PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors
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Kohei Taniguchi1,2, Miku Sakai1, Nobuhiko Sugito1, Minami Kumazaki1, Haruka Shinohara1, Nami Yamada1, Tatsushi Nakayama1, Hiroshi Ueda1, Yoshihito Nakagawa3, Yuko Ito4, Manabu Futamura5, Bunji Uno1, Yoshinori Otsuki4, Kazuhiro Yoshida5, Kazuhisa Uchiyama2, Yukihiro Akao1
1United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan
2Department of General and Gastroenterological Surgery, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
3Department of Gastroenterology, Fujita Health University, School of Medicine, Kutsukake-cho, Toyoake, Aichi, 470-1192, Japan
4Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan
5Department of Oncological Surgery, Gifu University School of Medicine, Gifu 501-1193, Japan
Kohei Taniguchi, e-mail: email@example.com
Keywords: miR-1, miR-133, Warburg effect, PTBP1, PKM
Received: September 28, 2015 Accepted: February 05, 2016 Published: March 09, 2016
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.
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