title: Genomic loss of tumor suppressor miRNA-204 promotes cancer cell migration and invasion by activating AKT/mTOR/Rac1 signaling and actin reorganization.
abstract: Increasing evidence suggests that chromosomal regions containing microRNAs are functionally important in cancers. Here, we show that genomic loci encoding miR-204 are frequently lost in multiple cancers, including ovarian cancers, pediatric renal tumors, and breast cancers. MiR-204 shows drastically reduced expression in several cancers and acts as a potent tumor suppressor, inhibiting tumor metastasis in vivo when systemically delivered. We demonstrated that miR-204 exerts its function by targeting genes involved in tumorigenesis including brain-derived neurotrophic factor (BDNF), a neurotrophin family member which is known to promote tumor angiogenesis and invasiveness. Analysis of primary tumors shows that increased expression of BDNF or its receptor tropomyosin-related kinase B (TrkB) parallel a markedly reduced expression of miR-204. Our results reveal that loss of miR-204 results in BDNF overexpression and subsequent activation of the small GTPase Rac1 and actin reorganization through the AKT/mTOR signaling pathway leading to cancer cell migration and invasion. These results suggest that microdeletion of genomic loci containing miR-204 is directly linked with the deregulation of key oncogenic pathways that provide crucial stimulus for tumor growth and metastasis. Our findings provide a strong rationale for manipulating miR-204 levels therapeutically to suppress tumor metastasis.
authors.affiliation: Greehey Children's Cancer Research Institute, University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA.
authors.forename: J Saadi
authors.initials: JS
authors.lastname: Imam
authors.forename: Jason R
authors.initials: JR
authors.lastname: Plyler
authors.forename: Hima
authors.initials: H
authors.lastname: Bansal
authors.forename: Suresh
authors.initials: S
authors.lastname: Prajapati
authors.forename: Sanjay
authors.initials: S
authors.lastname: Bansal
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rebeles
authors.forename: Hung-I Harry
authors.initials: HI
authors.lastname: Chen
authors.forename: Yao-Fu
authors.initials: YF
authors.lastname: Chang
authors.forename: Subbarayalu
authors.initials: S
authors.lastname: Panneerdoss
authors.forename: Behyar
authors.initials: B
authors.lastname: Zoghi
authors.forename: Kalyan C
authors.initials: KC
authors.lastname: Buddavarapu
authors.forename: Russell
authors.initials: R
authors.lastname: Broaddus
authors.forename: Peter
authors.initials: P
authors.lastname: Hornsby
authors.forename: Gail
authors.initials: G
authors.lastname: Tomlinson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Dome
authors.forename: Ratna K
authors.initials: RK
authors.lastname: Vadlamudi
authors.forename: Alexander
authors.initials: A
authors.lastname: Pertsemlidis
authors.forename: Yidong
authors.initials: Y
authors.lastname: Chen
authors.forename: Manjeet K
authors.initials: MK
authors.lastname: Rao
mesh_terms: D000199:Actins / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human / Q000235:genetics*; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000473:pathology; D021381:Protein Transport; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D019208:Brain-Derived Neurotrophic Factor; C549404:MIRN204 microRNA, human; D035683:MicroRNAs; C107953:RAC1 protein, human; C579455:BDNF protein, human; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D020830:rac1 GTP-Binding Protein