title: Role of TGF-β-induced Claudin-4 expression through c-Jun signaling in non-small cell lung cancer.
abstract: Claudin-4 has been identified as an integral member of tight junctions and has been found to be upregulated in various types of cancers especially in metastatic cancers. However, the molecular mechanism of the upregulation of Claudin-4 and its role in lung tumorigenesis are unknown. The aim of the present study is to investigate the role of Claudin-4 on migration and tumorigenicity of lung cancer cells and to examine the regulatory effects of TGF-β on Claudin-4 expression. We have observed that TGF-β induces the expression of Claudin-4 dramatically in lung cell lines in a time dependent manner. TGF-β-induced Smad signaling is important for enhancing Claudin-4 mRNA level through inducing its promoter activity. Treatment with curcumin, a c-Jun inhibitor, or stable knockdown of c-Jun abrogates TGF-β-induced Claudin-4 expression suggesting an involvement of the c-Jun pathway. Notably, TGF-β-induced Claudin-4 expression through c-Jun pathway plays a role in TGF-β-mediated motility and tumorigenicity of these cells. In support of these observations, we have uncovered that Claudin-4 is upregulated in 14 of 24 (58%) lung tumors when compared with normal lung tissue. This is the first study to show how TGF-β regulates the expression of Claudin-4 through c-Jun signaling and how this pathway contributes to the migratory and tumorigenic phenotype of lung tumor cells.
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Girish
authors.initials: G
authors.lastname: Rachakonda
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States.
authors.forename: Trung
authors.initials: T
authors.lastname: Vu
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, United States; Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States; Birmingham Veterans Affairs Medical Center, Birmingham, AL, United States.
authors.forename: Lin
authors.initials: L
authors.lastname: Jin
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, United States.
authors.forename: Debangshu
authors.initials: D
authors.lastname: Samanta
authors.affiliation: Department of Surgery, Vanderbilt University Medical Center, Nashville, TN, United States; Division of Hematology and Oncology, Department of Medicine, UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, United States; Birmingham Veterans Affairs Medical Center, Birmingham, AL, United States. Electronic address: prandatta@uabmc.edu.
authors.forename: Pran K
authors.initials: PK
authors.lastname: Datta
mesh_terms: D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D062506:Claudin-4 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic / Q000235:genetics; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000235:genetics; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D062506:Claudin-4; D016755:Proto-Oncogene Proteins c-jun; D016212:Transforming Growth Factor beta
keywords: Claudin-4; Migration; Smad; TGF-β; Tumorigenicity; c-Jun