title: miR-9 targets CXCR4 and functions as a potential tumor suppressor in nasopharyngeal carcinoma.
abstract: MicroRNA deregulation and pathway alterations have been implicated in nasopharyngeal carcinoma (NPC), a highly invasive and metastatic cancer widely prevalent in Southern China. In this study, we report that miR-9 is commonly downregulated in NPC specimens and NPC cell lines with important functional consequences. The reduced expression of miR-9 was inversely correlated with clinical stages and marked the progression from locoregional to metastatic tumors. The CpG island hypermethylation contributed to miR-9 silencing in NPC cell lines and tissues. Ectopic expression of miR-9 dramatically inhibited the proliferative, migratory and invasive capacities of NPC cells in vitro and in vivo. We found that miR-9 strongly reduced the expression of CXCR4 in NPC cells. Luciferase assay demonstrated that miR-9 could directly bind to the 3' untranslated region of CXCR4. Similar to the restoring miR-9 expression, CXCR4 downregulation inhibited cell growth, migration and invasion, whereas CXCR4 overexpression rescued the suppressive effect of miR-9. Mechanistic investigations revealed that CXCR4 functionally mediated the SDF-1-stimulated activation of p38 mitogen-activated protein kinase pathway in NPC cells with miR-9 downregulation or CXCR4 overexpression. In clinical specimens, CXCR4 and phospho-p38 were widely overexpressed, and the levels increased with the progression from locoregional to metastatic tumors in NPC tissues. The levels of CXCR4 were inversely correlated with miR-9 or phospho-p38 expression. Taken together, our results indicate that miR-9 functions as a tumor-suppressive microRNA in NPC, and that its suppressive effects are mediated chiefly by repressing CXCR4 expression.
authors.affiliation: Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
authors.forename: Juan
authors.initials: J
authors.lastname: Lu
authors.forename: Huanan
authors.initials: H
authors.lastname: Luo
authors.forename: Xiong
authors.initials: X
authors.lastname: Liu
authors.forename: Ying
authors.initials: Y
authors.lastname: Peng
authors.forename: Bao
authors.initials: B
authors.lastname: Zhang
authors.forename: Lu
authors.initials: L
authors.lastname: Wang
authors.forename: Xia
authors.initials: X
authors.lastname: Xu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Peng
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Wendong
authors.initials: W
authors.lastname: Tian
authors.forename: Ming-Liang
authors.initials: ML
authors.lastname: He
authors.forename: Hsiangfu
authors.initials: H
authors.lastname: Kung
authors.forename: Xiang-Ping
authors.initials: XP
authors.lastname: Li
mesh_terms: D000818:Animals; D002277:Carcinoma; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D018450:Disease Progression; D016147:Genes, Tumor Suppressor; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D000077274:Nasopharyngeal Carcinoma; D009303:Nasopharyngeal Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D009362:Neoplasm Metastasis; D019718:Receptors, CXCR4 / Q000235:genetics*
chemical_list: C527276:CXCR4 protein, human; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D019718:Receptors, CXCR4