Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms

Kohei Taniguchi; Yuko Ito; Nobuhiko Sugito; Minami Kumazaki; Haruka Shinohara; Nami Yamada; Yoshihito Nakagawa; Tarou Sugiyama; Manabu Futamura; Yoshinori Otsuki; Kazuhiro Yoshida; Kazuhisa Uchiyama; Yukihiro Akao

doi:10.1038/srep08647

Organ-specific PTB1-associated microRNAs determine expression of pyruvate kinase isoforms

Sci Rep. 2015 Feb 27:5:8647. doi: 10.1038/srep08647.

Authors

Affiliations

¹ 1] United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan [2] Department of General and Gastroenterological Surgery, Osaka Medical College, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
² Department of Anatomy and Cell Biology, Division of Life Sciences, Osaka Medical College, 2-7 Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.
³ United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan.
⁴ Department of Gastroenterology, Fujita Health University, School of Medicine, Kutsukake-cho, Toyoake, Aichi 470-1192, Japan.
⁵ Department of Oncological surgery, Gifu University School of medicine, 1-1 Yanagido, Gifu 501-1193, Japan.
⁶ Department of General and Gastroenterological Surgery, Osaka Medical College, Daigaku-machi, Takatsuki, Osaka 569-8686, Japan.

Abstract

The Warburg effect is a well-known feature of cancer cells. However, its' functional significance hasn't been elucidated yet. Pyruvate kinase muscle (PKM), which is a rate-limiting glycolytic enzyme, has 2 isoforms, PKM1 and PKM2. It has been reported that PKM2 is a tumor-specific isoform and promotes the Warburg effect. Also, it has been thought that tumor cells switch their PKM isoform from PKM1 to PKM2 during tumor development. Here, we showed that this switching machinery was induced only in limited cases, based on PKM expression in normal tissues, and that brain-specific microRNA (miR)-124 and muscle-specific miR-133b regulated this machinery by controlling PKM expression through targeting polypyrimidine tract-binding protein 1 (PTB1), which is a splicer of the PKM gene. Also, we confirmed that the PKM2/PKM1 ratio was further elevated in other PKM2-dominant organs such as colon through the down-regulation of these PTB1-associated microRNAs during tumor development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Animals
Carrier Proteins / genetics
Carrier Proteins / metabolism
Cell Line
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism
Colorectal Neoplasms / pathology
Down-Regulation
Female
Gene Expression Regulation*
Heterogeneous-Nuclear Ribonucleoproteins / metabolism*
Humans
Isoenzymes
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mice
MicroRNAs / genetics*
Middle Aged
Models, Biological
Neoplasm Grading
Neoplasm Staging
Organ Specificity
Polypyrimidine Tract-Binding Protein / metabolism*
Pyruvate Kinase / genetics*
Pyruvate Kinase / metabolism
Thyroid Hormone-Binding Proteins
Thyroid Hormones / genetics
Thyroid Hormones / metabolism

Substances

Carrier Proteins
Heterogeneous-Nuclear Ribonucleoproteins
Isoenzymes
MIRN124 microRNA, human
MIRN133 microRNA, human
Membrane Proteins
MicroRNAs
PTBP1 protein, human
Thyroid Hormones
Polypyrimidine Tract-Binding Protein
Pyruvate Kinase