title: Enhanced expression of the M2 isoform of pyruvate kinase is involved in gastric cancer development by regulating cancer-specific metabolism.
abstract: Recent studies have indicated that increased expression of the M2 isoform of pyruvate kinase (PKM2) is involved in glycolysis and tumor development. However, little is known about the role of PKM2 in gastric cancer (GC). Therefore, we examined the expression and function of PKM2 in human GC. We evaluated PKM1 and PKM2 expression by quantitative RT-PCR in gastric tissues from 10 patients who underwent gastric endoscopic submucosal dissection, 80 patients who underwent gastrectomy, and seven healthy volunteers, and analyzed the correlation with clinicopathological variables. To assess the function of PKM2, we generated PKM2-knockdown GC cells, and investigated the phenotypic changes. Furthermore, we examined the induction of PKM2 expression by cytotoxin-associated gene A (CagA), a pathogenic factor of Helicobacter pylori, using CagA-inducible GC cells. We found that PKM2 was predominantly expressed not only in GC lesions but also in the normal gastric regions of GC patients and in the gastric mucosa of healthy volunteers. The PKM2 expression was significantly higher in carcinoma compared to non-cancerous tissue and was associated with venous invasion. Knockdown of PKM2 in GC cells caused significant decreases in cellular proliferation, migration, anchorage-independent growth, and sphere formation in vitro, and in tumor growth and liver metastasis in vivo. The serine concentration-dependent cell proliferation was also inhibited by PKM2 silencing. Furthermore, we found that PKM2 expression was upregulated by CagA by way of the Erk pathway. These results suggested that enhanced PKM2 expression plays a pivotal role in the carcinogenesis and development of GC in part by regulating cancer-specific metabolism.
authors.affiliation: Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.|Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Takeharu
authors.initials: T
authors.lastname: Shiroki
authors.affiliation: Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Misa
authors.initials: M
authors.lastname: Yokoyama
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Nobuhiro
authors.initials: N
authors.lastname: Tanuma
authors.affiliation: Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.|Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Ryuhei
authors.initials: R
authors.lastname: Maejima
authors.affiliation: Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Keiichi
authors.initials: K
authors.lastname: Tamai
authors.affiliation: Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Kazunori
authors.initials: K
authors.lastname: Yamaguchi
authors.affiliation: Department of Gastroenterology, Miyagi Cancer Center, Natori, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Oikawa
authors.affiliation: Department of Gastroenterology, Miyagi Cancer Center, Natori, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Noguchi
authors.affiliation: Department of Gastroenterological Surgery, Miyagi Cancer Center, Natori, Japan.
authors.forename: Koh
authors.initials: K
authors.lastname: Miura
authors.affiliation: Department of Gastroenterological Surgery, Miyagi Cancer Center, Natori, Japan.
authors.forename: Tsuneaki
authors.initials: T
authors.lastname: Fujiya
authors.affiliation: Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shima
authors.affiliation: Department of Pathology, Miyagi Cancer Center, Natori, Japan.
authors.forename: Ikuro
authors.initials: I
authors.lastname: Sato
authors.affiliation: Department of Microbiology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Murata-Kamiya
authors.affiliation: Department of Microbiology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Hatakeyama
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Katsunori
authors.initials: K
authors.lastname: Iijima
authors.affiliation: Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan.
authors.forename: Tooru
authors.initials: T
authors.lastname: Shimosegawa
authors.affiliation: Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan.
authors.forename: Kennichi
authors.identifier: http://orcid.org/0000-0003-1324-6387
authors.initials: K
authors.lastname: Satoh
mesh_terms: D000368:Aged; D000942:Antigens, Bacterial / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006019:Glycolysis / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics* / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics* / Q000378:metabolism; D013274:Stomach Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D013963:Thyroid Hormones / Q000235:genetics* / Q000378:metabolism*; D015854:Up-Regulation / Q000235:genetics; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D000942:Antigens, Bacterial; D001426:Bacterial Proteins; D002352:Carrier Proteins; D008565:Membrane Proteins; D020033:Protein Isoforms; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins; C080866:cagA protein, Helicobacter pylori
keywords: Aerobic glycolysis; CagA; cancer development; gastric cancer; pyruvate kinase