title: Nobiletin inhibited hypoxia-induced epithelial-mesenchymal transition of lung cancer cells by inactivating of Notch-1 signaling and switching on miR-200b.
abstract: Epithelial-mesenchymal transition (EMT) is an early step in the process of tumor metastasis. It is well known that tumor microenvironment affects malignancy in various carcinomas; in particular, that hypoxia induces EMT. Deregulated notch signaling also contributes a lot to the development of EMT in lung cancer. In this study, we investigated the use of Notch-1-inhibiting compound as novel therapeutic candidates to regulate hypoxia-induced EMT in lung cancer cells. According to previous screening, nobiletin was selected as a Notch-1 inhibitor. Hypoxia-induced EMT was characteristic of increased N-cadherin & vimentin expressions and decreased E-cadherin expressions. Treatment with nobiletin notably attenuated hypoxia-induced EMT, invasion and migration in H1299 cells, accompanied with reduced Notch-1, Jagged1/2 expressions and its downstream genes Hey-1 and Hes-1. Nobiletin treatment also promoted tumorsuppressive miR-200b level. Moreover, notch-1 siRNA prevented hypoxia-mediated cell migration and decreased Twist1, Snail1, and ZEB1/2 expressions, which are key EMT markers. Re-expression of miR-200b blocked hypoxia-induced EMT and cell invasion. Our findings suggest that downregulation of Notch-1 and reexpression of miR-200b by nobiletin might be a novel remedy for the therapy of lung cancer.
authors.forename: Xue-Jun
authors.initials: XJ
authors.lastname: Gao
authors.forename: Jian-Wei
authors.initials: JW
authors.lastname: Liu
authors.forename: Qing-Guang
authors.initials: QG
authors.lastname: Zhang
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhang
authors.forename: Hai-Tao
authors.initials: HT
authors.lastname: Xu
authors.forename: Hong-Jian
authors.initials: HJ
authors.lastname: Liu
mesh_terms: D000975:Antioxidants / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D047309:Flavones / Q000494:pharmacology*; D006801:Humans; D000860:Hypoxia / Q000473:pathology*; D008175:Lung Neoplasms / Q000473:pathology*; D035683:MicroRNAs / Q000187:drug effects*; D009361:Neoplasm Invasiveness; D051881:Receptor, Notch1 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects
chemical_list: D000975:Antioxidants; D047309:Flavones; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C497761:NOTCH1 protein, human; D051881:Receptor, Notch1; C008661:nobiletin