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.
Highlights
The Warburg effect is a well-known feature of cancer cell metabolism [1]
MiR-1 and -133b were relatively highly expressed in colon tissue and very frequently down-regulated in clinical colorectal tumor samples
In the human colon cancer cell lines tested, the expression levels of both miRs were significantly down-regulated (Figure 1C). These findings suggested that dysregulation of the expression of both miR-1 and -133b was closely associated with the development of colorectal tumors
Summary
The Warburg effect is a well-known feature of cancer cell metabolism [1]. it is well known that there are many factors that establish the Warburg effect, e.g., HIF-1 and c-Myc [2]. PKM isoform expression is regulated by the protein family of splicers of heterogeneous nuclear ribonucleoproteins (hnRNPs) [5]. Polypyrimidine tract-binding protein 1 (PTBP1, known as hnRNPI), is a member of the hnRNP family and www.impactjournals.com/oncotarget promotes PKM2 expression in cancer cells [6]. PTBP1 represses the inclusion of downstream exon by binding to the sequence UCUUC, which exists near the 3’ splice site [7, 8]. This favorable sequence for PTBP1 exists only in intron 8 of PKM mRNA. PTBP1 represses the inclusion of exon 9 and promotes the expression of PKM2 [6, 9]
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