title: miR-18a promotes malignant progression by impairing microRNA biogenesis in nasopharyngeal carcinoma.
abstract: Dysregulation of microRNA (miRNA) biogenesis is implicated in cancer development and progression. Dicer and Drosha are established regulators of miRNA biogenesis. In this study, we used a miRNA array to evaluate the miRNA expression profiles in nasopharyngeal carcinoma (NPC) samples. The significance analysis of microarrays showed a global downregulation of miRNA expression in NPC samples compared with normal nasopharyngeal epithelial tissues. Notably, miR-18a, a member of the oncogenic miR-17-92 cluster, was upregulated in the NPC samples and cell lines. Clinical parameter studies showed that higher levels of miR-18a correlated with NPC advanced stage, lymph node metastasis, Epstein-Barr virus infection and a higher death rate from NPC, indicating oncogenic roles in NPC development. The expression levels of miR-18a and Dicer1 were inversely related in NPC tissues. Further studies demonstrated that miR-18a negatively regulated Dicer1 by binding to the 3' untranslated regions of Dicer1. In vitro and in vivo biological function assays showed that miR-18a promoted the growth, migration and invasion of NPC cells by regulating Dicer1 expression, which caused the global downregulation of miRNA expression levels including miR-200 family and miR-143. Furthermore, we found that the epithelial mesenchymal transition marker E-cadherin and the oncogene K-Ras were aberrantly expressed after miR-18a transduction, and these alterations were directly induced by downregulation of the miR-200 family and miR-143. Collectively, our findings indicate that miR-18a plays an oncogenic role in the development of NPC by widespread downregulation of the miRNome and could be a potential therapeutic target for NPC.
authors.affiliation: Hunan Key Laboratory of Nonresolving Inflammation and Cancer,  Changsha, Hunan 410013, China.
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Luo
authors.forename: Yafei
authors.initials: Y
authors.lastname: Dai
authors.forename: Liyang
authors.initials: L
authors.lastname: Zhang
authors.forename: Chen
authors.initials: C
authors.lastname: Jiang
authors.forename: Zheng
authors.initials: Z
authors.lastname: Li
authors.forename: Jianbo
authors.initials: J
authors.lastname: Yang
authors.forename: James B
authors.initials: JB
authors.lastname: McCarthy
authors.forename: Xiaoling
authors.initials: X
authors.lastname: She
authors.forename: Wenling
authors.initials: W
authors.lastname: Zhang
authors.forename: Jian
authors.initials: J
authors.lastname: Ma
authors.forename: Wei
authors.initials: W
authors.lastname: Xiong
authors.forename: Minghua
authors.initials: M
authors.lastname: Wu
authors.forename: Jianhong
authors.initials: J
authors.lastname: Lu
authors.forename: Xiayu
authors.initials: X
authors.lastname: Li
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Li
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Xiang
authors.forename: Guiyuan
authors.initials: G
authors.lastname: Li
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D002277:Carcinoma; D016022:Case-Control Studies; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D018450:Disease Progression; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D017403:In Situ Hybridization; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D008875:Middle Aged; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000401:mortality / Q000473:pathology*; D009305:Nasopharynx / Q000378:metabolism; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D014945:Wound Healing
chemical_list: D014408:Biomarkers, Tumor; C522576:MIRN18A microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D008156:Luciferases