Enhanced expression of the M2 isoform of pyruvate kinase is involved in gastric cancer development by regulating cancer‐specific metabolism |
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Authors: | Takeharu Shiroki Misa Yokoyama Nobuhiro Tanuma Ryuhei Maejima Keiichi Tamai Kazunori Yamaguchi Tomoyuki Oikawa Tetsuya Noguchi Koh Miura Tsuneaki Fujiya Hiroshi Shima Ikuro Sato Naoko Murata‐Kamiya Masanori Hatakeyama Katsunori Iijima Tooru Shimosegawa Kennichi Satoh |
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Institution: | 1. Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan;2. Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan;3. Division of Cancer Chemotherapy, Miyagi Cancer Center Research Institute, Natori, Japan;4. Division of Molecular and Cellular Oncology, Miyagi Cancer Center Research Institute, Natori, Japan;5. Department of Gastroenterology, Miyagi Cancer Center, Natori, Japan;6. Department of Gastroenterological Surgery, Miyagi Cancer Center, Natori, Japan;7. Department of Pathology, Miyagi Cancer Center, Natori, Japan;8. Department of Microbiology, Graduate School of Medicine and Faculty of Medicine, The University of Tokyo, Tokyo, Japan |
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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. |
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Keywords: | Aerobic glycolysis CagA cancer development gastric cancer pyruvate kinase |
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