title: Replacement treatment with microRNA-143 and -145 induces synergistic inhibition of the growth of human bladder cancer cells by regulating PI3K/Akt and MAPK signaling pathways.
abstract: We recently reported that both microRNA (miR)-143 and -145 are downregulated in human bladder cancer T24 cells and that miR-143 targets ERK5. In this study, we assessed the anti-tumor effects of combination treatment with miR-143 and -145 on bladder cancer cell lines T24, SNK57, and NKB1, in which the expression levels of miR-143 and -145 are downregulated. The ectopic expression of both miR-143 and -145 led to a significantly synergistic growth inhibition of T24 and NKB1 cells, but not that of SNK57 cells with the levels of miR-143 and -145 higher than those in T24 and NKB1 cells. The MAPK signaling pathway in NKB1 cells and both PI3K/Akt and MAPK signaling pathways in T24 cells were synergistically repressed by the co-treatment with miR-143 and -145. We newly elucidated that miR-143 targeted akt and that miR-145 targeted integrin-linked kinase (ilk) in T24 cells based on the results of a luciferase activity assay. Silencing of ilk significantly inhibited the growth of all the bladder cancer cells tested. Also, the level of phosphorylated ERK1/2 in T24 cells and that of phosphorylated Akt in SNK57 and NKB1 cells were decreased by ilk silencing. This study has provided novel important evidence with regard to the functions of anti-oncogenic miR-143 and -145 and also suggests the possible use of miR-143 and -145 for combination replacement therapy in cancers in which both miRNAs are downregulated.
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan. snoguchi@gifu-u.ac.jp
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Noguchi
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yasui
authors.forename: Junya
authors.initials: J
authors.lastname: Iwasaki
authors.forename: Minami
authors.initials: M
authors.lastname: Kumazaki
authors.forename: Nami
authors.initials: N
authors.lastname: Yamada
authors.forename: Seiji
authors.initials: S
authors.lastname: Naito
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
mesh_terms: D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D022661:RNA, Untranslated / Q000235:genetics; D015398:Signal Transduction; D001749:Urinary Bladder Neoplasms / Q000201:enzymology* / Q000235:genetics* / Q000378:metabolism; D000099200:Scaffold Protein ILK
chemical_list: D035683:MicroRNAs; D020928:Mitogen-Activated Protein Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D022661:RNA, Untranslated; D000099200:Scaffold Protein ILK; C542359:MIRN143 microRNA, human; C541010:MIRN145 microRNA, human