title: miR-93 promotes TGF-β-induced epithelial-to-mesenchymal transition through downregulation of NEDD4L in lung cancer cells.
abstract: The level of microRNA-93 (miR-93) in tumors has been recently reported to be negatively correlated with survival of lung cancer patients. Considering that the most devastating aspect of lung cancer is metastasis, which can be promoted by transforming growth factor-β (TGF-β)-induced epithelial-to-mesenchymal transition (EMT), we sought to determine whether miR-93 is involved in this process. Here, we report that a previously unidentified target of miR-93, neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L), is able to mediate TGF-β-mediated EMT in lung cancer cells. miR-93 binds directly to the 3'-UTR of the NEDD4L messenger RNA (mRNA), leading to a downregulation of NEDD4L expression at the protein level. We next demonstrated that the downregulation of NEDD4L enhanced, while overexpression of NEDD4L reduced TGF-β signaling, reflected by increased phosphorylation of SMAD2 in the lung cancer cell line after TGF-β treatment. Furthermore, overexpression of miR-93 in lung cancer cells promoted TGF-β-induced EMT through downregulation of NEDD4L. The analysis of publicly available gene expression array datasets indicates that low NEDD4L expression correlates with poor outcomes among patients with lung cancer, further supporting the oncogenic role of miR-93 in lung tumorigenesis and metastasis.
authors.affiliation: Department of Pharmacology, Key Lab of Applied Pharmacology in Universities of Shandong, Weifang Medical University, 7166 Baotong West St, Weifang, 261053, Shandong, China. qumeihua@hotmail.com.|Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA. qumeihua@hotmail.com.
authors.forename: Mei-Hua
authors.initials: MH
authors.lastname: Qu
authors.affiliation: Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA.
authors.forename: Chunhua
authors.initials: C
authors.lastname: Han
authors.affiliation: Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA.
authors.forename: Amit Kumar
authors.initials: AK
authors.lastname: Srivastava
authors.affiliation: Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Cui
authors.affiliation: Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA.
authors.forename: Ning
authors.initials: N
authors.lastname: Zou
authors.affiliation: Department of Pharmacology, Key Lab of Applied Pharmacology in Universities of Shandong, Weifang Medical University, 7166 Baotong West St, Weifang, 261053, Shandong, China.
authors.forename: Zhi-Qin
authors.initials: ZQ
authors.lastname: Gao
authors.affiliation: Department of Radiology, The Ohio State University Wexner Medical Center, Room 1014, 460 W. 12th Ave, Columbus, OH, 43210, USA. qi-en.wang@osumc.edu.
authors.forename: Qi-En
authors.initials: QE
authors.lastname: Wang
mesh_terms: D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D056827:Endosomal Sorting Complexes Required for Transport / Q000096:biosynthesis / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D000075702:Nedd4 Ubiquitin Protein Ligases; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D051899:Smad2 Protein / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000235:genetics*; D044767:Ubiquitin-Protein Ligases / Q000096:biosynthesis / Q000235:genetics*
chemical_list: D056827:Endosomal Sorting Complexes Required for Transport; C543350:MIRN93 microRNA, human; D035683:MicroRNAs; C497782:SMAD2 protein, human; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D000075702:Nedd4 Ubiquitin Protein Ligases; C000618485:Nedd4L protein, human; D044767:Ubiquitin-Protein Ligases
keywords: EMT; Lung cancer; NEDD4L; TGF-β signaling; miR-93