RRC ID 61542
Author Shiroki T, Yokoyama M, Tanuma N, Maejima R, Tamai K, Yamaguchi K, Oikawa T, Noguchi T, Miura K, Fujiya T, Shima H, Sato I, Murata-Kamiya N, Hatakeyama M, Iijima K, Shimosegawa T, Satoh K.
Title Enhanced expression of the M2 isoform of pyruvate kinase is involved in gastric cancer development by regulating cancer-specific metabolism.
Journal Cancer Sci
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.
Volume 108(5)
Pages 931-940
Published 2017-5
DOI 10.1111/cas.13211
PMID 28235245
PMC PMC5448664
MeSH Aged Antigens, Bacterial / genetics Bacterial Proteins / genetics Carrier Proteins / genetics* Carrier Proteins / metabolism* Cell Line, Tumor Cell Movement / genetics Cell Proliferation / genetics Female Gene Expression Regulation, Neoplastic / genetics Glycolysis / genetics Humans Liver Neoplasms / genetics Liver Neoplasms / metabolism Liver Neoplasms / pathology MAP Kinase Signaling System / genetics Male Membrane Proteins / genetics* Membrane Proteins / metabolism* Protein Isoforms / genetics* Protein Isoforms / metabolism Stomach Neoplasms / genetics* Stomach Neoplasms / metabolism Stomach Neoplasms / pathology Thyroid Hormones / genetics* Thyroid Hormones / metabolism* Up-Regulation / genetics
Human and Animal Cells MKN7(RCB0999) MKN45(RCB1001) MKN74(RCB1002) Kato III(RCB2088)