PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors

// Kohei Taniguchi 1, 2 , Miku Sakai 1 , Nobuhiko Sugito 1 , Minami Kumazaki 1 , Haruka Shinohara 1 , Nami Yamada 1 , Tatsushi Nakayama 1 , Hiroshi Ueda 1 , Yoshihito Nakagawa 3 , Yuko Ito 4 , Manabu Futamura 5 , Bunji Uno 1 , Yoshinori Otsuki 4 , Kazuhiro Yoshida 5 , Kazuhisa Uchiyama 2 , Yukihiro Akao 1 1 United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan 2 Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan 3 Department of Gastroenterology, Fujita Health University, School of Medicine, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan 4 Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan 5 Department of Oncological Surgery, Gifu University School of Medicine, Gifu 501-1193, Japan Correspondence to: Kohei Taniguchi, e-mail: sur144@osaka-med.ac.jp Keywords: miR-1, miR-133, Warburg effect, PTBP1, PKM Received: September 28, 2015 Accepted: February 05, 2016 Published: March 09, 2016 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.