title: Therapeutic effects of microRNA-582-5p and -3p on the inhibition of bladder cancer progression.
abstract: Many reports have indicated that the abnormal expression of microRNAs (miRNAs) is associated with the progression of disease and have identified miRNAs as attractive targets for therapeutic intervention. However, the bifunctional mechanisms of miRNA guide and passenger strands in RNA interference (RNAi) therapy have not yet been clarified. Here, we show that miRNA (miR)-582-5p and -3p, which are strongly decreased in high-grade bladder cancer clinical samples, regulate tumor progression in vitro and in vivo. Significantly, the overexpression of miR-582-5p or -3p reduced the proliferation and invasion of UM-UC-3 human bladder cancer cells. Furthermore, transurethral injections of synthetic miR-582 molecule suppressed tumor growth and metastasis in an animal model of bladder cancer. Most interestingly, our study revealed that both strands of miR-582-5p and -3p suppressed the expression of the same set of target genes such as protein geranylgeranyltransferase type I beta subunit (PGGT1B), leucine-rich repeat kinase 2 (LRRK2) and DIX domain containing 1 (DIXDC1). Knockdown of these genes using small interfering RNA (siRNA) resulted in the inhibition of cell growth and invasiveness of UM-UC-3. These findings uncover the unique regulatory pathway involving tumor suppression by both strands of a single miRNA that is a potential therapeutic target in the treatment of invasive bladder cancer.
authors.affiliation: National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
authors.forename: Keita
authors.initials: K
authors.lastname: Uchino
authors.forename: Fumitaka
authors.initials: F
authors.lastname: Takeshita
authors.forename: Ryou-U
authors.initials: RU
authors.lastname: Takahashi
authors.forename: Nobuyoshi
authors.initials: N
authors.lastname: Kosaka
authors.forename: Kae
authors.initials: K
authors.lastname: Fujiwara
authors.forename: Haruna
authors.initials: H
authors.lastname: Naruoka
authors.forename: Satoru
authors.initials: S
authors.lastname: Sonoke
authors.forename: Junichi
authors.initials: J
authors.lastname: Yano
authors.forename: Hideo
authors.initials: H
authors.lastname: Sasaki
authors.forename: Shiari
authors.initials: S
authors.lastname: Nozawa
authors.forename: Miki
authors.initials: M
authors.lastname: Yoshiike
authors.forename: Kazuki
authors.initials: K
authors.lastname: Kitajima
authors.forename: Tatsuya
authors.initials: T
authors.lastname: Chikaraishi
authors.forename: Takahiro
authors.initials: T
authors.lastname: Ochiya
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000235:genetics / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015316:Genetic Therapy; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000627:therapeutic use*; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*
chemical_list: C513335:DIXDC1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; D008840:Microfilament Proteins; D034741:RNA, Small Interfering; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I; C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2; D017346:Protein Serine-Threonine Kinases