title: PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors.
abstract: It is known that pyruvate kinase in muscle (PKM), which is a rate-limiting glycolytic enzyme, has essential roles in the Warburg effect and that expression of cancer-dominant PKM2 is increased by polypyrimidine tract-binding protein 1 (PTBP1), which is a splicer of the PKM gene. In other words, PKM2 acts as a promoter of the Warburg effect. Previously, we demonstrated that the Warburg effect was partially established by down-regulation of several microRNAs (miRs) that bind to PTBP1 and that ectopic expression of these miRs suppressed the Warburg effect. In this study, we investigated the functions of miR-1 and -133b, which are well known as muscle-specific miRs, from the viewpoint of the Warburg effect in colorectal tumors. The expression levels of miR-1 and -133b were relatively high in colon tissue except muscle and very frequently down-regulated in 75 clinical colorectal tumors samples, even in adenomas, compared with those of the adjacent normal tissue samples. The ectopic expression of these miRs induced growth suppression and autophagic cell death through the switching of PKM isoform expression from PKM2 to PKM1 by silencing PTBP1 expression both in vitro and in vivo. Also, we showed that the resultant increase in the intracellular level of reactive oxygen species (ROS) was involved in this mechanism. Furthermore, PTBP1 was highly expressed in most of the 30 clinical colorectal tumor samples examined, even in adenomas. Our results suggested that PTBP1 and PTBP1-associated miR-1 and -133b are crucial molecules for the maintenance of the Warburg effect in colorectal tumors.
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.|Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Kohei
authors.initials: K
authors.lastname: Taniguchi
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
authors.forename: Miku
authors.initials: M
authors.lastname: Sakai
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Sugito
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
authors.forename: Minami
authors.initials: M
authors.lastname: Kumazaki
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
authors.forename: Haruka
authors.initials: H
authors.lastname: Shinohara
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
authors.forename: Nami
authors.initials: N
authors.lastname: Yamada
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
authors.forename: Tatsushi
authors.initials: T
authors.lastname: Nakayama
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ueda
authors.affiliation: Department of Gastroenterology, Fujita Health University, School of Medicine, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Nakagawa
authors.affiliation: Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Ito
authors.affiliation: Department of Oncological Surgery, Gifu University School of Medicine, Gifu 501-1193, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Futamura
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
authors.forename: Bunji
authors.initials: B
authors.lastname: Uno
authors.affiliation: Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Otsuki
authors.affiliation: Department of Oncological Surgery, Gifu University School of Medicine, Gifu 501-1193, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Yoshida
authors.affiliation: Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan.
authors.forename: Kazuhisa
authors.initials: K
authors.lastname: Uchiyama
authors.affiliation: United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Akao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology; D015536:Down-Regulation; D005260:Female; D034441:Heterogeneous-Nuclear Ribonucleoproteins / Q000235:genetics* / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D038941:Polypyrimidine Tract-Binding Protein / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection
chemical_list: D034441:Heterogeneous-Nuclear Ribonucleoproteins; C544547:MIRN1 microRNA, human; C548234:MIRN133 microRNA, human; D035683:MicroRNAs; C450006:PTBP1 protein, human; D038941:Polypyrimidine Tract-Binding Protein
keywords: PKM; PTBP1; Warburg effect; miR-1; miR-133