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Do TT, Nguyen VT, Nguyen NTN, Duong KTT, Nguyen TTM, Le DNT, Nguyen TH. A Review of a Breakdown in the Barrier: Tight Junction Dysfunction in Dental Diseases. Clin Cosmet Investig Dent 2024; 16:513-531. [PMID: 39758089 PMCID: PMC11697688 DOI: 10.2147/ccide.s492107] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 11/15/2024] [Indexed: 01/07/2025] Open
Abstract
The tight junction (TJ), a type of cell-cell junction, regulates the permeability of solutes across epithelial and endothelial cellular sheets and is believed to maintain cell polarity. However, recent studies have provided conflicting views on the roles of TJs in epithelial polarity. Membrane proteins, including occludin, claudin, and the junction adhesion molecule, have been identified as TJ components. TJs are predominantly found at the stratum granulosum and stratum corneum. Although it remains unclear whether the disruption of TJs is the cause or consequence of certain dental diseases, evidence suggests that TJ dysfunction may be a crucial factor in gingival epithelial barrier impairment and the progression of oral diseases. Bacterial infection is among the most specific factors we found that may contribute to the breakdown of the epithelial barrier formed by TJs in dental diseases. Bacteria and their products may weaken the epithelial barrier by directly destroying intercellular junctions or altering the expression of junctional proteins. Additionally, they may induce the production of inflammatory cytokines, which could lead to the downregulation of TJ proteins and, consequently, impair the epithelial barrier. This review introduces a novel perspective by exploring, for the first time, the role of TJs dysfunction in the breakdown of the oral epithelial barrier and its potential link to the progression of dental diseases such as gingivitis, periodontitis, Sjӧgren syndrome, and oral squamous cell carcinoma.
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Affiliation(s)
- Thao Thi Do
- Oral Diagnosis and Periodontology Department, Faculty of Odonto-Stomatology, Can Tho University of Medicine and Pharmacy, Can Tho City, 900000, Vietnam
| | - Vy Thuy Nguyen
- Oral Diagnosis and Periodontology Department, Faculty of Odonto-Stomatology, Can Tho University of Medicine and Pharmacy, Can Tho City, 900000, Vietnam
| | - Ngoc Tran Nhu Nguyen
- Oral Diagnosis and Periodontology Department, Faculty of Odonto-Stomatology, Can Tho University of Medicine and Pharmacy, Can Tho City, 900000, Vietnam
| | - Kim Tran Thien Duong
- Oral Diagnosis and Periodontology Department, Faculty of Odonto-Stomatology, Can Tho University of Medicine and Pharmacy, Can Tho City, 900000, Vietnam
| | - Tri Ta Minh Nguyen
- Oral Diagnosis and Periodontology Department, Faculty of Odonto-Stomatology, Can Tho University of Medicine and Pharmacy, Can Tho City, 900000, Vietnam
| | - Duong Nguyen Thuy Le
- Oral Diagnosis and Periodontology Department, Faculty of Odonto-Stomatology, Can Tho University of Medicine and Pharmacy, Can Tho City, 900000, Vietnam
| | - Tin Hoang Nguyen
- Department of Physiology, Faculty of Medicine, Can Tho University of Medicine and Pharmacy, Can Tho City, 900000, Vietnam
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Zhou X, Liu Q, Li Z, Liu X, Zhao Q, Wang Y, Wu F, Zhao G, Sun R, Guo X. The activation of adenosine monophosphate-activated protein kinase inhibits the migration of tongue squamous cell carcinoma cells by targeting Claudin-1 via epithelial-mesenchymal transition. Animal Model Exp Med 2024; 7:606-616. [PMID: 39017036 PMCID: PMC11528389 DOI: 10.1002/ame2.12444] [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: 02/26/2024] [Revised: 05/15/2024] [Accepted: 05/26/2024] [Indexed: 07/18/2024] Open
Abstract
BACKGROUND The role of Claudin-1 in tongue squamous cell carcinoma (TSCC) metastasis needs further clarification, particularly its impact on cell migration. Herein, our study aims to investigate the role of Claudin-1 in TSCC cell migration and its underlying mechanisms. METHODS 36 TSCC tissue samples underwent immunohistochemical staining for Claudin-1. Western blotting and immunofluorescence analyses were conducted to evaluate Claudin-1 expression and distribution in TSCC cells. Claudin-1 knockdown cell lines were established using short hairpin RNA transfection. Migration effects were assessed through wound healing assays. Furthermore, the expression of EMT-associated molecules was measured via western blotting. RESULTS Claudin-1 expression decreased as TSCC malignancy increased. Adenosine monophosphate-activated protein kinase (AMPK) activation led to increased Claudin-1 expression and membrane translocation, inhibiting TSCC cell migration and epithelial-mesenchymal transition (EMT). Conversely, Claudin-1 knockdown reversed these inhibitory effects on migration and EMT caused by AMPK activation. CONCLUSIONS Our results indicated that AMPK activation suppresses TSCC cell migration by targeting Claudin-1 and EMT pathways.
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Affiliation(s)
- Xin‐Yue Zhou
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
- Hubei Shizhen LaboratoryWuhanHubeiChina
| | - Qiu‐Ming Liu
- Sino‐German Biomedical CenterHubei University of TechnologyWuhanChina
- Center of Applied BiotechnologyWuhan Institute of BioengineeringWuhanChina
| | - Zhuang Li
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Xia‐Yang Liu
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Qi‐Wei Zhao
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Yu Wang
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Feng‐Hua Wu
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
- Hubei Shizhen LaboratoryWuhanHubeiChina
| | - Gang Zhao
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
| | - Rui Sun
- Department of Stomatology, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi HospitalThird Hospital of Shanxi Medical UniversityTaiyuanChina
- Department of Oral and Maxillofacial SurgeryShanxi Provincial People's HospitalTaiyuanChina
| | - Xiao‐Hong Guo
- Department of Basic MedicineHubei University of Chinese MedicineWuhanChina
- Hubei Shizhen LaboratoryWuhanHubeiChina
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Akhlaghipour I, Moghbeli M. MicroRNA-98 as a novel diagnostic marker and therapeutic target in cancer patients. Discov Oncol 2024; 15:385. [PMID: 39210158 PMCID: PMC11362465 DOI: 10.1007/s12672-024-01270-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/14/2024] [Accepted: 08/23/2024] [Indexed: 09/04/2024] Open
Abstract
The progress of cancer treatment methods in the last decade has significantly reduced mortality rate among these patients. Nevertheless, cancer is still recognized as one of the main causes of human deaths. One of the main reasons for the high death rate in cancer patients is the late diagnosis in the advanced tumor stages. Therefore, it is necessary to investigate the molecular biology of tumor progressions in order to introduce early diagnostic markers. MicroRNAs (miRNAs) have an important role in regulating cellular processes associated with tumor progression. Due to the high stability of miRNAs in body fluids, they are widely used as non-invasive markers in the early tumor diagnosis. Since, deregulation of miR-98 has been reported in a wide range of cancers, we investigated the molecular mechanisms of miR-98 during tumor progression. It has been reported that miR-98 mainly inhibits the tumor growth by the modulation of transcription factors and signaling pathways. Therefore, miR-98 can be introduced as a tumor marker and therapeutic target among cancer patients.
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Affiliation(s)
- Iman Akhlaghipour
- Student Research Committee, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Meysam Moghbeli
- Department of Medical Genetics and Molecular Medicine, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
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Cavalieri S, Bergamini C, Lenoci D, Ottini A, Lucchetta M, Torchia E, Licitra L, De Cecco L. Claudin-1 in Head and Neck Squamous Cell Carcinoma. Oncology 2024; 103:107-111. [PMID: 39231459 DOI: 10.1159/000540775] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Accepted: 07/24/2024] [Indexed: 09/06/2024]
Abstract
INTRODUCTION The objective response rate to immunotherapy is limited in recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) patients, whose prognosis is still dismal. Few prognostic factors are clinically available, mostly related to patient or disease characteristics. Gene expression signatures offer better prognostic abilities but are mainly used in research. One such GE model classifies HNSCC into 6 clusters with different prognoses. Claudin-1 (CLDN1), which influences tumor microenvironment and immune cell infiltration, has emerged as a potential target, especially in cancers like HNSCC with high CLDN1 expression. METHODS A single-center cohort of 100 loco-regionally advanced HNSCC patients from the BD2Decide observational study was analyzed. Patients were selected to balance long-term survivors and deceased patients, including HPV-negative and HPV-positive cases. Primary tumor specimens underwent GE analysis using Affymetrix ClariomD chips. Primary endpoint was overall survival (OS). RESULTS The cohort comprised 100 HNSCC patients with a median age of 60 years, predominantly men (76%). Median OS and disease-free survival (DFS) were 94.24 and 42.79 months, respectively. CLDN1 expression varied significantly among primary sites, being highest in hypopharynx cancers. Differences in expression were not significant when stratified by HPV status or clinical stage. CLDN1 expression differed across the 6 transcriptomic clusters, with the highest levels in clusters associated with mesenchymal and hypoxic features. Higher CLDN1 expression correlated with shorter OS (hazard ratio [HR]: 3, p = 0.0023) and DFS (HR: 2.14, p = 0.02). CONCLUSION CLDN1 expression is heterogeneous in HNSCC and carries prognostic significance. It is highest in tumors with HPV-like biology and hypoxic environments, and lowest in immune-sensitive clusters. High CLDN1 is a negative prognostic factor and a promising therapeutic target. Anti-CLDN1 treatments could improve outcomes of CLDN1+ HNSCC patients, and combination therapies with ICIs might overcome resistance in CLDN1- cases. These findings support the need for clinical studies on anti-CLDN1 therapies.
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Affiliation(s)
- Stefano Cavalieri
- Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
| | - Cristiana Bergamini
- Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
| | - Deborah Lenoci
- Integrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Arianna Ottini
- Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Marta Lucchetta
- Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Erica Torchia
- Integrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Lisa Licitra
- Head and Neck Medical Oncology Department, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
- Department of Oncology and Hemato-oncology, University of Milan, Milan, Italy
| | - Loris De Cecco
- Integrated Biology of Rare Tumors, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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Apostolova D, Apostolov G, Moten D, Batsalova T, Dzhambazov B. Claudin-12: guardian of the tissue barrier or friend of tumor cells. Tissue Barriers 2024:2387408. [PMID: 39087432 DOI: 10.1080/21688370.2024.2387408] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2024] [Revised: 07/28/2024] [Accepted: 07/28/2024] [Indexed: 08/02/2024] Open
Abstract
Tight junctions (TJs) are an important component of cellular connectivity. Claudin family proteins, as a constituent of TJs, determine their barrier properties, cell polarity and paracellular permeability. Claudin-12 is an atypical member of the claudin family, as it belongs to the group of non-classical claudins that lack a PDZ-binding domain. It has been shown that claudin-12 is involved in paracellular Ca2+ transients and it is present in normal and hyperplastic tissues in addition to neoplastic tissues. Dysregulation of claudin-12 expression has been reported in various cancers, suggesting that this protein may play an important role in cancer cell migration, invasion, and metastasis. Some studies have shown that claudin-12 gene functions as a tumor suppressor, but others have reported that overexpression of claudin-12 significantly increases the metastatic properties of various tumor cells. Investigating this dual role of claudin-12 is of utmost importance and should therefore be studied in detail. The aim of this review is to provide an overview of the information available to date on claudin-12, including its structure, expression in various tissues and substances that may affect it, with a final focus on its role in cancer.
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Affiliation(s)
- Desislava Apostolova
- Department of Developmental Biology, Faculty of Biology, Paisii Hilendarski University of Plovdiv, Plovdiv, Bulgaria
| | - Georgi Apostolov
- Department of Neurosurgery, Faculty of Medicine, Medical University of Plovdiv, Plovdiv, Bulgaria
| | - Dzhemal Moten
- Department of Developmental Biology, Faculty of Biology, Paisii Hilendarski University of Plovdiv, Plovdiv, Bulgaria
| | - Tsvetelina Batsalova
- Department of Developmental Biology, Faculty of Biology, Paisii Hilendarski University of Plovdiv, Plovdiv, Bulgaria
| | - Balik Dzhambazov
- Department of Developmental Biology, Faculty of Biology, Paisii Hilendarski University of Plovdiv, Plovdiv, Bulgaria
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Haughton PD, Haakma W, Chalkiadakis T, Breimer GE, Driehuis E, Clevers H, Willems S, Prekovic S, Derksen PWB. Differential transcriptional invasion signatures from patient derived organoid models define a functional prognostic tool for head and neck cancer. Oncogene 2024; 43:2463-2474. [PMID: 38942893 PMCID: PMC11315671 DOI: 10.1038/s41388-024-03091-4] [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: 10/24/2023] [Revised: 06/07/2024] [Accepted: 06/18/2024] [Indexed: 06/30/2024]
Abstract
Clinical outcome for patients suffering from HPV-negative head and neck squamous cell carcinoma (HNSCC) remains poor. This is mostly due to highly invasive tumors that cause loco-regional relapses after initial therapeutic intervention and metastatic outgrowth. The molecular pathways governing the detrimental invasive growth modes in HNSCC remain however understudied. Here, we have established HNSCC patient derived organoid (PDO) models that recapitulate 3-dimensional invasion in vitro. Single cell mRNA sequencing was applied to study the differences between non-invasive and invasive conditions, and in a collective versus single cell invading PDO model. Differential expression analysis under invasive conditions in Collagen gels reveals an overall upregulation of a YAP-centered transcriptional program, irrespective of the invasion mode. However, we find that collectively invading HNSCC PDO cells show elevated levels of YAP transcription targets when compared to single cell invasion. Also, collectively invading cells are characterized by increased nuclear translocation of YAP within the invasive strands, which coincides with Collagen-I matrix alignment at the invasive front. Using gene set enrichment analysis, we identify immune cell-like migratory pathways in the single cell invading HNSCC PDO, while collective invasion is characterized by overt upregulation of adhesion and migratory pathways. Lastly, based on clinical head and neck cancer cohorts, we demonstrate that the identified collective invasion signature provides a candidate prognostic platform for survival in HNSCC. By uncoupling collective and single cell invasive programs, we have established invasion signatures that may guide new therapeutic options.
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Affiliation(s)
- Peter D Haughton
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Wisse Haakma
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Theofilos Chalkiadakis
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Gerben E Breimer
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Else Driehuis
- Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences (KNAW) and UMC Utrecht, 3584, CT, Utrecht, The Netherlands
| | - Hans Clevers
- Roche Pharmaceutical Research and Early Development, Basel, Switzerland
| | - Stefan Willems
- Department Pathology and Medical biology, University Medical Center Groningen, Groningen, The Netherlands
| | - Stefan Prekovic
- Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, The Netherlands.
| | - Patrick W B Derksen
- Department of Pathology, University Medical Center Utrecht, Utrecht, The Netherlands.
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Gabusi A, Asioli S, Fabbri VP, Fellegara G, Gibertoni D, Rossi R, Battaglia S, Tarsitano A, Balbi T, Marchetti C, Montebugnoli L, Foschini MP, Gissi DB. Pre-operative incisional biopsy of oral squamous cell carcinoma: high podoplanin expression is related to perineural invasion and may be a useful predictor of disease progression. Oral Surg Oral Med Oral Pathol Oral Radiol 2024; 137:53-60. [PMID: 37891118 DOI: 10.1016/j.oooo.2023.08.011] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 07/28/2023] [Accepted: 08/13/2023] [Indexed: 10/29/2023]
Abstract
OBJECTIVE Immunohistochemical analysis of podoplanin expression as a pre-operative molecular marker for perineural invasion (PNI) may represent an attractive strategy for surgical management of oral squamous cell cancer (OSCC). We evaluated the relationship between podoplanin expression and PNI in pre-operative incisional biopsies of OSCC. STUDY DESIGN After performing pathological staging and histologic and immunohistochemical evaluation of 83 surgical specimens, we performed multivariable logistic regression analysis to examine the relationship between PNI and independent variables. To evaluate the utility of podoplanin immunopositivity for discrimination of PNI status pre-operatively, we calculated the sensitivity, specificity, positive predictive value, and negative predictive value. We performed receiver operating characteristic curve analysis to evaluate the diagnostic accuracy of podoplanin immunopositivity for predicting PNI alone and in combination with age, T stage, N stage, and index site. RESULTS We observed podoplanin expression in 42 (50.6%) of all the 83 pre-operative incisional biopsies and 29 of the pre-operative biopsies of the 31 (93.5%) postoperative specimens with PNI. The rate of podoplanin expression was significantly higher in patients with pT3 to pT4 stage and pN+ stage disease. Podoplanin positivity in the pre-operative biopsy showed high sensitivity in predicting PNI in the surgical specimen. CONCLUSION Podoplanin expression appears to be an independent pre-operative variable significantly related to PNI and a possibly valuable prognostic marker for therapeutical planning and surgical treatment of OSCC.
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Affiliation(s)
- Andrea Gabusi
- Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy
| | - Sofia Asioli
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, M. Malpighi Bellaria Hospital, Bologna, Italy
| | | | - Giovanni Fellegara
- Pathology and Laboratory Medicine Centro Diagnostico Italiano, Milan Italy
| | - Dino Gibertoni
- Research and Innovation Unit, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Roberto Rossi
- Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy
| | - Salvatore Battaglia
- Unit of Maxillofacial Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, Unit of Maxillofacial Surgery, University of Bologna, Bologna, Italy
| | - Achille Tarsitano
- Unit of Maxillofacial Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, Unit of Maxillofacial Surgery, University of Bologna, Bologna, Italy
| | - Tiziana Balbi
- Unit of Anatomic Pathology S. Orsola Hospital, IRCCS Azienda Ospedaliero Universitaria, Bologna, Italy
| | - Claudio Marchetti
- Unit of Maxillofacial Surgery, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, Unit of Maxillofacial Surgery, University of Bologna, Bologna, Italy
| | - Lucio Montebugnoli
- Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy
| | - Maria Pia Foschini
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, M. Malpighi Bellaria Hospital, Bologna, Italy
| | - Davide B Gissi
- Department of Biomedical and Neuromotor Sciences, Section of Oral Sciences, University of Bologna, Bologna, Italy.
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Xia Y, Hei N, Peng S, Cui Z. The role and mechanism of circ-BNC2 on the malignant progression of oral squamous cell carcinoma. Head Neck 2023; 45:2424-2437. [PMID: 37377048 DOI: 10.1002/hed.27442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 06/16/2023] [Accepted: 06/18/2023] [Indexed: 06/29/2023] Open
Abstract
BACKGROUND Circular RNAs (circRNAs) play a key part in the progression of oral squamous cell carcinoma (OSCC). However, the role of circ-BNC2 (circRNA ID hsa_circ_0086414) in OSCC progression is still unclear. METHODS Plasmid transfection was used to induce overexpression of circ-BNC2. RNA expression of circ-BNC2, microRNA-142-3p (miR-142-3p) and GNAS complex locus (GNAS) was detected by quantitative real-time polymerase chain reaction. Protein expression was assessed by western blot assay or immunohistochemistry assay. Cell proliferation was investigated by 3-(4,5-dimethylthazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, colony formation assay and flow cytometry analysis. Cell migratory and invasive abilities and cell apoptosis were assessed by transwell assay and flow cytometry analysis, respectively. Oxidative stress was evaluated by superoxide dismutase activity detection assay, lipid peroxidation malondialdehyde assay and cellular reactive oxygen species assay. The binding relationship between miR-142-3p and circ-BNC2 or GNAS was proved by dual-luciferase reporter assay and RNA immunoprecipitation assay. The impacts of circ-BNC2 overexpression on tumor growth in vivo were unveiled by a xenograft mouse model assay. RESULTS Circ-BNC2 expression was downregulated in OSCC tissues and cells when compared with adjacent healthy tissues and normal human oral keratinocytes. Circ-BNC2 overexpression repressed the proliferation, migration and invasion of OSCC cells but induced cell apoptosis and oxidative stress. Additionally, circ-BNC2 overexpression inhibited tumor growth in vivo. Furthermore, circ-BNC2 bound to miR-142-3p, and miR-142-3p targeted GNAS. MiR-142-3p mimic attenuated circ-BNC2 overexpression-mediated effects on the proliferation, migration, invasion, apoptosis and oxidative stress of OSCC cells. The regulation of miR-142-3p in OSCC cell tumor properties involved GNAS. Further, circ-BNC2 introduction promoted GNAS expression by inhibiting miR-142-3p. CONCLUSION Circ-BNC2 suppressed OSCC malignant progression by upregulating GNAS expression in a miR-142-3p-dependent manner, which suggested that circ-BNC2 might be a novel target for OSCC therapy.
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Affiliation(s)
- Yingjie Xia
- Department of Stomatology, Hengshui People's Hospital, Hengshui City, Hebei Province, China
| | - Naiheng Hei
- Department of Stomatology, the Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Shixiong Peng
- Department of Stomatology, the Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
| | - Zifeng Cui
- Department of Stomatology, the Fourth Hospital of Hebei Medical University, Shijiazhuang City, Hebei Province, China
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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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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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11
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Goswami PR, Singh G. Perineural Invasion (PNI) Definition, Histopathological Parameters of PNI in Oral Squamous Cell Carcinoma With Molecular Insight and Prognostic Significance. Cureus 2023; 15:e40165. [PMID: 37431326 PMCID: PMC10329772 DOI: 10.7759/cureus.40165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/09/2023] [Indexed: 07/12/2023] Open
Abstract
Oral squamous cell carcinoma is associated with severe morbidity, recurrence of tumor, and reduced survival rate despite advances in treatment. Perineural invasion (PNI) is associated with neurotropic malignancy. PNI is due to the tropism of cancer cells toward nerve bundles in tissue. The aim of this literature review is to study the definition, patterns of PNI, Prognostic and therapeutic significance, and mechanism of PNI along with a molecular insight into oral cavity squamous cell carcinoma. Liebig type A pattern defines PNI as the presence of tumor cells within the peripheral nerve sheath & infiltration into the epineurium, perineurium, or endoneurium. Liebig type B pattern defines PNI as a tumor encircling at least 33% of a nerve. Few studies demonstrated an association between PNI and cervical metastasis which indicate poor prognosis. A higher level of expression of nerve growth factor and tyrosine kinase is associated with PNI in OSCC which can be considered as a biomarker of PNI. PNI needs to be studied in detail as it is associated with the aggressiveness of the tumor and decreased survival.
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Affiliation(s)
- Parth R Goswami
- Pathology, All India Institute of Medical Sciences, Rajkot, Rajkot, IND
| | - Gyanendra Singh
- Pathology, All India Institute of Medical Sciences, Rajkot, Rajkot, IND
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Fatima I, Uppada JP, Chhonker YS, Gowrikumar S, Barman S, Roy S, Tolentino KT, Palermo N, Natarajan A, Beauchamp DR, Vecchio A, Murry DJ, Singh AB, Hopkins CR, Dhawan P. Identification and characterization of a first-generation inhibitor of claudin-1 in colon cancer progression and metastasis. Biomed Pharmacother 2023; 159:114255. [PMID: 36696800 PMCID: PMC10824272 DOI: 10.1016/j.biopha.2023.114255] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2022] [Revised: 01/07/2023] [Accepted: 01/14/2023] [Indexed: 01/25/2023] Open
Abstract
Colorectal cancer (CRC) is a leading cause of the cancer-related deaths worldwide. Thus, developing novel and targeted therapies for inhibiting CRC progression and metastasis is urgent. Several studies, including ours, have reported a causal role for an upregulated claudin-1 expression in promoting CRC metastasis through the activation of the Src and β-catenin-signaling. In murine models of colon tumorigenesis, claudin-1 overexpression promotes oncogenic properties such as transformation and invasiveness. Conversely, the downregulation of claudin-1 inhibits colon tumorigenesis. Despite being a desirable target for cancer treatment, there are currently no known claudin-1 inhibitors with antitumor efficacy. Using a rigorous analytical design and implementing in- vitro and in-vivo testing and a brief medicinal chemistry campaign, we identified a claudin-1-specific inhibitor and named it I-6. Despite its high potency, I-6 was rapidly cleared in human liver microsomes. We, therefore, synthesized I-6 analogs and discovered a novel small molecule, PDS-0330. We determined that PDS0330 inhibits claudin-1-dependent CRC progression without exhibiting toxicity in in-vitro and in-vivo models of CRC and that it binds directly and specifically to claudin-1 with micromolar affinity. Further analyses revealed that PDS-0330 exhibits antitumor and chemosensitizer activities with favorable pharmacokinetic properties by inhibiting the association with metastatic oncogene Src. Overall, our data propose that PDS-0330 interferes with claudin-1/Src association to inhibit CRC progression and metastasis. Our findings are of direct clinical relevance and may open new therapeutic opportunities in colon cancer treatment and/or management by targeting claudin-1.
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Affiliation(s)
- Iram Fatima
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Jaya Prakash Uppada
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Yashpal S Chhonker
- Department of Pharmacy Practice and Science, University of Nebraska Medical Center, Omaha, NE, USA
| | - Saiprasad Gowrikumar
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Susmita Barman
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sourav Roy
- Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0664, USA
| | - Kirsten T Tolentino
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| | - Nicholas Palermo
- Computational Chemistry Core, University of Nebraska Medical Center, Omaha, NE, USA
| | - Amar Natarajan
- Eppley Institute for Cancer Research, University of Nebraska Medical Center, Omaha, NE, USA
| | - Daniel R Beauchamp
- Surgical Oncology Research Laboratories, Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Alex Vecchio
- Department of Biochemistry, University of Nebraska-Lincoln, Lincoln, NE 68588-0664, USA
| | - Daryl J Murry
- Department of Pharmacy Practice and Science, 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; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA
| | - Corey R Hopkins
- Department of Pharmaceutical Sciences, University of Nebraska Medical Center, Omaha, NE, USA
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, USA; VA Nebraska-Western Iowa Health Care System, Omaha, NE, USA; Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE, USA.
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13
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Liu Q, Ma Z, Cao Q, Zhao H, Guo Y, Liu T, Li J. Perineural invasion-associated biomarkers for tumor development. Biomed Pharmacother 2022; 155:113691. [PMID: 36095958 DOI: 10.1016/j.biopha.2022.113691] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2022] [Accepted: 09/08/2022] [Indexed: 11/17/2022] Open
Abstract
Perineural invasion (PNI) is the process of neoplastic invasion of peripheral nerves and is considered to be the fifth mode of cancer metastasis. PNI has been detected in head and neck tumors and pancreatic, prostate, bile duct, gastric, and colorectal cancers. It leads to poor prognostic outcomes and high local recurrence rates. Despite the increasing number of studies on PNI, targeted therapeutic modalities have not been proposed. The identification of PNI-related biomarkers would facilitate the non-invasive and early diagnosis of cancers, the establishment of prognostic panels, and the development of targeted therapeutic approaches. In this review, we compile information on the molecular mediators involved in PNI-associated cancers. The expression and prognostic significance of molecular mediators and their receptors in PNI-associated cancers are analyzed, and the possible mechanisms of action of these mediators in PNI are explored, as well as the association of cells in the microenvironment where PNI occurs.
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Affiliation(s)
- Qi Liu
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, China
| | - Zhiming Ma
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, China
| | - Qian Cao
- Department of Education, The Second Hospital of Jilin University, Changchun 130041, China
| | - Hongyu Zhao
- Gastroenterology and Center of Digestive Endoscopy, The Second Hospital of Jilin University, Changchun 130041, China
| | - Yu Guo
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, China
| | - Tongjun Liu
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, China
| | - Jiannan Li
- Department of General Surgery, The Second Hospital of Jilin University, Changchun 130041, China.
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Zejc T, Piontek J, Schulzke JD, Fromm M, Ervens J, Rosenthal R. Clinical Significance of Claudin Expression in Oral Squamous Cell Carcinoma. Int J Mol Sci 2022; 23:ijms231911234. [PMID: 36232536 PMCID: PMC9569574 DOI: 10.3390/ijms231911234] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/16/2022] [Accepted: 09/19/2022] [Indexed: 12/24/2022] Open
Abstract
A change in claudin expression has been demonstrated in various tumors. The present study specifically compares claudin expression in oral squamous cell carcinoma (OSCC) with healthy oral epithelium from the same individual and analyzes the association between claudin expression and the clinically relevant course parameters. Our study includes tissue samples and clinically relevant follow-up data from 60 patients with primary and untreated OSCC. The oral mucosa was analyzed via Western blot for the expression of claudin-1, -2, -3, -4, -5, and -7. Importantly, the tumor and healthy tissues were obtained pairwise from patients, allowing for intraindividual comparisons. Both the healthy and tumor epithelium from the oral cavity did not express the claudin-3 protein. The intraindividual comparison revealed that, in OSCC, claudin-2 expression was higher, and the expression of claudin-4, -5, and -7 was lower than in healthy epithelium. An association was found between increased claudin-2 expression and shorter relapse-free survival. In addition, the reduced expression of claudin-4 had a negative impact on relapse-free survival. Furthermore, associations between the reduced expression of claudin-7 and the stage of a tumor, or the presence of lymph node metastases, were found. Thus, the expression level of claudin-2, -4, and -7 appears to be predictive of the diagnosis and prognosis of OSCC.
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Affiliation(s)
- Tatjana Zejc
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Jörg Piontek
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Jörg-Dieter Schulzke
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Michael Fromm
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
| | - Jürgen Ervens
- Klinik für HNO-Heilkunde, Kopf- und Halschirurgie, Plastische Chirurgie, Vivantes Klinikum Neukölln, Rudower Straße 48, Neukölln, 12351 Berlin, Germany
| | - Rita Rosenthal
- Department of Gastroenterology, Rheumatology and Infectious Diseases, Clinical Physiology/Nutritional Medicine, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany
- Correspondence: ; Tel.: +49-30-450-514-527
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15
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Mukherjee A, Ha P, Wai KC, Naara S. The Role of ECM Remodeling, EMT, and Adhesion Molecules in Cancerous Neural Invasion: Changing Perspectives. Adv Biol (Weinh) 2022; 6:e2200039. [PMID: 35798312 DOI: 10.1002/adbi.202200039] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2022] [Revised: 05/05/2022] [Indexed: 01/28/2023]
Abstract
Perineural invasion (PNI) refers to the cancerous invasion of nerves. It provides an alternative route for metastatic invasion and can exist independently in the absence of lymphatic or vascular invasion. It is a prominent characteristic of specific aggressive malignancies where it correlates with poor prognosis. The clinical significance of PNI is widely recognized despite a lack of understanding of the molecular mechanisms underlying its pathogenesis. The interaction between the nerve and the cancer cells is the most pivotal PNI step which is mediated by the activation or inhibition of multiple signaling pathways that include chemokines, interleukins, nerve growth factors, and matrix metalloproteinases, to name a few. The nerve-cancer cell interaction brings about specific changes in the perineural niche, which not only affects the regular nerve functions, but also enhances the migratory, invasive, and adherent properties of the tumor cells. This review aims to elucidate the vital role of adhesion molecules, extracellular matrix, and epithelial-mesenchymal proteins that promote PNI, which may serve as therapeutic targets in the future.
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Affiliation(s)
- Abhishek Mukherjee
- Department of Genetics and Developmental BiologyRappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525422, Israel
| | - Patrick Ha
- Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA
| | - Katherine C Wai
- Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA
| | - Shorook Naara
- Department of Genetics and Developmental BiologyRappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, 3525422, Israel.,Department of Otolaryngology-Head and Neck Surgery, University of California-San Francisco, Helen Diller Family Comprehensive Cancer Center, San Francisco, CA, 94158, USA
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Monteiro L, Delgado L, Amaral B, Ricardo S, Fraga M, Lopes C, Warnakulasuryia S. Occludin and Claudin-1 are potential prognostic biomarkers in patients with oral squamous cell carcinomas. An observational study. Oral Surg Oral Med Oral Pathol Oral Radiol 2022; 134:588-598. [DOI: 10.1016/j.oooo.2022.06.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Revised: 04/21/2022] [Accepted: 06/22/2022] [Indexed: 11/30/2022]
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Kołat D, Kałuzińska Ż, Bednarek AK, Płuciennik E. Determination of WWOX Function in Modulating Cellular Pathways Activated by AP-2α and AP-2γ Transcription Factors in Bladder Cancer. Cells 2022; 11:cells11091382. [PMID: 35563688 PMCID: PMC9106060 DOI: 10.3390/cells11091382] [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: 03/29/2022] [Revised: 04/16/2022] [Accepted: 04/18/2022] [Indexed: 02/07/2023] Open
Abstract
Following the invention of high-throughput sequencing, cancer research focused on investigating disease-related alterations, often inadvertently omitting tumor heterogeneity. This research was intended to limit the impact of heterogeneity on conclusions related to WWOX/AP-2α/AP-2γ in bladder cancer which differently influenced carcinogenesis. The study examined the signaling pathways regulated by WWOX-dependent AP-2 targets in cell lines as biological replicates using high-throughput sequencing. RT-112, HT-1376 and CAL-29 cell lines were subjected to two stable lentiviral transductions. Following CAGE-seq and differential expression analysis, the most important genes were identified and functionally annotated. Western blot was performed to validate the selected observations. The role of genes in biological processes was assessed and networks were visualized. Ultimately, principal component analysis was performed. The studied genes were found to be implicated in MAPK, Wnt, Ras, PI3K-Akt or Rap1 signaling. Data from pathways were collected, explaining the differences/similarities between phenotypes. FGFR3, STAT6, EFNA1, GSK3B, PIK3CB and SOS1 were successfully validated at the protein level. Afterwards, a definitive network was built using 173 genes. Principal component analysis revealed that the various expression of these genes explains the phenotypes. In conclusion, the current study certified that the signaling pathways regulated by WWOX and AP-2α have more in common than that regulated by AP-2γ. This is because WWOX acts as an EMT inhibitor, AP-2γ as an EMT enhancer while AP-2α as a MET inducer. Therefore, the relevance of AP-2γ in targeted therapy is now more evident. Some of the differently regulated genes can find application in bladder cancer treatment.
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18
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Ahmadi N, Kelly G, Low TH(H, Clark J, Gupta R. Molecular factors governing perineural invasion in malignancy. Surg Oncol 2022; 42:101770. [PMID: 35490532 DOI: 10.1016/j.suronc.2022.101770] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 03/27/2022] [Accepted: 04/10/2022] [Indexed: 12/30/2022]
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Tight junction protein CLDN17 serves as a tumor suppressor to reduce the invasion and migration of oral cancer cells by inhibiting epithelial-mesenchymal transition. Arch Oral Biol 2021; 133:105301. [PMID: 34781072 DOI: 10.1016/j.archoralbio.2021.105301] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Revised: 10/25/2021] [Accepted: 10/27/2021] [Indexed: 12/11/2022]
Abstract
OBJECTIVE To investigate claudin-17 (CLDN17) expression in oral cancer and its effect on epithelial-mesenchymal transition (EMT), invasion and migration in oral cancer cells. METHODS The GEO2R tool was used to analyze gene expression in two microarray datasets (GSE74530 and GSE146483) derived from the Gene Expression Omnibus (GEO) database. Gene Expression Profiling Interactive Analysis (GEPIA) verified CLDN17 expression in head and neck squamous cell carcinoma (HNSC) patients. Moreover, oral cancer cells were transfected with CLDN17 overexpression plasmid or CLDN17 shRNA to evaluate cell invasion and migration. Gene and protein expression was detected by qRT-PCR, immunohistochemistry and western blotting. RESULTS CLDN17 was one of the top 200 differentially expressed genes in the GSE74530 and GSE146483 datasets and was downregulated in oral cancer. CLDN17 expression was higher in HNSC tissues, and it was related to TNM staging. In HNSC tumors, CLDN17 expression was positively correlated with CDH1 but negatively related to VIM, SNAIL1, SNAIL2, and TWIST1. Meanwhile, we found that CLDN17 expression was lower in oral cancer tissues; it declined with higher T status, N status, M status and staging, lower differentiation grade, and a worse prognosis. Upregulation of CLDN17 inhibited the invasion and migration of oral cancer cells, with elevated CDH1 and reduced VIM, SNAIL1, SNAIL2, and TWIST1, while CLDN17 downregulation had the opposite effects. CONCLUSION CLDN17 may serve as a tumor suppressor in oral cancer since it could reduce the invasion and migration of cells by inhibiting the EMT process, thus becoming a potential therapeutic target in oral cancer.
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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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21
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Upadhaya P, Giri S, Barhoi D, Bhattacharjee A. Altered expression of junctional proteins as a potential biomarker in oral precancerous and cancerous patients. Tissue Barriers 2021; 10:1973329. [PMID: 34534039 DOI: 10.1080/21688370.2021.1973329] [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: 12/24/2022] Open
Abstract
Due to a lower survival rate in patients with advanced clinical stages of oral cancer, discovering a biomarker that could diagnose and predict disease progression is vital. Cell-cell junctional proteins play a crucial role in the maintenance of tissue architecture but are often deregulated in different cancer. The present study investigates the expression of cell-cell junctional proteins viz: e-cadherin (E-cad) and zonula occludens-1 (ZO-1) in oral precancerous (OED) and cancerous (OSCC) patients to monitor if they can serve as practicable molecular markers. The ultrastructural junctional complex was studied by transmission electron microscopy, and the expression of proteins was performed by immunohistochemistry. The relationship between the expression of protein and clinicopathological features of the patients was checked by Pearson's correlation test. Furthermore, the survival curve of the follow-up data was estimated by the Kaplan-Meier method. We observed a disrupted junctional complex and a significantly decreased immunoexpression of E-cad and ZO-1 in OED and OSCC when compared to the adjacent non-cancerous tissues. The expression of ZO-1 was associated with TNM stages, whereas E-cad was associated with histological grades as well as TNM stages. A positive correlation was observed between the expression of ZO-1 and E-cad proteins in OED and OSCC. Further, follow-up studies revealed that high ZO-1 and E-cad expressing patients survived longer than their low expressed counterparts. The present study shows disruption of junctional complex and alteration of junctional proteins expression that could draw the attention of health professionals to explore junctional proteins as a possible therapeutic target in oral cancer.
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Affiliation(s)
- Puja Upadhaya
- Laboratory of Molecular and Cell Biology, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Sarbani Giri
- Laboratory of Molecular and Cell Biology, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Dharmeswar Barhoi
- Laboratory of Molecular and Cell Biology, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
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22
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Gomez-Casado C, Sanchez-Solares J, Izquierdo E, Díaz-Perales A, Barber D, Escribese MM. Oral Mucosa as a Potential Site for Diagnosis and Treatment of Allergic and Autoimmune Diseases. Foods 2021; 10:970. [PMID: 33925074 PMCID: PMC8146604 DOI: 10.3390/foods10050970] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Revised: 04/23/2021] [Accepted: 04/26/2021] [Indexed: 12/15/2022] Open
Abstract
Most prevalent food allergies during early childhood are caused by foods with a high allergenic protein content, such as milk, egg, nuts, or fish. In older subjects, some respiratory allergies progressively lead to food-induced allergic reactions, which can be severe, such as urticaria or asthma. Oral mucosa remodeling has been recently proven to be a feature of severe allergic phenotypes and autoimmune diseases. This remodeling process includes epithelial barrier disruption and the release of inflammatory signals. Although little is known about the immune processes taking place in the oral mucosa, there are a few reports describing the oral mucosa-associated immune system. In this review, we will provide an overview of the recent knowledge about the role of the oral mucosa in food-induced allergic reactions, as well as in severe respiratory allergies or food-induced autoimmune diseases, such as celiac disease.
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Affiliation(s)
- Cristina Gomez-Casado
- Institute of Applied Molecular Medicine, Department of Basic Medical Sciences, Faculty of Medicine, San Pablo CEU University, 28003 Madrid, Spain; (J.S.-S.); (E.I.); (D.B.); (M.M.E.)
| | - Javier Sanchez-Solares
- Institute of Applied Molecular Medicine, Department of Basic Medical Sciences, Faculty of Medicine, San Pablo CEU University, 28003 Madrid, Spain; (J.S.-S.); (E.I.); (D.B.); (M.M.E.)
| | - Elena Izquierdo
- Institute of Applied Molecular Medicine, Department of Basic Medical Sciences, Faculty of Medicine, San Pablo CEU University, 28003 Madrid, Spain; (J.S.-S.); (E.I.); (D.B.); (M.M.E.)
| | - Araceli Díaz-Perales
- Center of Plant Biotechnology and Genomics, Technical University of Madrid, 28040 Madrid, Spain;
| | - Domingo Barber
- Institute of Applied Molecular Medicine, Department of Basic Medical Sciences, Faculty of Medicine, San Pablo CEU University, 28003 Madrid, Spain; (J.S.-S.); (E.I.); (D.B.); (M.M.E.)
| | - María M. Escribese
- Institute of Applied Molecular Medicine, Department of Basic Medical Sciences, Faculty of Medicine, San Pablo CEU University, 28003 Madrid, Spain; (J.S.-S.); (E.I.); (D.B.); (M.M.E.)
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Withaferin A mitigates metastatic traits in human oral squamous cell carcinoma caused by aberrant claudin-1 expression. Cell Biol Toxicol 2021; 38:147-165. [PMID: 33665778 DOI: 10.1007/s10565-021-09584-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Accepted: 01/24/2021] [Indexed: 12/27/2022]
Abstract
Abnormal expression of claudin-1 (CLDN1) has important roles in carcinogenesis and metastasis in various cancers. The role of CLDN1 in human oral squamous cell carcinoma (OSCC) remains unknown. Here, we report the functional role of CLDN1 in metastasis of human OSCC, as a potential target regulated by withaferin A. From gene expression profiling with microarray technology, we found that the majority of notable differentially expressed genes were classified into migration/invasion category. Withaferin A impaired the motility of human OSCC cells in vitro and suppressed metastatic nodule formation in an in vivo metastasis model, both associated with reduced CLDN1. CLDN1 overexpression enhanced metastatic nodule formation in vivo, resulting in severe metastatic lesions in lung tissue. Moreover, CLDN1 expression was positively correlated to lymphatic metastasis in OSCC patients. The impaired motility of human OSCC cells upon withaferin A treatment was restored by CLDN1 overexpression. Furthermore, upregulation of let-7a induced by withaferin A was inversely correlated to CLDN1 expression. Overall, these give us an insight into the function of CLDN1 for prognosis and treatment of human OSCC, substantiating further investigation into the use of withaferin A as good anti-metastatic drug candidate.
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Kakiuchi A, Kakuki T, Ohwada K, Kurose M, Kondoh A, Obata K, Nomura K, Miyata R, Kaneko Y, Konno T, Kohno T, Himi T, Takano KI, Kojima T. HDAC inhibitors suppress the proliferation, migration and invasiveness of human head and neck squamous cell carcinoma cells via p63‑mediated tight junction molecules and p21‑mediated growth arrest. Oncol Rep 2021; 45:46. [PMID: 33649777 PMCID: PMC7934225 DOI: 10.3892/or.2021.7997] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 04/07/2020] [Indexed: 12/27/2022] Open
Abstract
In human head and neck squamous cell carcinoma (HNSCC), the invasion and metastatic properties of cancer cells are promoted by junctional adhesion molecule-A (JAM-A) and claudin-1; these are epithelial tight junction molecules regulated by histone deacetylases (HDACs) and transcription factor p63. HDAC expression is reportedly upregulated in HNSCC, and HDAC inhibitors suppress cancer cell proliferation by initiating proliferative arrest or apoptosis. However, little is known of the anti-cancer mechanisms of HDAC inhibitors in HNSCC. Thus, in the present study, the HNSCC Detroit 562 cell line and primary cultured HNSCC cells were treated with HDAC inhibitors to investigate their effects in HNSCC. Higher expression of p63, HDAC1, JAM-A and claudin-1 was observed in HNSCC tissues compared with the adjacent dysplastic regions. In Detroit 562 cells, treatment with trichostatin A (TSA), an inhibitor of HDAC1 and 6, downregulated the expression of p63, JAM-A and claudin-1, and upregulated that of acetylated tubulin; conversely, p63 knockdown resulted in the downregulation of JAM-A and claudin-1. Collectively, inhibiting HDAC suppressed the migration and invasiveness of cancer cells. In addition, treatment with TSA suppressed cancer cell proliferation via G2/M arrest, as well as upregulating p21 and downregulating cyclin D1 expression. TSA also downregulated the expression of epidermal growth factor receptor (EGFR) and phospho-ERK1/2. p63 knockdown and treatment with an EGFR inhibitor induced G1 arrest and downregulated EGFR and phospho-ERK1/2 levels, respectively. HDAC inhibition also suppressed the migration and invasiveness of primary cultured HNSCC cells. Collectively, the results of the present study indicate that HDAC inhibitors suppress the proliferation, migration and invasiveness of HNSCC by downregulating the p63-mediated tight junction molecules JAM-A and claudin-1, and inducing p63 or p21-mediated growth arrest.
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Affiliation(s)
- Akito Kakiuchi
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Takuya Kakuki
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Kizuku Ohwada
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Makoto Kurose
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Atsushi Kondoh
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Kazufumi Obata
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Kazuaki Nomura
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Ryo Miyata
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Yakuto Kaneko
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Takumi Konno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Takayuki Kohno
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Tetsuo Himi
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Ken-Ichi Takano
- Department of Otolaryngology, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
| | - Takashi Kojima
- Department of Cell Science, Research Institute for Frontier Medicine, Sapporo Medical University School of Medicine, Sapporo 060‑8556, Japan
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Ouban A. Expression of Claudin-1 in laryngeal squamous cell carcinomas (LSCCs) and its significance. Histol Histopathol 2021; 36:437-446. [PMID: 33629735 DOI: 10.14670/hh-18-320] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
BACKGROUND A large body of scientific evidence points to the important roles of tight junction proteins in tumor development, progression and dissemination. The larynx has only a few studies, analyzing the role of this group of junctional proteins in its oncogenesis. In this study, the author sheds some light on the expression and possible role of claudin-1 in laryngeal squamous cell carcinomas. MATERIALS AND METHODS This study analyzed the expression of claudin-1, using immunohistochemistry, in a tissue microarray of 80 cases of laryngeal squamous cell cancers. Clinicopathological parameters were analyzed according to claudin-1 expression in the tissue microarray. Furthermore, the expression of slug/snail1, an Epithelial-Mesenchymal Transition (EMT) linked protein, was analyzed by immunohistochemistry in the same microarray, and the expressions of the two proteins were assessed for correlation. RESULTS A significant majority of laryngeal squamous cell cancers exhibited positive expression of claudin-1 proteins. The majority of those tumors expressed claudin-1 in their cytoplasm. The overall majority of those same tumors also exhibited a cytoplasmic shift of the slug-snail-1 protein from the nuclei to the cytoplasm. There was also evidence of correlation of the two proteins' expressions in the cytoplasm of laryngeal tumors. CONCLUSION The above may suggest a role for claudin-1 in the development and progression of laryngeal squamous cell carcinoma. Overall, claudin-1's aberrant expression in laryngeal cancer is in line with evidence seen in other head and neck cancers. Its co-expression with slug/snail-1 in LSCC patients should be investigated further to understand the nature of the relationship of the two proteins in LSCC and their possible contribution to its development and progression.
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Affiliation(s)
- Abderrahman Ouban
- Department of Pathology, College of Medicine , Alfaisal University, Riyadh, Saudi Arabia.
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Wu P, Wang J, Mao X, Xu H, Zhu Z. PDCD4 regulates apoptosis in human peritoneal mesothelial cells and promotes gastric cancer peritoneal metastasis. Histol Histopathol 2021; 36:447-457. [PMID: 33442866 DOI: 10.14670/hh-18-305] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Programmed cell death 4 (PDCD4) is a tumor suppressor gene, however, the function and regulatory mechanism remain to be discovered. The connection between tumorigenesis and apoptosis is one of the most important foci of cancer research. Our study aimed to explore the connections between PDCD4-mediated apoptosis of human peritoneal mesothelial cells (HPMC) and peritoneal metastasis in gastric cancer. METHODS The PDCD4 expression in 31 pairs of HPMC and tumor tissues was assessed by immunohistochemistry and RT-PCR. In cell experiments, we monitored gastric cancer cell migration with a Transwell chamber assay when PDCD4 was silenced in HPMC. Subsequently, apoptosis of HPMC was detected by a flow cytometric assay and western blotting. After analyzing cytokines in culture supernatants from gastric cancer with enzyme-linked immunosorbent assays (ELISAs), transforming growth factor-beta 1 (TGF-β1) was abundant in the culture supernatants of gastric cancer. Then, PDCD4 expression in HMrSV5 cells was analyzed by western blotting after retreatment with different concentrations of TGF-β1. Moreover, apoptosis of peritoneal mesothelial cells treated with TGF-β1 was detected according to the above methods. RESULTS In human metastatic peritoneal tissues, the expression of PDCD4 was significantly lower than that in normal tissues. At the same time, decreased expression of PDCD4 in HPMC was associated with increased migration capacity of gastric cancer cells. Moreover, suppressing the expression of PDCD4 promoted apoptosis in mesothelial cells which may be regulated by TGF-β secreted from gastric cancer cells. CONCLUSIONS These data suggested that decreased expression of PDCD4 significantly promoted apoptosis in human peritoneal mesothelial cells, thus inducing peritoneal metastasis, and that TGF-β1 secreted from gastric cancer cells may have played a crucial role.
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Affiliation(s)
- Pei Wu
- Department of Surgical Oncology, Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, China
| | - Jinou Wang
- Department of Pathology, Shengjing Hospital of China Medical University, Senyang, China
| | - Xiaoyun Mao
- Department of Breast Surgery, Department of Surgical Oncology, Research Unit of General Surgery, The First Affiliated Hospital of China Medical University, Shenyang, China
| | - Huimian Xu
- Department of Surgical Oncology, Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, China
| | - Zhi Zhu
- Department of Surgical Oncology, Department of General Surgery, First Affiliated Hospital, China Medical University, Shenyang, China.
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Guo J, Su Y, Zhang M. Circ_0000140 restrains the proliferation, metastasis and glycolysis metabolism of oral squamous cell carcinoma through upregulating CDC73 via sponging miR-182-5p. Cancer Cell Int 2020; 20:407. [PMID: 32863766 PMCID: PMC7448321 DOI: 10.1186/s12935-020-01501-7] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2020] [Revised: 07/27/2020] [Accepted: 08/17/2020] [Indexed: 02/06/2023] Open
Abstract
Background Oral squamous cell carcinoma (OSCC) is a more common cancer in the world. Emerging evidence suggests that circular RNAs (circRNAs) participate in the progression of OSCC. However, the role of circ_0000140 in OSCC is still unknown. Methods The expression of circ_0000140 and microRNA-182-5p (miR-182-5p) were assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Also, cell proliferation, migration and invasion were measured by colony formation and transwell assays, respectively. Western blot (WB) analysis was used to test the levels of proliferation, metastasis and glycolysis metabolism-related proteins as well as cell division cycle 73 (CDC73) protein. Further, the extracellular acidification rate (ECAR) of cells was detected by the Seahorse XF Extracellular Flux Analyzer. The lactate acid level of cells was tested by Lactate Assay Kit. Moreover, dual-luciferase reporter was used to verify the interaction between miR-182-3p and circ_0000140 or CDC73, and RNA immunoprecipitation (RIP) assay was employed to further confirm the relationship between miR-182-3p and circ_0000140. In addition, mice xenograft models were built to measure the effect of circ_0000140 on OSCC tumor growth in vivo. Results Circ_0000140 was lowly expressed in OSCC, and its overexpression hindered proliferation, migration, invasion and glycolysis metabolism in OSCC cells. MiR-182-5p could be sponged by circ_0000140, and its mimic could invert the suppression of circ_0000140 overexpression on OSCC progression. CDC73 could be targeted by miR-182-3p, and its silencing could reverse the inhibition of miR-182-3p inhibitor on OSCC progression. Further, overexpressed circ_0000140 reduced the OSCC tumor growth in vivo. Conclusions Circ_0000140 might play an anti-cancer role in OSCC, which provided a novel target for clinical therapy of OSCC.
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Affiliation(s)
- Jia Guo
- Stomatological Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Yuanyuan Su
- Stomatological Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
| | - Meng Zhang
- Stomatological Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052 Henan China
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Arruda CFJD, Coutinho-Camillo CM, Marques MM, Nagano CP, Bologna SB, Bettim BB, Germano JN, Pinto CAL, Hsieh R, Lourenço SV. Claudin expression is maintained in mucoepidermoid carcinoma of the salivary gland. Pathol Res Pract 2020; 216:153161. [PMID: 32862070 DOI: 10.1016/j.prp.2020.153161] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 08/03/2020] [Accepted: 08/04/2020] [Indexed: 10/23/2022]
Abstract
OBJECTIVE The aim of the present study was to investigate the expression of claudin-1, -3, -4, -5 and -7 proteins in mucoepidermoid carcinoma of oral cavity and analyze whether EGF may interfere in the expression of the genes that encode claudins using in vitro models. MATERIAL AND METHODS Using immunohistochemistry, the expression of claudins was searched in 36 histologically graded cases of mucoepidermoid carcinoma. The association of expression of claudins with clinical-pathological parameters was evaluated. An in vitro step investigated the influence of EGF on gene expression of claudins by real time RT-PCR technique. RESULTS Claudin-1, -3, -4, -5, and -7 were highly expressed in most mucoepidermoid carcinomas. These expressions were compared with clinicopathological parameters. High expression of claudin-1 was associated with patients over 40 years-old (p = 0.05) and Caucasians (p = 0.024). In vitro experiments demonstrated a tendency for Claudin gene expression increase after EGF stimulus. CONCLUSIONS The expression of claudins is maintained in mucoepidermoid carcinoma cells and EGF could be related with this expression. Our results point out to a fundamental biological importance to CLDNs in normal and neoplastic tissue. The expression patterns of CLDNs does not yet allow a clinical application, but the biological knowledge will ground evidence to new studies towards possible target-therapies.
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Affiliation(s)
| | | | - Marcia Martins Marques
- Post Graduation Program, School of Dentistry, Ibirapuera University, São Paulo, Brazil; School of Health Sciences Eugenio Espejo, UTE University, Quito, Ecuador
| | | | | | | | | | | | - Ricardo Hsieh
- Tropical Medicine Institute, University of São Paulo, Brazil
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Ni Z, Zheng Z, Yu E, Zu C, Huang D, Wu K, Hu J, Ye S, Zhuge Q, Yang J, Ruan L. Distribution pattern of invasion-related bio-markers in head Marjolin's ulcer. Exp Ther Med 2020; 20:3316-3323. [PMID: 32855703 DOI: 10.3892/etm.2020.9034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 01/14/2020] [Indexed: 02/06/2023] Open
Abstract
Marjolin's ulcer (MU) is a rare and aggressive cutaneous malignancy that typically presented in an area of traumatized or chronically inflamed skin and particularly in burn scars. Among them, the MU in the scalp with extensive invasion of the skull is exceptional and severe. The principle of management for MU is to obtain an early diagnosis and perform prompt surgical interventions. The invasive capacity of MU may vary among different sites of the scalp, which may require different therapeutic strategies for surgical excision. However, no clear evidence has been provided to determine the invasion ability of MU at different regions of the lesion as a surgical guidance. In present study, a 41-year-old female with a 40-year history of scalp ulceration has been examined. After resection of the MU lesion, hematoxylin and eosin (H&E) staining was performed to confirm the pathology of the cutaneous malignancy after surgical excision. Furthermore, reverse transcription-quantitative PCR experiment was performed out to determine the expression levels of invasion-associated biomarkers at different sites of the scalp affected by MU. Pathological analysis with H&E staining indicated a differentiated squamous cell carcinoma with invasion of the skull. The invasion-associated biomarkers were highly expressed in the core region compared to the middle region as well as the edge of MU tissue. Taken together, the present study suggests that the expression pattern of invasion-associated biomarkers varies between different regions of the MU lesion. High expression levels in the core region of MU indicates that the resection of the center area may be critical for the successful surgical treatment of MU.
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Affiliation(s)
- Zhihui Ni
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Zhao Zheng
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Enxing Yu
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Can Zu
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Dongdong Huang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Ke Wu
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jiangnan Hu
- Department of Pharmaceutical Sciences, University of North Texas Health Science Center, Fort Worth, TX 76107, USA
| | - Sheng Ye
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Qichuan Zhuge
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Jianjing Yang
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
| | - Linhui Ruan
- Zhejiang Provincial Key Laboratory of Aging and Neurological Disorder Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China.,Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325000, P.R. China
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Lin GC, Leitgeb T, Vladetic A, Friedl HP, Rhodes N, Rossi A, Roblegg E, Neuhaus W. Optimization of an oral mucosa in vitro model based on cell line TR146. Tissue Barriers 2020; 8:1748459. [PMID: 32314665 PMCID: PMC7549749 DOI: 10.1080/21688370.2020.1748459] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Revised: 03/20/2020] [Accepted: 03/24/2020] [Indexed: 12/22/2022] Open
Abstract
During the last years, the popularity of saliva has been increasing for its applicability as a diagnostic fluid. Blood biomarker molecules have to cross the blood-saliva barrier (BSB) in order to appear in saliva. The BSB consists of all oral and salivary gland epithelial barriers. Within this context, the optimization of in vitro models for mechanistic studies about the transport of molecules across the oral mucosa is an important task. Here, we describe the optimization and comprehensive characterization of a Transwell model of the oral mucosa based on the epithelial cell line TR146. Through systematic media optimization investigating 12 different set-ups, a significant increase of barrier integrity upon airlift cultivation is described here for TR146 cell layers. The distinct improvement of the paracellular barrier was described by measurements of transepithelial electrical resistance (TEER) and carboxyfluorescein permeability assays. Histological characterization supported TEER data and showed a stratified, non-keratinized multilayer of the optimized TR146 model. High-Throughput qPCR using 96 selected markers for keratinization, cornification, epithelial-mesenchymal transition, aquaporins, mucins, tight junctions, receptors, and transporter proteins was applied to comprehensively characterize the systematic optimization of the cellular model and validate against human biopsy samples. Data revealed the expression of several genes in the oral mucosa epithelium for the first time and elucidated novel regulations dependent on culture conditions. Moreover, functional activity of ABC-transporters ABCB1 and ABCC4 was shown indicating the applicability of the model for drug transport studies. In conclusion, a Transwell model of the oral mucosa epithelium was optimized suitably for transport studies.
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Affiliation(s)
- Grace C. Lin
- Competence Unit Molecular Diagnostics, Center for Health and Bioresources, Austrian Institute of Technology (AIT) GmbH, Vienna, Austria
| | - Tamara Leitgeb
- Competence Unit Molecular Diagnostics, Center for Health and Bioresources, Austrian Institute of Technology (AIT) GmbH, Vienna, Austria
| | - Alexandra Vladetic
- Competence Unit Molecular Diagnostics, Center for Health and Bioresources, Austrian Institute of Technology (AIT) GmbH, Vienna, Austria
| | - Heinz-Peter Friedl
- Competence Unit Molecular Diagnostics, Center for Health and Bioresources, Austrian Institute of Technology (AIT) GmbH, Vienna, Austria
| | - Nadine Rhodes
- Fraunhofer Institute for Silicate Research (ISC), Translational Center Regenerative Therapies, Würzburg, Germany
| | - Angela Rossi
- Fraunhofer Institute for Silicate Research (ISC), Translational Center Regenerative Therapies, Würzburg, Germany
| | - Eva Roblegg
- Institute of Pharmaceutical Sciences, Pharmaceutical Technology and Biopharmacy, University of Graz, Graz, Austria
| | - Winfried Neuhaus
- Competence Unit Molecular Diagnostics, Center for Health and Bioresources, Austrian Institute of Technology (AIT) GmbH, Vienna, Austria
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Yamamoto D, Kayamori K, Sakamoto K, Tsuchiya M, Ikeda T, Harada H, Yoda T, Watabe T, Hara-Yokoyama M. Intracellular claudin-1 at the invasive front of tongue squamous cell carcinoma is associated with lymph node metastasis. Cancer Sci 2019; 111:700-712. [PMID: 31769164 PMCID: PMC7004554 DOI: 10.1111/cas.14249] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 11/12/2019] [Accepted: 11/18/2019] [Indexed: 12/15/2022] Open
Abstract
Claudins are the major component of tight junctions, which form a primary barrier to paracellular diffusion and maintain cell polarity in normal epithelia and endothelia. In cancer cells, claudins play additional roles besides serving as components of the tight junctions, and participate in anoikis or invasion. Among the claudin family proteins, claudin‐1 has the most promising potential, both diagnostically and prognostically, in many types of cancers, including oral, gastric, liver, and colon cancers. However, conflicting results have been reported in relation to the degree of claudin‐1 expression and the prognosis, suggesting that the expression level of claudin‐1 alone is not sufficient to analyze the relationship between claudin‐1 and cancer progression. As endocytic trafficking of claudin‐1 has been reported in several epithelial cell types in vitro, we aimed to determine whether intracellular localization of claudin‐1 is the missing aspect between claudin‐1 and cancer. We investigated the expression of claudin‐1 in 83 tongue squamous cell carcinoma (TSCC) pathological specimens. Although the expression level of claudin‐1 based on immunohistochemistry was not associated with TSCC progression, within the high claudin‐1 expression group, the incidence of intracellular localization of claudin‐1 was correlated with cervical lymph node metastasis. In an in vitro experiment, claudin‐1 was constitutively internalized in TSCC‐derived cells. Motility of TSCC‐derived cells was increased by deficiency of claudin‐1, suggesting that the decrease in cell‐surface claudin‐1 promoted the cell migration. Therefore, intracellular localization of claudin‐1 at the invasion front may represent a promising diagnostic marker of TSCC.
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Affiliation(s)
- Daisuke Yamamoto
- Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kou Kayamori
- Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Kei Sakamoto
- Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Maiko Tsuchiya
- Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tohru Ikeda
- Department of Oral Pathology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Hiroyuki Harada
- Department of Oral and Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tetsuya Yoda
- Department of Maxillofacial Surgery, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Tetsuro Watabe
- Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Miki Hara-Yokoyama
- Department of Biochemistry, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
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Hämäläinen L, Soini Y, Pasonen-Seppänen S, Siponen M. Alterations in the expression of EMT-related proteins claudin-1, claudin-4 and claudin-7, E-cadherin, TWIST1 and ZEB1 in oral lichen planus. J Oral Pathol Med 2019; 48:735-744. [PMID: 31228209 DOI: 10.1111/jop.12917] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2019] [Revised: 06/05/2019] [Accepted: 06/13/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Oral lichen planus (OLP) is a chronic T-cell-mediated inflammatory disease, which is associated with increased risk of developing oral squamous cell carcinoma. Epithelial-to-mesenchymal transition is a physiological phenomenon occurring during growth and organogenesis, but it has also an important role in tumorigenesis. In the present work, we studied the expression of known epithelial-to-mesenchymal transition markers in oral lichen planus. METHODS In total, 54 oral lichen planus and 22 control samples were analyzed for epithelial-to-mesenchymal transition markers. Samples were immunohistochemically stained for claudin-1, claudin-4 and claudin-7, cadherin-1 (E-cadherin), Twist-related protein 1 (TWIST1) and zinc finger E-box-binding homeobox 1 (ZEB1). RESULTS The expression of claudin-1, claudin-4 and E-cadherin was significantly weaker in oral lichen planus epithelium compared to controls (P < 0.001). The quantity of claudin-7-expressing cells (P < 0.001) and claudin-7 staining intensity (P < 0.05) in the stroma was greater in lichen planus than in control samples. TWIST1 and ZEB1 stainings were negative in the epithelium in both lichen planus and controls. The number of TWIST1-expressing cells in the stroma was higher in lichen planus than in controls (P < 0.001). There was a statistically significant difference in ZEB1 staining intensity in the stroma between lichen planus and control samples (P < 0.05). CONCLUSIONS The data indicate that the expression of claudin-1, claudin-4 and E-cadherin is decreased in oral lichen planus. This may lead to disturbance in epithelial tight junctions, cell-cell connections and epithelial permeability, contributing to oral lichen planus pathogenesis. Based on the present study, the role of TWIST1 and ZEB1 in oral lichen planus remains unclear.
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Affiliation(s)
- Lasse Hämäläinen
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Ylermi Soini
- Department of Clinical Pathology and Forensic Medicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.,Cancer Center of Eastern Finland, Kuopio, Finland
| | - Sanna Pasonen-Seppänen
- Institute of Biomedicine, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
| | - Maria Siponen
- Cancer and Translational Medicine Research Unit, University of Oulu, Oulu, Finland.,Institute of Dentistry, School of Medicine, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland.,Department of Oral and Maxillofacial Diseases, Kuopio University Hospital, Kuopio, Finland
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Samiei M, Ahmadian E, Eftekhari A, Eghbal MA, Rezaie F, Vinken M. Cell junctions and oral health. EXCLI JOURNAL 2019; 18:317-330. [PMID: 31338005 PMCID: PMC6635732 DOI: 10.17179/excli2019-1370] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Accepted: 06/04/2019] [Indexed: 12/21/2022]
Abstract
The oral cavity and its appendices are exposed to considerable environmental and mechanical stress. Cell junctions play a pivotal role in this context. Among those, gap junctions permit the exchange of compounds between cells, thereby controlling processes such as cell growth and differentiation. Tight junctions restrict paracellular transportation and inhibit movement of integral membrane proteins between the different plasma membrane poles. Adherens junctions attach cells one to another and provide a solid backbone for resisting to mechanistical stress. The integrity of oral mucosa, normal tooth development and saliva secretion depend on the proper function of all these types of cell junctions. Furthermore, deregulation of junctional proteins and/or mutations in their genes can alter tissue functioning and may result in various human disorders, including dental and periodontal problems, salivary gland malfunction, hereditary and infectious diseases as well as tumorigenesis. The present manuscript reviews the role of cell junctions in the (patho)physiology of the oral cavity and its appendices, including salivary glands.
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Affiliation(s)
- Mohammad Samiei
- Faculty of Dentistry, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Elham Ahmadian
- Dental and Periodontal Research center, Tabriz University of Medical Sciences, Tabriz, Iran.,Students Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Aziz Eftekhari
- Pharmacology and Toxicology department, Maragheh University of Medical Sciences, Maragheh, Iran
| | - Mohammad Ali Eghbal
- Drug Applied Research Center and Pharmacology and Toxicology department, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Fereshte Rezaie
- General Practitioner, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mathieu Vinken
- Department of In Vitro Toxicology and Dermato-Cosmetology, Vrije Universiteit Brussel, Brussels, Belgium
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Upadhaya P, Barhoi D, Giri A, Bhattacharjee A, Giri S. Joint detection of claudin-1 and junctional adhesion molecule-A as a therapeutic target in oral epithelial dysplasia and oral squamous cell carcinoma. J Cell Biochem 2019; 120:18117-18127. [PMID: 31161679 DOI: 10.1002/jcb.29115] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2018] [Revised: 01/28/2019] [Accepted: 05/13/2019] [Indexed: 12/29/2022]
Abstract
Abnormal expression of claudin-1 (CLDN-1) and junctional adhesion molecule-A (JAM-A) has been described in certain malignancies but their clinical relevance is poorly understood. The present study aims to elucidate the role of CLDN-1 and JAM-A in oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC). Changes in the expression of these proteins were identified immunohistochemically on tissue sections from patients with OED and OSCC and compared with control. A correlation between the expression level of proteins and clinicopathological features was analyzed by Pearson's correlation χ2 test. The survival curve of the follow-up data was estimated by the Kaplan-Meier method followed by the log-rank test. CLDN-1 and JAM-A were highly expressed in OED and OSCC tissues when compared to control. Also, delocalization of CLDN-1 from the membrane to the cytoplasm to the nucleus was observed as the cell proceeds from normal to malignancy. Increased expression of CLDN-1 and JAM-A in both OED and OSCC were concomitant with histological grades. In addition, increased JAM-A was associated with perineural invasion of cancer cells. A positive correlation between the expression level of proteins was observed in OED (r = 0.733) and OSCC (r = 0.577). Kaplan-Meier analysis in patients with OSCC showed that the survival rate was lower in patients with high CLDN-1 and high JAM-A expression compared to low expressed patients. To conclude, the elevated level and delocalization of CLDN-1 and JAM-A suggest their use as tumor markers. A positive correlation between CLDN-1 and JAM-A suggests joint detection of these proteins as a future diagnostic tool in oral precancerous and cancerous conditions.
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Affiliation(s)
- Puja Upadhaya
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Dharmeswar Barhoi
- Molecular and Cell Biology Laboratory, Department of Life Science and Bioinformatics, Assam University, Silchar, Assam, India
| | - Anirudha Giri
- Environmental Toxicology 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
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Al-Afifi NA, Alabsi AM, Shaghayegh G, Ramanathan A, Ali R, Alkoshab M, Bakri MM. The in vitro and in vivo antitumor effects of Dracaena cinnabari resin extract on oral cancer. Arch Oral Biol 2019; 104:77-89. [PMID: 31176147 DOI: 10.1016/j.archoralbio.2019.05.030] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2019] [Revised: 05/16/2019] [Accepted: 05/27/2019] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To study the potential for apoptosis induction of Dracaena cinnabari Balf. f methanolic extract (DCBME) on tongue squamous cell carcinoma cell line, H103. We evaluated the chemopreventive activity of DCBME against 4-nitroquinolone-1-oxide (4NQO)-induced tongue carcinogenesis in rat. DESIGN Phase contrast microscope, acridine orange/propidium iodide (AO/PI) analysis of cells under fluorescence microscope, annexin-V flow-cytometry, DNA fragmentation, mitochondrial membrane potential, and caspase 3/7, 8 and 9 assays were performed. In vivo study, the rats were given 4NQO in their drinking water. The tongue was subjected to histopathological study to evaluate the incidence of squamous cell carcinoma (SCC). RESULTS DCBME showed cytotoxic effect on H103 cells in a dose- and time-dependent manner. Furthermore, DCBME showed low cytotoxic effect on a normal cell line. In H103 cells, it caused cell morphology changes, S and G2/M-phase cell cycle arrest, significant reduction of cell migration and induced apoptosis through the intrinsic (mitochondrial) pathway. The incidence of SCC was 85.7% in the induced cancer and vehicle groups while in rats treated with DCBME at 100, 500 and 1000 mg/kg was 57.1%, 28.6% and 14.3%, respectively. CONCLUSIONS (DCBME)-apoptosis induction reported in this work can be exploited as a potential antitumor agent with applications in medicinal treatments of tongue SCC.
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Affiliation(s)
- Nashwan Abdullah Al-Afifi
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Aied M Alabsi
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia; Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Bandar Saujana Putra, 42610 Jenjarom Kuala Langat, Selangor, Malaysia.
| | - Gohar Shaghayegh
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Anand Ramanathan
- Department of Oral & Maxillofacial Clinical Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia; Oral Cancer Research and Coordinating Centre, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Rola Ali
- Department of Oral Biology and Biomedical Sciences, Faculty of Dentistry, MAHSA University, Bandar Saujana Putra, 42610 Jenjarom Kuala Langat, Selangor, Malaysia
| | - May Alkoshab
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
| | - Marina Mohd Bakri
- Department of Oral and Craniofacial Sciences, Faculty of Dentistry, University of Malaya, 50603 Kuala Lumpur, Malaysia
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36
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Zheng YF, Luo J, Gan GL, Li W. Overexpression of microRNA-98 inhibits cell proliferation and promotes cell apoptosis via claudin-1 in human colorectal carcinoma. J Cell Biochem 2019; 120:6090-6105. [PMID: 30506722 DOI: 10.1002/jcb.27895] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2018] [Accepted: 09/24/2018] [Indexed: 02/05/2023]
Abstract
Colorectal carcinoma (CRC) is a major cause of cancer-related deaths worldwide, and investigations on novel targets are imperative. MiR-98 has been reported to act as a tumor suppressor in several cancers. To evaluate miR-98 as a novel anticancer molecule for CRC, examinations to validate whether miR-98 conferred an inhibiting effect on proliferation, migration, and invasion were performed. The microarray-based gene expression profiling involving CRC was used to identify the differentially expressed genes. The potential relationship between miR-98 and CLDN1 was analyzed by cell experimentation. Then, the CRC cells were transfected with miR-98 mimic or miR-98 inhibitor to investigate the potential effect of miR-98 overexpression and depletion on CRC cell proliferation, migration, invasion, and apoptosis. The expressions of CLDN1, Bcl-2 associated protein x (Bax), runt-related transcription factor 3 (RUNX3), B-cell lymphoma 2 (Bcl-2), C-myc, and proliferating cell nuclear antigen (PCNA) were determined. The downregulated miR-98 along with an upregulated CLDN1 was observed in CRC, in which miR-98 could target to regulate CLDN1. The overexpression of miR-98 or silencing of CLDN1 was shown to increase the expression of Bax and RUNX3 along with promoted cell apoptosis and arrested cells in G1 phase, while decreasing the expression of CLDN1, Bcl-2, C-myc, and PCNA with suppressed proliferation, migration, and invasion. Collectively, the current study supports the notion that miR-98 plays an inhibitory role in human CRC cell proliferation, migration, and invasion and act as a contributor for cell apoptosis by downregulating CLDN1. The current study highlights a potential future strategy to help prevent the development of CRC.
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Affiliation(s)
- Yi-Feng Zheng
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Jie Luo
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Guo-Lian Gan
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
| | - Wei Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Shantou University Medical College, Shantou, China
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Zeisel MB, Dhawan P, Baumert TF. Tight junction proteins in gastrointestinal and liver disease. Gut 2019; 68:547-561. [PMID: 30297438 PMCID: PMC6453741 DOI: 10.1136/gutjnl-2018-316906] [Citation(s) in RCA: 202] [Impact Index Per Article: 33.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2018] [Revised: 08/16/2018] [Accepted: 08/19/2018] [Indexed: 12/11/2022]
Abstract
Over the past two decades a growing body of evidence has demonstrated an important role of tight junction (TJ) proteins in the physiology and disease biology of GI and liver disease. On one side, TJ proteins exert their functional role as integral proteins of TJs in forming barriers in the gut and the liver. Furthermore, TJ proteins can also be expressed outside TJs where they play important functional roles in signalling, trafficking and regulation of gene expression. A hallmark of TJ proteins in disease biology is their functional role in epithelial-to-mesenchymal transition. A causative role of TJ proteins has been established in the pathogenesis of colorectal cancer and gastric cancer. Among the best characterised roles of TJ proteins in liver disease biology is their function as cell entry receptors for HCV-one of the most common causes of hepatocellular carcinoma. At the same time TJ proteins are emerging as targets for novel therapeutic approaches for GI and liver disease. Here we review our current knowledge of the role of TJ proteins in the pathogenesis of GI and liver disease biology and discuss their potential as therapeutic targets.
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Affiliation(s)
- Mirjam B. Zeisel
- Inserm U1052, CNRS UMR 5286, Cancer Research Center of Lyon (CRCL), Université de Lyon (UCBL), Lyon, France
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
| | - Punita Dhawan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE
- Buffet Cancer Center, University of Nebraska Medical Center, Omaha, NE
- VA Nebraska-Western Iowa Health Care System, Omaha, NE
| | - Thomas F. Baumert
- Inserm, U1110, Institut de Recherche sur les Maladies Virales et Hépatiques, Strasbourg, France
- Université de Strasbourg, Strasbourg, France
- Institut Hospitalo-Universitaire, Pôle hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France
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38
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Bhat AA, Uppada S, Achkar IW, Hashem S, Yadav SK, Shanmugakonar M, Al-Naemi HA, Haris M, Uddin S. Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk. Front Physiol 2019; 9:1942. [PMID: 30728783 PMCID: PMC6351700 DOI: 10.3389/fphys.2018.01942] [Citation(s) in RCA: 255] [Impact Index Per Article: 42.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Accepted: 12/22/2018] [Indexed: 12/14/2022] Open
Abstract
The ability of epithelial cells to organize through cell–cell adhesion into a functioning epithelium serves the purpose of a tight epithelial protective barrier. Contacts between adjacent cells are made up of tight junctions (TJ), adherens junctions (AJ), and desmosomes with unique cellular functions and a complex molecular composition. These proteins mediate firm mechanical stability, serves as a gatekeeper for the paracellular pathway, and helps in preserving tissue homeostasis. TJ proteins are involved in maintaining cell polarity, in establishing organ-specific apical domains and also in recruiting signaling proteins involved in the regulation of various important cellular functions including proliferation, differentiation, and migration. As a vital component of the epithelial barrier, TJs are under a constant threat from proinflammatory mediators, pathogenic viruses and bacteria, aiding inflammation and the development of disease. Inflammatory bowel disease (IBD) patients reveal loss of TJ barrier function, increased levels of proinflammatory cytokines, and immune dysregulation; yet, the relationship between these events is partly understood. Although TJ barrier defects are inadequate to cause experimental IBD, mucosal immune activation is changed in response to augmented epithelial permeability. Thus, the current studies suggest that altered barrier function may predispose or increase disease progression and therapies targeted to specifically restore the barrier function may provide a substitute or supplement to immunologic-based therapies. This review provides a brief introduction about the TJs, AJs, structure and function of TJ proteins. The link between TJ proteins and key signaling pathways in cell proliferation, transformation, and metastasis is discussed thoroughly. We also discuss the compromised intestinal TJ integrity under inflammatory conditions, and the signaling mechanisms involved that bridge inflammation and cancer.
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Affiliation(s)
- Ajaz A Bhat
- Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Srijayaprakash Uppada
- Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, NE, United States
| | - Iman W Achkar
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
| | - Sheema Hashem
- Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | - Santosh K Yadav
- Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar
| | | | - Hamda A Al-Naemi
- Laboratory Animal Research Center, Qatar University, Doha, Qatar.,Department of Biological and Environmental Sciences, Qatar University, Doha, Qatar
| | - Mohammad Haris
- Division of Translational Medicine, Research Branch, Sidra Medicine, Doha, Qatar.,Laboratory Animal Research Center, Qatar University, Doha, Qatar
| | - Shahab Uddin
- Translational Research Institute, Academic Health System, Hamad Medical Corporation, Doha, Qatar
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39
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Liao YT, Liu CH, Chin Y, Chen SY, Liu SH, Hsu YC, Wu KCW. Biocompatible and multifunctional gold nanorods for effective photothermal therapy of oral squamous cell carcinoma. J Mater Chem B 2019. [DOI: 10.1039/c9tb00574a] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Functionalized gold nanorods were successfully synthesized for the effective photothermal therapy of oral cancer.
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Affiliation(s)
- Yu-Te Liao
- Department of Chemical Engineering
- National Taiwan University
- Taipei 10617
- Taiwan
| | - Chia-Hung Liu
- Institute of Toxicology
- College of Medicine
- National Taiwan University
- Taipei
- Taiwan
| | - Yin Chin
- Department of Bioscience
- Department of Chemistry
- Center for Nanotechnology
- Center of Biomedical Technology
- Center of Cancer Theranostics
| | - Sin-Yuan Chen
- Department of Chemical Engineering
- National Taiwan University
- Taipei 10617
- Taiwan
| | - Shing Hwa Liu
- Institute of Toxicology
- College of Medicine
- National Taiwan University
- Taipei
- Taiwan
| | - Yih-Chih Hsu
- Department of Bioscience
- Department of Chemistry
- Center for Nanotechnology
- Center of Biomedical Technology
- Center of Cancer Theranostics
| | - Kevin C.-W. Wu
- Department of Chemical Engineering
- National Taiwan University
- Taipei 10617
- Taiwan
- Division of Medical Engineering Research
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40
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Song CK, Oh E, Kang MS, Shin BS, Han SY, Jung M, Lee ES, Yoon SY, Sung MM, Ng WB, Cho NJ, Lee H. Fluorescence-based immunosensor using three-dimensional CNT network structure for sensitive and reproducible detection of oral squamous cell carcinoma biomarker. Anal Chim Acta 2018; 1027:101-108. [DOI: 10.1016/j.aca.2018.04.025] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2018] [Revised: 04/06/2018] [Accepted: 04/12/2018] [Indexed: 11/30/2022]
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41
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Siriwardena SBSM, Tsunematsu T, Qi G, Ishimaru N, Kudo Y. Invasion-Related Factors as Potential Diagnostic and Therapeutic Targets in Oral Squamous Cell Carcinoma-A Review. Int J Mol Sci 2018; 19:ijms19051462. [PMID: 29758011 PMCID: PMC5983574 DOI: 10.3390/ijms19051462] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2018] [Revised: 05/07/2018] [Accepted: 05/10/2018] [Indexed: 01/06/2023] Open
Abstract
It is well recognized that the presence of cervical lymph node metastasis is the most important prognostic factor in oral squamous cell carcinoma (OSCC). In solid epithelial cancer, the first step during the process of metastasis is the invasion of cancer cells into the underlying stroma, breaching the basement membrane (BM)—the natural barrier between epithelium and the underlying extracellular matrix (ECM). The ability to invade and metastasize is a key hallmark of cancer progression, and the most complicated and least understood. These topics continue to be very active fields of cancer research. A number of processes, factors, and signaling pathways are involved in regulating invasion and metastasis. However, appropriate clinical trials for anti-cancer drugs targeting the invasion of OSCC are incomplete. In this review, we summarize the recent progress on invasion-related factors and emerging molecular determinants which can be used as potential for diagnostic and therapeutic targets in OSCC.
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Affiliation(s)
- Samadarani B S M Siriwardena
- Department of Oral Pathology, Faculty of Dental Sciences, University of Peradeniya, Peradeniya 20400, Sri Lanka.
| | - Takaaki Tsunematsu
- Department of Pathology and Laboratory Medicine, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8503, Japan.
| | - Guangying Qi
- Department of Pathology and Physiopathology, Guilin Medical University, Guilin 541004, China.
| | - Naozumi Ishimaru
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan.
| | - Yasusei Kudo
- Department of Oral Molecular Pathology, Tokushima University Graduate School of Biomedical Sciences, Tokushima 770-8504, Japan.
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Abstract
Perineural invasion (PNI) is a mechanism of tumor dissemination that can provide a challenge to tumor eradication and that is correlated with poor survival. Squamous cell carcinoma, the most common type of head and neck cancer, has a high prevalence of PNI. This review provides an overview of clinical studies on the outcomes and factors associated with PNI in head and neck cancer and on findings on cancer-nerve crosstalk.
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Affiliation(s)
- L B Schmitd
- 1 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - C S Scanlon
- 1 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA
| | - N J D'Silva
- 1 Department of Periodontics and Oral Medicine, School of Dentistry, University of Michigan, Ann Arbor, MI, USA.,2 Department of Pathology, Medical School, University of Michigan, Ann Arbor, MI, USA
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Rai V, Mukherjee R, Ghosh AK, Routray A, Chakraborty C. "Omics" in oral cancer: New approaches for biomarker discovery. Arch Oral Biol 2017; 87:15-34. [PMID: 29247855 DOI: 10.1016/j.archoralbio.2017.12.003] [Citation(s) in RCA: 41] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2017] [Revised: 12/03/2017] [Accepted: 12/04/2017] [Indexed: 12/27/2022]
Abstract
OBJECTIVES In this review paper, we explored the application of "omics" approaches in the study of oral cancer (OC). It will provide a better understanding of how "omics" approaches may lead to novel biomarker molecules or molecular signatures with potential value in clinical practice. A future direction of "omics"-driven research in OC is also discussed. METHODS Studies on "omics"-based approaches [genomics/proteomics/transcriptomics/metabolomics] were investigated for differentiating oral squamous cell carcinoma,oral sub-mucous fibrosis, oral leukoplakia, oral lichen planus, oral erythroplakia from normal cases. Electronic databases viz., PubMed, Springer, and Google Scholar were searched. RESULTS One eighty-one studies were included in this review. The review shows that the fields of genomics, transcriptomics, proteomics, and metabolomics-based marker identification have implemented advanced tools to screen early changes in DNA, RNA, protein, and metabolite expression in OC population. CONCLUSIONS It may be concluded that despite advances in OC therapy, symptomatic presentation occurs at an advanced stage, where various curative treatment options become very limited. A molecular level study is essential for detecting an OC biomarker at an early stage. Modern "Omics" strategies can potentially make a major contribution to meet this need.
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Affiliation(s)
- Vertika Rai
- School of Medical Science and Technology, IIT Kharagpur, India
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44
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Velmurugan BK, Yeh KT, Lee CH, Lin SH, Chin MC, Chiang SL, Wang ZH, Hua CH, Tsai MH, Chang JG, Ko YC. Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) association with lymph node metastasis predicts poor survival in oral squamous cell carcinoma patients. Oncotarget 2017; 7:10879-90. [PMID: 26918356 PMCID: PMC4905446 DOI: 10.18632/oncotarget.7681] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2015] [Accepted: 02/16/2016] [Indexed: 11/26/2022] Open
Abstract
Acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) is a multifunctional protein aberrantly expressed in various types of cancers. However, its expression pattern and clinical significance in oral squamous cell carcinoma (OSCC) remains unclear. In this study, we immunohistochemically investigated the expression pattern of ANP32A in 259 OSCC patients and the results were correlated with clinicopathological factors using Allred, Klein and Immunoreactive scoring (IRS) system. Our data indicated that high expression of ANP32A was significantly associated with N stage and tumor differentiation status in OSCC patients. High ANP32A expression with N2/N3 stage had an increased mortality risk than low ANP32A expressing OSCC patients with N0/N1 stage. Functional studies revealed that knockdown of ANP32A significantly decreased the migration and invasion ability thereby concomitantly increasing E-cadherin and decreasing Slug, Claudin-1 and Vimentin expression in vitro. These results suggest that ANP32A is commonly increased in oral squamous cell carcinoma and ANP32A protein could act as a potential biomarker for prognosis assessment of oral cancer patients with lymph node metastasis.
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Affiliation(s)
| | - Kun-Tu Yeh
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Chien-Hung Lee
- Department of Public Health, College of Health Science, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - Shu-Hui Lin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan.,School of Medicine, Chung Shan Medical University, Taichung, Taiwan
| | - Mei-Chung Chin
- Department of Pathology, Changhua Christian Hospital, Changhua, Taiwan
| | - Shang-Lun Chiang
- Environment-Omics-Diseases Research, China Medical University Hospital, Taichung, Taiwan.,Department of Health Risk Management, College of Public Health, China Medical University, Taichung, Taiwan
| | - Zhi-Hong Wang
- Environment-Omics-Diseases Research, China Medical University Hospital, Taichung, Taiwan
| | - Chun-Hung Hua
- Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan
| | - Ming-Hsui Tsai
- Department of Otorhinolaryngology, China Medical University Hospital, Taichung, Taiwan
| | - Jan-Gowth Chang
- Department of Laboratory Medicine, China Medical University Hospital, Taichung, Taiwan
| | - Ying-Chin Ko
- Environment-Omics-Diseases Research, China Medical University Hospital, Taichung, Taiwan.,Graduate Institute of Clinical Medical Science, China Medical University, Taichung, Taiwan
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45
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Shiotsu N, Kawamoto T, Kawai M, Ikegame M, Torii Y, Sasaki H, Yamamoto T. Morphological and Functional Analyses of the Tight Junction in the Palatal Epithelium of Mouse. Acta Histochem Cytochem 2017; 50:119-125. [PMID: 28928541 PMCID: PMC5593814 DOI: 10.1267/ahc.17006] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2017] [Accepted: 07/05/2017] [Indexed: 11/30/2022] Open
Abstract
Tight junction (TJ) is one of the cell-cell junctions and known to have the barrier and fence functions between adjacent cells in both simple and stratified epithelia. We examined the distribution pattern, constitutive proteins, and permeability of TJ in the stratified squamous epithelium of the palatal mucosa of mice. Ultrastructural observations based on the ultrathin section and freeze-fracture methods revealed that poorly developed TJs are located at the upper layer of the stratum granulosum. The positive immunofluorescence of occludin (OCD), claudin (CLD)-1 and -4 were localized among the upper layer of the stratum granulosum showing a dot-like distribution pattern. And CLD-1 and -4 were localized among the stratum spinosum and the lower part of stratum granulosum additionally showed a positive reaction along the cell profiles. Western blotting of TJ constitutive proteins showed OCD, CLD-1, -2, -4, and -5 bands. The permeability test using biotin as a tracer revealed both the areas where biotin passed through beyond OCD positive points and the areas where biotin stopped at OCD positive points. These results show that poor TJs localize at the upper layer of the stratum granulosum of the palatal epithelium, and the TJs are leaky and include at least CLD-1 and -4.
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Affiliation(s)
- Noriko Shiotsu
- Department of Oral Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
- Comprehensive Dental Clinic, Okayama University Hospital
| | | | - Mariko Kawai
- Department of Pharmacology, Osaka Dental University
| | - Mika Ikegame
- Department of Oral Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
| | - Yasuhiro Torii
- Comprehensive Dental Clinic, Okayama University Hospital
| | | | - Toshio Yamamoto
- Department of Oral Morphology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences
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The role of perineural invasion in treatment decisions for oral cancer patients: A review of the literature. J Craniomaxillofac Surg 2017; 45:821-825. [PMID: 28359633 DOI: 10.1016/j.jcms.2017.02.022] [Citation(s) in RCA: 54] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2016] [Revised: 01/29/2017] [Accepted: 02/17/2017] [Indexed: 12/25/2022] Open
Abstract
PURPOSE The role of perineural invasion (PNI) in the management of patients with oral squamous cell carcinoma (OSSC) is still controversial, and there is no consensus regarding the most appropriate therapeutic approach. The purpose of this study is to review the findings in the literature describing OSCC as a neurotropic malignancy, with the aim of correlating perineural invasion with treatment decisions and disease prognosis. MATERIALS AND METHODS A literature search was conducted of references based on the MEDLINE and Cochrane Database of Systematic Reviews, with subject keywords including four main categories: perineural invasion, perineural spread, oral squamous cell cancinoma, neurotropic carcinoma. RESULTS In this systematic review and analysis, more than 350 publications met the eligibility criteria of the authors. CONCLUSION Perineural invasion (PNI) is a widely recognized indicator of poor prognosis in oral cancer patients, strongly correlating with aggressive tumor behavior, disease recurrence, and increased morbidity and mortality. Elective neck dissection could be an indicator in improving neck control in PNI-positive patients, while the addition of adjuvant postoperative radiotherapy may not significantly improve survival rates. Various molecular markers have been correlated with perineural tumor spread, but further investigations are required before targeting PNI as part of advanced cancer therapies.
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Tang Q, Cheng B, Xie M, Chen Y, Zhao J, Zhou X, Chen L. Circadian Clock Gene Bmal1 Inhibits Tumorigenesis and Increases Paclitaxel Sensitivity in Tongue Squamous Cell Carcinoma. Cancer Res 2017; 77:532-544. [PMID: 27821487 DOI: 10.1158/0008-5472.can-16-1322] [Citation(s) in RCA: 107] [Impact Index Per Article: 13.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2016] [Revised: 10/27/2016] [Accepted: 11/01/2016] [Indexed: 11/16/2022]
Abstract
Circadian clock genes regulate cancer development and chemotherapy susceptibility. Accordingly, chronotherapy based on circadian phenotypes might be applied to improve therapeutic efficacy. In this study, we investigated whether the circadian clock gene Bmal1 inhibited tumor development and increased paclitaxel sensitivity in tongue squamous cell carcinoma (TSCC). Bmal1 expression was downregulated and its rhythmic pattern of expression was affected in TSCC samples and cell lines. Ectopic Bmal1 inhibited cell proliferation, migration and invasion in vitro, and tumor growth in mouse xenograft models of TSCC. After exposure to paclitaxel, Bmal1-overexpressing cells displayed a relative increase in apoptosis and were more susceptible to paclitaxel treatment in vivo Mechanistic investigations suggested a regulatory connection between Bmal1, TERT, and the oncogenic transcriptional repressor EZH2 (enhancer of zeste homolog 2), the recruitment of which to the TERT promoter increased paclitaxel-induced apoptosis and cell growth inhibition. Clinically, paclitaxel efficacy correlated positively with Bmal1 expression levels in TSCC. Overall, our results identified Bmal1 as a novel tumor suppressor gene that elevates the sensitivity of cancer cells to paclitaxel, with potential implications as a chronotherapy timing biomarker in TSCC. Cancer Res; 77(2); 532-44. ©2016 AACR.
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Affiliation(s)
- Qingming Tang
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Bo Cheng
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Mengru Xie
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Yatao Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Jiajia Zhao
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Xin Zhou
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China
| | - Lili Chen
- Department of Stomatology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, P.R. China E-mail:
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Tarsitano A, Asioli S, Morandi L, Monti V, Righi A, Morselli Labate AM, Nardi E, Foschini MP, Marchetti C. Laminin-5 and insulin-like growth factor-II mRNA binding protein-3 (IMP3) expression in preoperative biopsy specimens from oral cancer patients: Their role in neural spread risk and survival stratification. J Craniomaxillofac Surg 2016; 44:1896-1902. [PMID: 27863864 DOI: 10.1016/j.jcms.2016.07.012] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 06/08/2016] [Accepted: 07/13/2016] [Indexed: 11/29/2022] Open
Abstract
Perineural invasion (PNI) hinders the ability to establish local control of oral squamous cell carcinoma (OSCC). To date, PNI can be evaluated only in surgical specimens and not in preoperative biopsy material, rendering timely therapeutic planning impossible. Insulin-like growth factor-II mRNA binding protein-3 (IMP3) expression appears to be of diagnostic and prognostic utility for many solid tumours, and laminin-5 expression in surgical specimens has been identified as a valid predictor of neural spread of head-and-neck neoplasms. The ability to use preoperative biopsy material to identify patients exhibiting PNI is fundamental for good management of OSCC. We examined a series of 64 consecutive patients treated (primarily via surgery) for OSCC between 2009 and 2014 at the Maxillofacial Surgery Unit, University of Bologna. We evaluated IMP3 and laminin-5 expression in preoperative biopsy material using immunohistochemistry and quantitative reverse transcription polymerase chain reaction. We sought to correlate expression of IMP3 and laminin-5 with PNI evident in surgical specimens. Expression of IMP3 and laminin-5 in preoperative biopsy material appeared to be predictive of PNI in patients with OSCC (P < 0.001). Additionally, the results of multivariate analyses showed that IMP3 status was an independent predictor of death of patients with OSCC (P = 0.001). The present study demonstrates that IMP3 and laminin-5 expression in preoperative biopsy material correlate well with PNI status and may allow accurate preoperative risk stratification of patients with OSCC.
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Affiliation(s)
- Achille Tarsitano
- Department of Biomedical and Neuromotor Sciences, Section of Maxillofacial Surgery, University of Bologna, Policlinico S. Orsola, Bologna, Italy.
| | - Sofia Asioli
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy
| | - Luca Morandi
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy
| | - Valentina Monti
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy
| | - Alberto Righi
- Unit of Anatomic Pathology, Istituto Ortopedico Rizzoli, Bologna, Italy
| | | | - Elena Nardi
- Laboratory of Biostatistics, Department of Medical and Surgical Sciences, University of Bologna, Italy
| | - Maria Pia Foschini
- Department of Biomedical and Neuromotor Sciences, Section of Anatomic Pathology, University of Bologna, Bellaria Hospital, Bologna, Italy
| | - Claudio Marchetti
- Department of Biomedical and Neuromotor Sciences, Section of Maxillofacial Surgery, University of Bologna, Policlinico S. Orsola, Bologna, Italy
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Serglycin in tumor microenvironment promotes non-small cell lung cancer aggressiveness in a CD44-dependent manner. Oncogene 2016; 36:2457-2471. [PMID: 27819672 PMCID: PMC5415946 DOI: 10.1038/onc.2016.404] [Citation(s) in RCA: 92] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Revised: 08/20/2016] [Accepted: 09/19/2016] [Indexed: 02/06/2023]
Abstract
Tumor microenvironment (TME) plays an active role in promoting tumor progression. To further understand the communication between TME and tumor cells, this study aimed at investigating the involvement of CD44, a type I cell surface receptor, in the crosstalk between tumor cells and TME. We have previously shown that chondroitin sulfate proteoglycan serglycin (SRGN), a CD44-interacting factor, was preferentially secreted by cancer-associated fibroblasts (CAFs) for promoting tumor growth in breast cancer patients. In this study, we show that SRGN is overexpressed in primary non-small cell lung cancers (NSCLCs), by both carcinoma and stromal cells. Using gain-of-function and loss-of-function approaches, we show that SRGN promotes NSCLC cell migration and invasion as well as colonization in the lung and liver in a CD44-dependent manner. SRGN induces lung cancer cell stemness, as demonstrated by its ability to enhance NSCLC cell sphere formation via Nanog induction, accompanied with increased chemoresistance and anoikis-resistance. SRGN promotes epithelial-mesenchymal transition by enhancing vimentin expression via CD44/NF-κB/claudin-1 (CLDN1) axis. In support, CLDN1 and SRGN expression are tightly linked together in primary NSCLC. Most importantly, increased expression of SRGN and/or CLDN1 predicts poor prognosis in primary lung adenocarcinomas. In summary, we demonstrate that SRGN secreted by tumor cells and stromal components in the TME promotes malignant phenotypes through interacting with tumor cell receptor CD44, suggesting that a combined therapy targeting both CD44 and its ligands in the TME may be an attractive approach for cancer therapy.
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Hashimoto Y, Yagi K, Kondoh M. Roles of the first-generation claudin binder, Clostridium perfringens enterotoxin, in the diagnosis and claudin-targeted treatment of epithelium-derived cancers. Pflugers Arch 2016; 469:45-53. [PMID: 27629072 DOI: 10.1007/s00424-016-1878-6] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Revised: 08/20/2016] [Accepted: 09/06/2016] [Indexed: 12/11/2022]
Abstract
Given that most malignant tumors are derived from epithelium, developing a strategy for treatment of epithelium-derived cancers (i.e., carcinomas) is a pivotal issue in cancer therapy. Carcinomas, including ovarian, breast, prostate, and pancreatic cancers, are known to overexpress various claudins (CLDNs); in particular, CLDN-3 and -4 are frequently overexpressed in malignant case. The generation of CLDN binders is a key for expanding CLDN-targeted cancer therapy but has been delayed due to the small size of CLDN extracellular domains (approximately 50 amino acids for the first domain and 15 amino acids for the second) and their high homology among species. Interestingly, however, the receptors for Clostridium perfringens enterotoxin (CPE), a foodborne toxin in humans, happen to be identical to CLDN-3 and -4. Thus, the first CLDN binder, CPE, has provided us CLDN-targeted cancer therapy from a concept into a potential reality. In this review, we describe roles of CPE technology in cancer therapy and discuss future directions in the CLDN-targeting concept-to-therapy process.
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Affiliation(s)
- Yosuke Hashimoto
- Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Kiyohito Yagi
- Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan
| | - Masuo Kondoh
- Graduate School of Pharmaceutical Sciences, Osaka University, Suita, Osaka, 565-0871, Japan.
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