title: miRNA-128 suppresses prostate cancer by inhibiting BMI-1 to inhibit tumor-initiating cells.
abstract: microRNA-128 (miR128) is reduced in prostate cancer relative to normal/benign prostate tissues, but causal roles are obscure. Here we show that exogenously introduced miR128 suppresses tumor regeneration in multiple prostate cancer xenograft models. Cancer stem-like cell (CSC)-associated properties were blocked, including holoclone and sphere formation as well as clonogenic survival. Using a miR128 sensor to distinguish cells on the basis of miR128 expression, we found that miR128-lo cells possessed higher clonal, clonogenic, and tumorigenic activities than miR128-hi cells. miR128 targets the stem cell regulatory factors BMI-1, NANOG, and TGFBR1, the expression of which we found to vary inversely with miR128 expression in prostate cancer stem/progenitor cell populations. In particular, we defined BMI-1 as a direct and functionally relevant target of miR128 in prostate cancer cells, where these genes were reciprocally expressed and exhibited opposing biological functions. Our results define a tumor suppressor function for miR128 in prostate cancer by limiting CSC properties mediated by BMI-1 and other central stem cell regulators, with potential implications for prostate cancer gene therapy.
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville; Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei; and.
authors.forename: Min
authors.initials: M
authors.lastname: Jin
authors.affiliation: Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology (HUST), Wuhan, Hubei; and.
authors.forename: Tao
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville;
authors.forename: Can
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville;
authors.forename: Mark A
authors.initials: MA
authors.lastname: Badeaux
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville;
authors.forename: Bigang
authors.initials: B
authors.lastname: Liu
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville; Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
authors.forename: Ruifang
authors.initials: R
authors.lastname: Liu
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville;
authors.forename: Collene
authors.initials: C
authors.lastname: Jeter
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville;
authors.forename: Xin
authors.initials: X
authors.lastname: Chen
authors.affiliation: ThermoFisher Scientific, Austin, Texas;
authors.forename: Alexander V
authors.initials: AV
authors.lastname: Vlassov
authors.affiliation: Department of Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Science Park, Smithville; Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China dtang@mdanderson.org.
authors.forename: Dean G
authors.initials: DG
authors.lastname: Tang
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015316:Genetic Therapy; D006801:Humans; D008297:Male; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000008:administration & dosage* / Q000235:genetics; D014411:Neoplastic Stem Cells / Q000473:pathology; D063150:Polycomb Repressive Complex 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000628:therapy*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics / Q000473:pathology / Q000628:therapy; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: C069077:BMI1 protein, human; C545189:MIRN128 microRNA, human; D035683:MicroRNAs; D063150:Polycomb Repressive Complex 1