title: MiR-449a exerts tumor-suppressive functions in human glioblastoma by targeting Myc-associated zinc-finger protein.
abstract: Glioblastoma (GBM) is one of the most common and aggressive primary brain tumors in adults. Deregulated expression of microRNAs (miRNAs) has been associated with GBM progression through alterations in either oncogenic or tumor suppressor targets. Here, we elucidated the function and the possible molecular mechanisms of miR-449a in human GBM cell lines and tumor specimens-derived glioblastoma stem cells (GSCs). Quantitative real-time PCR demonstrated that miR-449a was down-regulated in human GBM cell lines and GSCs. Functionally, miR-449a acted as a tumor suppressor by reducing cell proliferation, migration and invasion as well as inducing apoptosis in human GBM cell lines and GSCs. Myc-associated zinc-finger protein (MAZ) was identified as a direct target of miR-449a, mediating these tumor-suppressive effects, demonstrated by Western blot assay and luciferase assays. Moreover, over-expression of miR-449a inhibited the expression of Podoplanin (PDPN) by down-regulating MAZ which could positively control the promoter activities via binding to the promoter of PDPN, demonstrated by luciferase assays and chromatin immunoprecipitation assays. Further, the PI3K/AKT pathway was blocked when MAZ was down-regulated by miR-449a. This process was coincided with the up-regulation of apoptotic proteins and the down-regulation of anti-apoptotic proteins, MMP2 and MMP9. Furthermore, nude mice carrying over-expressed miR-449a combined with knockdown MAZ tumors produced the smallest tumors and the highest survival. These results elucidated a novel molecular mechanism of GBM progression, and may thus suggest a promising application for GBM treatment.
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Yilong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Ma
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Yixue
authors.initials: Y
authors.lastname: Xue
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Ping
authors.initials: P
authors.lastname: Wang
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang 110001, People's Republic of China; Institute of Pathology and Pathophysiology, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Zhiqing
authors.initials: Z
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Department of Neurology, The First Affiliated Hospital, China Medical University, Shenyang 110001, People's Republic of China.
authors.forename: Xiuli
authors.initials: X
authors.lastname: Shang
authors.affiliation: Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, People's Republic of China. Electronic address: liuyh@sj-hospital.org.
authors.forename: Yunhui
authors.initials: Y
authors.lastname: Liu
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002469:Cell Separation; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D005909:Glioblastoma / Q000235:genetics* / Q000473:pathology; D057809:HEK293 Cells; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000378:metabolism; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D023041:Xenograft Model Antitumor Assays; D000098853:Podoplanin
chemical_list: D020413:3' Untranslated Regions; D004268:DNA-Binding Proteins; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D008562:Membrane Glycoproteins; D035683:MicroRNAs; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; D014157:Transcription Factors; C544530:MIRN449 microRNA, human; C117468:PDPN protein, human; D000098853:Podoplanin; C076035:c-MYC-associated zinc finger protein
keywords: Glioblastoma; MAZ; MiR-449a; MicroRNAs; PDPN; Stem cells