TY - JOUR
T1 - PTBP1-associated microRNA-1 and -133b suppress the Warburg effect in colorectal tumors
AU - Taniguchi, Kohei
AU - Sakai, Miku
AU - Sugito, Nobuhiko
AU - Kumazaki, Minami
AU - Shinohara, Haruka
AU - Yamada, Nami
AU - Nakayama, Tatsushi
AU - Ueda, Hiroshi
AU - Nakagawa, Yoshihito
AU - Ito, Yuko
AU - Futamura, Manabu
AU - Uno, Bunji
AU - Otsuki, Yoshinori
AU - Yoshida, Kazuhiro
AU - Uchiyama, Kazuhisa
AU - Akao, Yukihiro
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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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UR - http://www.scopus.com/inward/citedby.url?scp=84975522422&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.8005
DO - 10.18632/oncotarget.8005
M3 - Article
C2 - 26980745
AN - SCOPUS:84975522422
SN - 1949-2553
VL - 7
SP - 18940
EP - 18952
JO - Oncotarget
JF - Oncotarget
IS - 14
ER -