The research for developing a method for controlling cancer invasion and metastasis by elucidating the mechanism of cancer metabolic change

• Project/Area Number: 17K08663
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: University of Occupational and Environmental Health, Japan (2018-2019); Kumamoto University (2017)
• Principal Investigator: Endo Motoyoshi 産業医科大学, 医学部, 教授 (40398243)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 肺癌 / 癌浸潤・転移 / 癌代謝 / ANGPTL2 / GLUT3 / ZEB1 / miR-204-5p / c-Myc / IL-6 / TET2 / 癌

Outline of Final Research Achievements

It is known that the change of energy metabolism from oxidative phosphorylation to glycolysis in cancer cells promotes tumor aggressiveness and malignancy. In this study, we showed that tumor cell-derived ANGPTL2 upregulated expression of GLUT3 and activated glycolytic metabolism. ANGPTL2 signaling through integrin α5β1 increased GLUT3 expression through increasing TGF-β signaling and its downstream transcription factor ZEB1. ANGPTL2 knockdown in lung cancer cell lines decreased TGF-β, ZEB1 and GLUT3 expression and antagonized glycolytic metabolism. In addition, ANGPTL2 expression levels correlated with GLUT3 expression in primary tumor cells from lung cancer patients. Overall, tumor cell-derived ANGPTL2 expression promotes activities associated with glycolytic metabolism in lung cancer cells by activating TGF-β-ZEB1-GLUT3 signaling.

Academic Significance and Societal Importance of the Research Achievements

慢性炎症は様々な疾患の増悪因子であり、癌においても浸潤能や転移能を高めることが知られている。本研究では、慢性炎症因子の1つであるANGPTL2が肺癌細胞に作用すると、癌細胞の代謝が変化し癌細胞の悪性度（転移能や浸潤能の亢進）が高まることを明らかにした。肺癌患者のサンプルを用いた解析においても、in vitro実験の結果と同様の結果を得られていることから、肺癌細胞のANGPTL2発現抑制は癌浸潤・転移抑制につながることが示された。

Research Products

• [Journal Article] Tumor cell-derived angiopoietin-like protein 2 establishes a preference for glycolytic metabolism in lung cancer cells. (2020)
  • Author(s): Osumi H, Horiguchi H, Kadomatsu T, Tashiro K, Morinaga J, Takahashi T, Ikeda K, Ito T, Suzuki M, Endo M, Oike Y
  • Journal Title: Cancer Sci Volume: - Issue: 4 Pages: 1241-1253
  • DOI: 10.1111/cas.14337
  • Peer Reviewed / Open Access
• [Journal Article] The Roles of ANGPTL Families in Cancer Progression (2019)
  • Author(s): Endo M
  • Journal Title: Journal of UOEH Volume: 41 Issue: 3 Pages: 317-325
  • DOI: 10.7888/juoeh.41.317
  • NAID: 130007709766
  • ISSN: 0387-821X, 2187-2864
  • Year and Date: 2019-09-01
  • Peer Reviewed
• [Journal Article] Loss of Endogenous HMGB2 Promotes Cardiac Dysfunction and Pressure Overload-Induced Heart Failure in Mice (2019)
  • Author(s): Sato M, Miyata K, Tian Z, Kadomatsu T, Ujihara Y, Morinaga J, Horiguchi H, Endo M, Zhao J, Zhu S, Sugizaki T, Igata K, Muramatsu M, Minami T, Ito T, Bianchi ME, Mohri S, Araki K, Node K, Oike Y
  • Journal Title: Circulation Journal Volume: 83 Issue: 2 Pages: 368-378
  • DOI: 10.1253/circj.CJ-18-0925
  • NAID: 130007557092
  • ISSN: 1346-9843, 1347-4820
  • Year and Date: 2019-01-25
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] MiR-204-5p: a novel candidate urinary biomarker of Xp11.2 translocation renal cell carcinoma. (2019)
  • Author(s): Kurahashi R, Kadomatsu T, Baba M, Hara C, Itoh H, Miyata K, Endo M, Morinaga J, Terada K, Araki K, Eto M, Schmidt LS, Kamba T, Linehan WM, Oike Y.
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 6 Pages: 1897-1908
  • DOI: 10.1111/cas.14026
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] keratinocytes increase melanogenesis via ANGPTL2 induction, an activity antagonized by Chrysanthemum extract. (2019)
  • Author(s): Satou G, Maji D, Isamoto T, Oike Y, Endo M
  • Journal Title: Exp Dermatol Volume: 28 Issue: 2 Pages: 152-160
  • DOI: 10.1111/exd.13862
  • Peer Reviewed / Open Access
• [Journal Article] TET2-dependent IL-6 induction mediated by the tumor microenvironment promotes tumor metastasis in osteosarcoma. (2018)
  • Author(s): Itoh H, Kadomatsu T, Tanoue H, Yugami M, Miyata K, Endo M, Morinaga J, Kobayashi E, Miyamoto T, Kurahashi R, Terada K, Mizuta H, Oike Y.
  • Journal Title: Oncogene Volume: 印刷中 Issue: 22 Pages: 2903-2920
  • DOI: 10.1038/s41388-018-0160-0
  • Peer Reviewed / Open Access
• [Journal Article] Association of circulating ANGPTL 3, 4, and 8 levels with medical status in a population undergoing routine medical checkups: A cross-sectional study. (2018)
  • Author(s): Morinaga J, Zhao J, Endo M, Kadomatsu T, Miyata K, Sugizaki T, Okadome Y, Tian Z, Horiguchi H, Miyashita K, Maruyama N, Mukoyama M, Oike Y.
  • Journal Title: PLoS One Volume: 13 Issue: 3 Pages: e0193731-e0193731
  • DOI: 10.1371/journal.pone.0193731
  • Peer Reviewed / Open Access
• [Journal Article] Age-dependent increase in angiopoietin-like protein 2 accelerates skeletal muscle loss in mice. (2018)
  • Author(s): Zhao J, Tian Z, Kadomatsu T, Xie P, Miyata K, Sugizaki T, Endo M, Zhu S, Fan H, Horiguchi H, Morinaga J, Terada K, Yoshizawa T, Yamagata K, Oike Y.
  • Journal Title: J Biol Chem Volume: 293 Issue: 5 Pages: 1596-1609
  • DOI: 10.1074/jbc.m117.814996
  • Peer Reviewed / Open Access
• [Journal Article] Angiopoietin-like protein 2 promotes chondrogenic differentiation during bone growth as a cartilage matrix factor. (2018)
  • Author(s): Tanoue H, Morinaga J, Yoshizawa T, Yugami M, Itoh H, Nakamura T, Uehara Y, Masuda T, Odagiri H, Sugizaki T, Kadomatsu T, Miyata K, Endo M, Terada K, Ochi H, Takeda S, Yamagata K, Fukuda T, Mizuta H, Oike Y.
  • Journal Title: Osteoarthritis Cartilage Volume: 26 Issue: 1 Pages: 108-117
  • DOI: 10.1016/j.joca.2017.10.011
  • Peer Reviewed / Open Access
• [Journal Article] Circulating ANGPTL2 Levels Increase in Humans and Mice Exhibiting Cardiac Dysfunction (2018)
  • Author(s): Tian Z, Miyata K, Morinaga J, Horiguchi H, Kadomatsu T, Endo M, Zhao J, Zhu S, Sugizaki T, Sato M, Terada K, Okumura T, Murohara T, Oike Y.
  • Journal Title: Circulation Journal Volume: 82 Issue: 2 Pages: 437-447
  • DOI: 10.1253/circj.CJ-17-0327
  • NAID: 130006320284
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access
• [Journal Article] Treatment of diabetic mice with the SGLT2 inhibitor TA-1887 antagonizes diabetic cachexia and decreases mortality. (2017)
  • Author(s): Sugizaki T, Zhu S, Guo G, Matsumoto A, Zhao J, Endo M, Horiguchi H, Morinaga J, Tian Z, Kadomatsu T, Miyata K, Itoh H, Oike Y
  • Journal Title: NPJ Aging Mech Dis Volume: 3 Issue: 1 Pages: 12-12
  • DOI: 10.1038/s41514-017-0012-0
  • Peer Reviewed / Open Access
• [Journal Article] ANGPTL2 ― A New Causal Player in Accelerating Heart Disease Development in the Aging ― (2017)
  • Author(s): Oike Y, Tian Z, Miyata K, Morinaga J, Endo M, Kadomatsu T.
  • Journal Title: Circulation Journal Volume: 81 Issue: 10 Pages: 1379-1385
  • DOI: 10.1253/circj.CJ-17-0854
  • NAID: 130006099927
  • ISSN: 1346-9843, 1347-4820
  • Peer Reviewed / Open Access