title: Cycling hypoxia affects cell invasion and proliferation through direct regulation of claudin1 / claudin7 expression, and indirect regulation of P18 through claudin7.
abstract: Claudins (CLDNs), the major integral membrane proteins at tight junction, play critical roles in apical cell-to-cell adhesion, maintenance of epithelial polarity, and formation of impermeable barriers between epithelial cells.We investigated in this study the expression of CLDNs- Claudin1 (CLDN1) and Claudin7 (CLDN7), and their relation to tumor progression in nasopharyngeal cancer (NPC). CLDN7, rather than CLDN1, showed higher expression in both undifferentiated tumor tissue and the poorly differentiated CNE2 cells, compared with differentiated tissue and the highly differentiated CNE1 cells. Furthermore, knockdown of CLDN7 dramatically inhibited the metastasis and invasion of CNE2 cells suggesting that CLDN7 could act as a biomarker for NPC metastasis.Cycling hypoxia could induce significant changes in CLDN1 and CLDN7 expression in NPC cells. Genetics analysis demonstrated that CLDN1/CLDN7 were not only regulated directly by HIF1a but also affected each other through a feedback mechanism. CLDN7 acted as a bridge to promote HIF1a-induced P18 expression and cell differentiation. Taken together, our results provide evidence that adjusting the oxygenation time and cycles in NPC might be an effective method to prevent / delay the metastasis of poorly differentiated NPC cells.
authors.affiliation: Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Feifei
authors.initials: F
authors.lastname: Jiang
authors.affiliation: Department of Pathology, China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Xinshan
authors.initials: X
authors.lastname: Jia
authors.affiliation: Department of Dermatology, China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lan
authors.affiliation: Department of Dermatology, China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Hao
authors.initials: H
authors.lastname: Guo
authors.affiliation: Institute of Respiratory Disease, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Erran
authors.initials: E
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Aihui
authors.initials: A
authors.lastname: Yan
authors.affiliation: Department of Otolaryngology, The First Affiliated Hospital of China Medical University, Shenyang, Liaoning 110001, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wang
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D062445:Claudin-1 / Q000235:genetics / Q000378:metabolism*; D057167:Claudins / Q000235:genetics / Q000378:metabolism*; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D009361:Neoplasm Invasiveness; D034622:RNA Interference; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D000072258:Tumor Hypoxia; D059016:Tumor Microenvironment
chemical_list: D014408:Biomarkers, Tumor; C493971:CDKN2C protein, human; C568108:CLDN1 protein, human; C473255:CLDN7 protein, human; D062445:Claudin-1; D057167:Claudins; D050763:Cyclin-Dependent Kinase Inhibitor p18; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit
keywords: HIF1α; claudin1; claudin7; cycling hypoxia; nasopharyngeal carcinoma