/2013] [Accepted: 11/20/2013] [Indexed: 12/15/2022]
Abstract
Chemotherapy-induced gut toxicity is a major clinical and economic burden to oncology practice. The mechanisms responsible for its development are ill defined, hampering the development of therapeutic interventions. In light of newly published research foci and clinical practice guidelines in supportive care in cancer, there has been renewed interest in the role tight junctions play in the pathobiology of chemotherapy-induced gut toxicity. Several preclinical studies have identified molecular defects in intestinal tight junctions following chemotherapy. Despite these findings, the mechanisms responsible for chemotherapy-induced tight junction disruption remain unclear. Recent research has highlighted roles for toll-like receptor 4 and protein kinase C signalling in the regulation of tight junctions. This critical review therefore aims to provide evidence linking toll-like receptor 4 expression, protein kinase C activation and tight junction disruption and their relationship to clinical toxicity.
Collapse
Affiliation(s)
- Hannah R Wardill
- Discipline of Anatomy and Pathology, School of Medical Sciences, University of Adelaide, Adelaide, Australia
| | | | | | | |
Collapse
|
|
9
|
Hu YJ, Wang YD, Tan FQ, Yang WX. Regulation of paracellular permeability: factors and mechanisms. Mol Biol Rep 2013; 40:6123-42. [PMID: 24062072 DOI: 10.1007/s11033-013-2724-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2012] [Accepted: 09/14/2013] [Indexed: 12/20/2022]
Abstract
Epithelial permeability is composed of transcellular permeability and paracellular permeability. Paracellular permeability is controlled by tight junctions (TJs). Claudins and occludin are two major transmembrane proteins in TJs, which directly determine the paracellular permeability to different ions or large molecules. Intracellular signaling pathways including Rho/Rho-associated protein kinase, protein kinase Cs, and mitogen-activated protein kinase, modulate the TJ proteins to affect paracellular permeability in response for diverse stimuli. Cytokines, growth factors and hormones in organism can regulate the paracellular permeability via signaling pathway. The transcellular transporters such as Na-K-ATPase, Na(+)-coupled transporters and chloride channels, can interact with paracellular transport and regulate the TJs. In this review, we summarized the factors affecting paracellular permeability and new progressions of the related mechanism in recent studies, and pointed out further research areas.
Collapse
Affiliation(s)
- Yan-Jun Hu
- Department of Reproductive Endocrinology, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, People's Republic of China
| | | | | | | |
Collapse
|
|
10
|
Abstract
Spices and herbal remedies have been used since ancient times to treat a variety of disorders. It has been experimentally demonstrated that spices, herbs, and their extracts possess antimicrobial, anti-inflammatory, antirheumatic, lipid-lowering, hepatoprotective, nephroprotective, antimutagenic and anticancer activities, besides their gastroprotective and anti-ulcer activities. Despite a number of reports on the toxicity of herbs and spices, they are generally accepted as safer alternatives to conventional therapy against gastric ulcers. To this end, it is also believed, that excessive consumption of spices may favor the pathogenesis of gastric and duodenal ulcer and some studies have substantiated this common perception. Based on various in vivo experiments and clinical studies, on the effects of spices and herbs on gastric ulcers, it has indeed been shown that certain spices do possess remarkable anti-ulcer properties mediated by antisecretory, cytoprotective, antioxidant, and anti-Helicobacter pylori effects and mechanisms regulated by nitric oxide, prostaglandins, non-protein sulfhydryl molecules and epidermal growth factor expression. Accordingly, their consumption may attenuate and help prevent peptic ulcer disease. In the present review, the beneficial effects of spices and herbal nutritive components on the gastric mucosa are discussed against the paradigm of their deleterious potential.
Collapse
|
|
11
|
Martin TA, Jiang WG. Loss of tight junction barrier function and its role in cancer metastasis. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2009; 1788:872-91. [DOI: 10.1016/j.bbamem.2008.11.005] [Citation(s) in RCA: 357] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/14/2008] [Revised: 10/29/2008] [Accepted: 11/06/2008] [Indexed: 12/23/2022]
|
|
12
|
Grumbach Y, Quynh NVT, Chiron R, Urbach V. LXA4 stimulates ZO-1 expression and transepithelial electrical resistance in human airway epithelial (16HBE14o-) cells. Am J Physiol Lung Cell Mol Physiol 2008; 296:L101-8. [PMID: 18849442 DOI: 10.1152/ajplung.00018.2008] [Citation(s) in RCA: 54] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Lipoxin A(4) (LXA(4)) is a biologically active eicosanoid produced in human airways that displays anti-inflammatory properties. In cystic fibrosis and severe asthma, LXA(4) production has been reported to be decreased, and, in such diseases, one of the consequences of airway inflammation is disruption of the tight junctions. In the present study, we investigated the possible role of LXA(4) on tight junction formation, using transepithelial electrical resistance (TER) measurements, Western blotting, and immunofluorescence. We observed that exposure to LXA(4) (100 nM) for 2 days significantly increased zonula occludens-1 (ZO-1), claudin-1, and occludin expression at the plasma membrane of confluent human bronchial epithelial 16HBE14o- cells. LXA(4) (100 nM) stimulated the daily increase of the 16HBE14o- cell monolayer TER, and this effect was inhibited by boc-2 (LXA(4) receptor antagonist). LXA(4) also had a rapid effect on ZO-1 immunofluorescence at the plasma membrane and increased TER within 10 min. In conclusion, our experiments provide evidence that LXA(4) plays certainly a new role for the regulation of tight junction formation and stimulation of the localization and expression of ZO-1 at the plasma membrane through a mechanism involving the LXA(4) receptor.
Collapse
Affiliation(s)
- Yael Grumbach
- Institut National de la Santé et de la Recherche Médicale U454, Centre Hospitalier Universitaire Arnaud de Villeneuve, Montpellier, France
| | | | | | | |
Collapse
|
|
13
|
Crosstalk of tight junction components with signaling pathways. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2007; 1778:729-56. [PMID: 17950242 DOI: 10.1016/j.bbamem.2007.08.018] [Citation(s) in RCA: 592] [Impact Index Per Article: 32.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/30/2007] [Revised: 08/03/2007] [Accepted: 08/16/2007] [Indexed: 12/28/2022]
Abstract
Tight junctions (TJs) regulate the passage of ions and molecules through the paracellular pathway in epithelial and endothelial cells. TJs are highly dynamic structures whose degree of sealing varies according to external stimuli, physiological and pathological conditions. In this review we analyze how the crosstalk of protein kinase C, protein kinase A, myosin light chain kinase, mitogen-activated protein kinases, phosphoinositide 3-kinase and Rho signaling pathways is involved in TJ regulation triggered by diverse stimuli. We also report how the phosphorylation of the main TJ components, claudins, occludin and ZO proteins, impacts epithelial and endothelial cell function.
Collapse
|
|
14
|
Fink C, Weigel R, Hembes T, Lauke-Wettwer H, Kliesch S, Bergmann M, Brehm RH. Altered expression of ZO-1 and ZO-2 in Sertoli cells and loss of blood-testis barrier integrity in testicular carcinoma in situ. Neoplasia 2007; 8:1019-27. [PMID: 17217619 PMCID: PMC1783719 DOI: 10.1593/neo.06559] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Carcinoma in situ (CIS) is the noninvasive precursor of most human testicular germ cell tumors. In normal seminiferous epithelium, specialized tight junctions between Sertoli cells constitute the major component of the blood-testis barrier. Sertoli cells associated with CIS exhibit impaired maturation status, but their functional significance remains unknown. The aim was to determine whether the blood-testis barrier is morphologically and/or functionally altered. We investigated the expression and distribution pattern of the tight junction proteins zonula occludens (ZO) 1 and 2 in normal seminiferous tubules compared to tubules showing CIS. In normal tubules, ZO-1 and ZO-2 immunostaining was observed at the blood-testis barrier region of adjacent Sertoli cells. Within CIS tubules, ZO-1 and ZO-2 immunoreactivity was reduced at the blood-testis barrier region, but spread to stain the Sertoli cell cytoplasm. Western blot analysis confirmed ZO-1 and ZO-2, and their respective mRNA were shown by RT-PCR. Additionally, we assessed the functional integrity of the blood-testis barrier by lanthanum tracer study. Lanthanum permeated tight junctions in CIS tubules, indicating disruption of the blood-testis barrier. In conclusion, Sertoli cells associated with CIS show an altered distribution of ZO-1 and ZO-2 and lose their blood-testis barrier function.
Collapse
Affiliation(s)
- Cornelia Fink
- Institute of Veterinary Anatomy, Histology, and Embryology, University of Giessen, Giessen, Germany.
| | | | | | | | | | | | | |
Collapse
|
|
15
|
Brackenbury WJ, Djamgoz MBA. Nerve growth factor enhances voltage-gated Na+ channel activity and Transwell migration in Mat-LyLu rat prostate cancer cell line. J Cell Physiol 2007; 210:602-8. [PMID: 17149708 PMCID: PMC4123444 DOI: 10.1002/jcp.20846] [Citation(s) in RCA: 49] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
The highly dynamic nature of voltage-gated Na+ channel (VGSC) expression and its controlling mechanism(s) are not well understood. In this study, we investigated the possible involvement of nerve growth factor (NGF) in regulating VGSC activity in the strongly metastatic Mat-LyLu cell model of rat prostate cancer (PCa). NGF increased peak VGSC current density in a time- and dose-dependent manner. NGF also shifted voltage to peak and the half-activation voltage to more positive potentials, and produced currents with faster kinetics of activation; sensitivity to the VGSC blocker tetrodotoxin (TTX) was not affected. The NGF-induced increase in peak VGSC current density was suppressed by both the pan-trk antagonist K252a, and the protein kinase A (PKA) inhibitor KT5720. NGF did not affect the Nav1.7 mRNA level, but the total VGSC alpha-subunit protein level was upregulated. NGF potentiated the cells' migration in Transwell assays, and this was not affected by TTX. We concluded that NGF upregulated functional VGSC expression in Mat-LyLu cells, with PKA as a signaling intermediate, but enhancement of migration by NGF was independent of VGSC activity.
Collapse
Affiliation(s)
- William J. Brackenbury
- Neuroscience Solutions to Cancer Research Group, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
| | - Mustafa B. A. Djamgoz
- Neuroscience Solutions to Cancer Research Group, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
| |
Collapse
|
|
16
|
González-Mariscal L, Lechuga S, Garay E. Role of tight junctions in cell proliferation and cancer. ACTA ACUST UNITED AC 2007; 42:1-57. [PMID: 17502225 DOI: 10.1016/j.proghi.2007.01.001] [Citation(s) in RCA: 102] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
The acquisition of a cancerous phenotype by epithelial cells involves the disruption of intercellular adhesions. The reorganization of the E-cadherin/beta-catenin complex in adherens junctions during cell transformation is widely recognized. Instead the implication of tight junctions (TJs) in this process is starting to be unraveled. The aim of this article is to review the role of TJ proteins in cell proliferation and cancer.
Collapse
Affiliation(s)
- Lorenza González-Mariscal
- Center for Research and Advanced Studies (Cinvestav), Department of Physiology, Biophysics and Neuroscience, Ave. Instituto Politécnico Nacional 2508, México, DF 07360, México.
| | | | | |
Collapse
|
|
17
|
Kang ES, Oh MA, Lee SA, Kim TY, Kim SH, Gotoh N, Kim YN, Lee JW. EGFR phosphorylation-dependent formation of cell-cell contacts by Ras/Erks cascade inhibition. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2007; 1773:833-43. [PMID: 17368581 DOI: 10.1016/j.bbamcr.2007.02.003] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/02/2006] [Revised: 02/10/2007] [Accepted: 02/12/2007] [Indexed: 11/19/2022]
Abstract
Cell-cell contacts play important roles in the homeostasis of normal epithelium and in the steps of metastasis of tumor cells, although signaling mechanisms to regulate cell-cell contacts are unclear. In this study, we observed that phenotype of no cell-cell contacts in rat intestinal epithelial cell subline (RIE1-Sca) correlated with increased Erk1/2 signaling activity, compared to that of parental RIE1 cells growing in colonies. Furthermore, cell-cell contacts between RIE1-Sca cells were reformed by treatment with a specific MEK inhibitor (U0126), with translocation of ZO1 and beta-catenin to cell-cell contacts, without changes of their expression levels. U0126 treatment also increased EGFR phosphorylation in a ligand-independent manner. Pretreatment with EGFR kinase inhibitor abolished U0126 treatment-mediated EGFR phosphorylation, and expression of dominant negative H-Ras N17 allowed EGFR phosphorylation and cell-cell contacts even without U0126 treatment. Furthermore, the expression of a nonphosphorylatable EGFR Y5F mutant abolished U0126-mediated cell-cell contacts. U0126 treatment also caused less efficient wound healing by keeping monolayer integrity intact, compared to control untreated cells. This U0126-mediated reduction in wound healing was further altered either by pretreatment of EGFR kinase inhibitor or expression of H-Ras N17 or EGFR Y5F. Taken together, this study supports a unique mechanism of cell-cell contact formation through MEK/Erks inhibition-mediated EGFR phosphorylation.
Collapse
Affiliation(s)
- Eun-Sil Kang
- Cancer Research Institute, Department of Molecular and Clinical Oncology, College of Medicine, Seoul National University, 28, Yeongeon-dong, Jongno-gu, Seoul 110-799, South Korea
| | | | | | | | | | | | | | | |
Collapse
|
|
18
|
Brent L, Cohen IR, Doherty PC, Feldmann M, Matzinger P, Ghost Lab, Holgate ST, Lachmann P, Mitchison NA, Nossal G, Rose NR, Zinkernagel R. Crystal-ball gazing--the future of immunological research viewed from the cutting edge. Clin Exp Immunol 2007; 147:1-10. [PMID: 17177957 PMCID: PMC1810455 DOI: 10.1111/j.1365-2249.2006.03234.x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Affiliation(s)
- L Brent
- 30 Hugo Road, London N195EU, UK
| | | | | | | | | | | | | | | | | | | | | | | |
Collapse
|
|
19
|
Wang Y, Du D, Fang L, Yang G, Zhang C, Zeng R, Ullrich A, Lottspeich F, Chen Z. Tyrosine phosphorylated Par3 regulates epithelial tight junction assembly promoted by EGFR signaling. EMBO J 2006; 25:5058-70. [PMID: 17053785 PMCID: PMC1630420 DOI: 10.1038/sj.emboj.7601384] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2006] [Accepted: 09/12/2006] [Indexed: 11/08/2022] Open
Abstract
The conserved polarity complex, comprising the partitioning-defective (Par) proteins Par3 and Par6, and the atypical protein kinase C, functions in various cell-polarization events and asymmetric cell divisions. However, little is known about whether and how external stimuli-induced signals may regulate Par3 function in epithelial cell polarity. Here, we found that Par3 was tyrosine phosphorylated through phosphoproteomic profiling of pervanadate-induced phosphotyrosine proteins. We also demonstrated that the tyrosine phosphorylation event induced by multiple growth factors including epidermal growth factor (EGF) was dependent on activation of Src family kinase (SFK) members c-Src and c-Yes. The tyrosine residue 1127 (Y1127) of Par3 was identified as the major EGF-induced phosphorylation site. Moreover, we found that Y1127 phosphorylation reduced the association of Par3 with LIM kinase 2 (LIMK2), thus enabling LIMK2 to regulate cofilin phosphorylation dynamics. Substitution of Y1127 for phenylalanine impaired the EGF-induced Par3 and LIMK2 dissociation and delayed epithelial tight junction (TJ) assembly considerably. Collectively, these data suggest a novel, phosphotyrosine-dependent fine-tuning mechanism of Par3 in epithelial TJ assembly controlled by the EGF receptor-SFK signaling pathway.
Collapse
Affiliation(s)
- Yiguo Wang
- Key Laboratory of Proteomics and Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
- Graduate School of the Chinese Academy of Sciences, Beijing, China
| | - Dan Du
- Key Laboratory of Proteomics and Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
- Graduate School of the Chinese Academy of Sciences, Beijing, China
| | - Longhou Fang
- Key Laboratory of Proteomics and Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
- Graduate School of the Chinese Academy of Sciences, Beijing, China
| | - Guang Yang
- Key Laboratory of Proteomics and Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
- Graduate School of the Chinese Academy of Sciences, Beijing, China
| | - Chenyi Zhang
- Key Laboratory of Proteomics and Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Rong Zeng
- Key Laboratory of Proteomics and Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
| | - Axel Ullrich
- Department of Molecular Biology, Max-Planck-Institute of Biochemistry, Martinsried, Germany
| | | | - Zhengjun Chen
- Key Laboratory of Proteomics and Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China
- SHARF Laboratory, Shanghai, China
- Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China. Tel.: 86 21 54921081; Fax: 86 21 54921081; E-mail:
| |
Collapse
|
|
20
|
Brackenbury WJ, Djamgoz MBA. Activity-dependent regulation of voltage-gated Na+ channel expression in Mat-LyLu rat prostate cancer cell line. J Physiol 2006; 573:343-56. [PMID: 16543264 PMCID: PMC1779734 DOI: 10.1113/jphysiol.2006.106906] [Citation(s) in RCA: 93] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Revised: 02/03/2005] [Accepted: 03/15/2006] [Indexed: 12/12/2022] Open
Abstract
We have shown previously that voltage-gated Na(+) channels (VGSCs) are up-regulated in human metastatic disease (prostate, breast and small-cell lung cancers), and that VGSC activity potentiates metastatic cell behaviours. However, the mechanism(s) regulating functional VGSC expression in cancer cells remains unknown. We investigated the possibility of activity-dependent (auto)regulation of VGSC functional expression in the strongly metastatic Mat-LyLu model of rat prostate cancer. Pretreatment with tetrodotoxin (TTX) for 24-72 h subsequently suppressed peak VGSC current density without affecting voltage dependence. The hypothesis was tested that the VGSC auto-regulation occurred via VGSC-mediated Na(+) influx and subsequent activation of protein kinase A (PKA). Indeed, TTX pretreatment reduced the level of phosphorylated PKA, and the PKA inhibitor KT5720 decreased, whilst the adenylate cyclase activator forskolin and the Na(+) ionophore monensin both increased the peak VGSC current density. TTX reduced the mRNA level of Nav1.7, predominant in these cells, and VGSC protein expression at the plasma membrane, although the total VGSC protein level remained unchanged. TTX pretreatment eliminated the VGSC-dependent component of the cells' migration in Transwell assays. We concluded that the VGSC activity in Mat-LyLu rat prostate cancer cells was up-regulated in steady-state via a positive feedback mechanism involving PKA, and this enhanced the cells' migratory potential.
Collapse
Affiliation(s)
- William J Brackenbury
- Neuroscience Solutions to Cancer Research Group, Division of Cell and Molecular Biology, Sir Alexander Fleming Building, Imperial College London, South Kensington Campus, London SW7 2AZ, UK
| | | |
Collapse
|