Clarifying the significance of the shift to aerobic glycolysis and the role of mitochondrial function in kidney cancer development

• Project/Area Number: 15K14370
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Laboratory animal science
• Research Institution: Kumamoto University
• Principal Investigator: Baba Masaya 熊本大学, 国際先端医学研究機構, 准教授 (10347304)
• Co-Investigator(Renkei-kenkyūsha): SETOU MITSUTOSHI 浜松医科大学, 医学部, 教授 (20302664)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 腎細胞癌 / 糖代謝 / ミトコンドリア / マウスモデル / 腎がん / 疾患モデル

Outline of Final Research Achievements

Aerobic glycolysis predominates over mitochondrial oxidative phosphorylation in cancer. Cancer cells utilize this metabolic shift to aerobic glycolysis to drive proliferation and progression. However, the significance of this metabolic shift and the role of mitochondrial function during cancer development remains to be determined. Previously, we reported that mitochondrial biogenesis was upregulated with increased transcriptional activity of TFE3 in a rare type of hereditary renal cell carcinoma (RCC). This research aims to clarify the significance of the shift to aerobic glycolysis and the role of mitochondrial function in TFE3 translocation RCC, in which TFE3 transcriptional activity is constitutively activated by translocation. We have generated and analyzed a variety of TFE3-inducible stable cell lines and a mouse model of TFE3 translocation RCC, and found a potential function of ATP produced in the mitochondria as a signaling molecule which may contribute to cancer development.

Research Products

• [Int'l Joint Research] National Cancer Institute(米国)
• [Int'l Joint Research] McGill University(カナダ)
• [Int'l Joint Research] National University of Singapore(シンガポール)
• [Int'l Joint Research] 米国国立癌研究所(米国)
• [Int'l Joint Research] マギル大学(カナダ)
• [Int'l Joint Research] シンガポール国立大学(シンガポール)
• [Journal Article] Establishment and characterization of BHD-F59RSVT, an immortalized cell line derived from a renal cell carcinoma in a patient with Birt-Hogg-Dube syndrome (2017)
  • Author(s): Furuya M, Hasumi H, Baba M, Tanaka R, Iribe Y, Onishi T, Nagashima Y, Nakatani Y, Isono Y, Yao M.
  • Journal Title: Laboratory Investigation Volume: 97 Issue: 3 Pages: 343-351
  • DOI: 10.1038/labinvest.2016.137
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] H255Y and K508R missense mutations in tumour suppressor folliculin (FLCN) promote kidney cell proliferation. (2017)
  • Author(s): Hasumi H, Hasumi Y, Baba M, Nishi H, Furuya M, Vocke CD, Lang M, Irie N, Esumi C, Merino MJ, Kawahara T, Isono Y, Makiyama K, Warner AC, Haines DC, Wei MH, Zbar B, Hagenau H, Feigenbaum L, Kondo K, Nakaigawa N, Yao M, Metwalli AR, Marston Linehan W, Schmidt LS
  • Journal Title: Human Molecular Genetics Volume: 26 Pages: 354-366
  • DOI: 10.1093/hmg/ddw392
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Genetic, epidemiologic and clinicopathologic studies of Japanese Asian patients with Birt-Hogg-Dube syndrome. (2016)
  • Author(s): Furuya M, Yao M, Tanaka R, Nagashima Y, Kuroda N, Hasumi H, Baba M, Matsushima J, Nomura F, Nakatani Y
  • Journal Title: Clinical Genetics Volume: 90 Issue: 5 Pages: 403-412
  • DOI: 10.1111/cge.12807
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Chronic AMPK activation via loss of FLCN induces functional beige adipose tissue through PGC-1α/ERRα (2016)
  • Author(s): Yan M, Audet-Walsh E, Manteghi S, Rosa Dufour C, Walker B, Baba M, St-Pierre J, Giguere V, Pause A.
  • Journal Title: Genes & Development Volume: 30 Issue: 9 Pages: 1034-1046
  • DOI: 10.1101/gad.281410.116
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Loss of Folliculin Disrupts Hematopoietic Stem Cell Quiescence and Homeostasis Resulting in Bone Marrow Failure (2016)
  • Author(s): Baba M, Toyama H, Sun L, Takubo K, Suh HC, Hasumi H, Nakamura-Ishizu A, Hasumi Y, Klarmann KD, Nakagata N, Schmidt LS, Linehan WM, Suda T, Keller JR
  • Journal Title: Stem Cells Volume: 34 Issue: 4 Pages: 1068-1082
  • DOI: 10.1002/stem.2293
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Birt-Hogg-Dubé syndrome: Clinical and molecular aspects of recently identified kidney cancer syndrome. (2015)
  • Author(s): Hasumi H, Baba M, Hasumi Y, Furuya M, Yao M.
  • Journal Title: Int J Urol Volume: 23 Issue: 3 Pages: 204-210
  • DOI: 10.1111/iju.13015
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] GPNMBはTFE3活性化腎細胞癌の診断マーカーとして有用である (2016)
  • Author(s): 馬場理也、古屋充子、蓮見壽史、加藤生真、長嶋洋治、黒田直人、高橋 渡、河野吉昭、元島宗信、矢尾正祐、江藤正俊
  • Organizer: 第68回西日本泌尿器科学会総会
  • Place of Presentation: 小倉
  • Year and Date: 2016-11-24
• [Presentation] Birt-Hogg-Dube症候群における腎癌の分子病理学的検討 (2016)
  • Author(s): 古屋 充子、入部 康弘、蓮見 壽史、馬場 理也、長嶋 洋治、加 藤 生真、中谷 行雄、矢尾 正祐
  • Organizer: 第75回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Birt-Hogg-Dube症候群患者腎癌における mTOR シグナル分子の 局在と発現レベルの解析 (2016)
  • Author(s): 川上 兼堂、入部 康弘、矢尾 正祐、蓮見 壽史、馬場 理也、長 嶋 洋治、中谷 行雄、古屋 充子
  • Organizer: 第75回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] Birt-Hogg-Dube症候群患者における腎がん以外の諸臓器腫瘍に関する病理学的検討 (2016)
  • Author(s): 中谷 行雄、矢尾 正祐、蓮見 壽史、長嶋 洋治、馬場 理也、野 村 文夫、加藤 生真、古屋 充子
  • Organizer: 第75回日本癌学会
  • Place of Presentation: 横浜
  • Year and Date: 2016-10-06
• [Presentation] GPNMBはTFE3活性化腎細胞癌の診断マーカーとして有用である (2016)
  • Author(s): 馬場理也、古屋充子、蓮見壽史、黄 瑩、加藤生真、Martin Lang、長嶋洋治、黒田直人、入江信子、江角千晴、羽野博之、高橋渡、河野吉昭、杉山豊、田上憲一郎、山口隆大、Laura S. Schmidt、江藤正俊、中谷行雄、矢尾正祐、W. Marston Linehan
  • Organizer: 第47回腎癌研究会
  • Place of Presentation: 東京
• [Presentation] 腎癌抑制遺伝子ＦＬＣＮにおけるミスセンス変異の病原性についての検討 (2016)
  • Author(s): 蓮見壽史、馬場理也、古谷充子、矢尾正祐
  • Organizer: 第47回腎癌研究会
  • Place of Presentation: 東京
• [Presentation] Clarification of the molecular mechanism for cancer development in Xp11.2 translocation renal cell carcinoma. (2015)
  • Author(s): 馬場理也, 黄 瑩, 蓮見壽史, 矢尾正祐, 長嶋洋治, 古屋充子, 尾池雄一, 江藤正俊, Laura S Schmidt, W Marston Linehan
  • Organizer: 第74回日本癌学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-08
• [Presentation] 腎癌の代謝径路におけるFLCN/FNIP1/FNIP2遺伝子群の重要性 (2015)
  • Author(s): 蓮見壽史， 馬場理也，古屋充子， 矢尾正祐
  • Organizer: 第74回日本癌学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-08
• [Presentation] Birt-Hogg-Dube症候群における肺腫瘍発生の病理学的検討 (2015)
  • Author(s): 中谷行雄, 奥寺康司, 入部康弘, 矢尾正祐, 蓮見壽史, 長嶋洋治, 馬場理也, 野村文夫, 古屋充子
  • Organizer: 第74回日本癌学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-08
• [Presentation] Birt-Hogg-Dube症候群100家系における臨床病理像の特徴と腎癌およびその他の悪性腫瘍発症率の検討 (2015)
  • Author(s): 古屋充子, 入部康弘, 矢尾正祐, 蓮見壽史, 長嶋洋治, 馬場理也, 野村文夫, 中谷行雄
  • Organizer: 第74回日本癌学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-08
• [Presentation] Birt-Hogg-Dube症候群に発症する腎癌の臨床病理像, 遺伝子変異および網羅的染色体解析 (2015)
  • Author(s): 入部康弘, 矢尾正祐, 蓮見壽史, 長嶋洋治, 馬場理也, 野村文夫, 中谷行雄, 古屋充子
  • Organizer: 第74回日本癌学会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-10-08
• [Presentation] Folliculin-interacting protein, FNIP1および2の腎臓における役割 (2015)
  • Author(s): 蓮見壽史， 馬場理也，古屋充子， 矢尾正祐
  • Organizer: 第80回日本泌尿器科学会東部総会
  • Place of Presentation: 東京都
  • Year and Date: 2015-09-25
• [Presentation] Xp11.2 translocation RCC mouse model. (2015)
  • Author(s): Baba M, Huang Y, Hasumi H, Furuya M, Hasumi Y, Yao M, Schmidt LS, Linehan WM．
  • Organizer: 6th BHD Symposium
  • Place of Presentation: Syracuse, U.S.A.
  • Year and Date: 2015-09-23
  • Int'l Joint Research
• [Presentation] Xp11.2転座腎細胞癌発癌機構の解明 (2015)
  • Author(s): 馬場 理也，蓮見 壽史，黄 瑩，入江 信子，長嶋 洋治，矢尾 正祐，江藤 正俊，尾池 雄一，須田 年生，W. Marston Linehan
  • Organizer: 第46回腎癌研究会
  • Place of Presentation: 東京都
  • Year and Date: 2015-07-19
• [Presentation] FLCN結合蛋白FNIP1およびFNIP2の腎臓における役割 (2015)
  • Author(s): 蓮見壽史，馬場理也，古屋充子，矢尾正祐
  • Organizer: 第46回腎癌研究会
  • Place of Presentation: 東京都
  • Year and Date: 2015-07-19
• [Presentation] 癌抑制遺伝子産物FLCNの生体における多様な働き (2015)
  • Author(s): 馬場 理也
  • Organizer: 第10回 Biomedical Frontier TOKAI
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-07-10
• [Presentation] BHD 症候群関連腎癌の発生メカニズムの解析 (2015)
  • Author(s): 蓮見壽史，馬場理也，古屋充子，矢尾正祐
  • Organizer: 第21回日本家族性腫瘍学会学術集会
  • Place of Presentation: 埼玉市
  • Year and Date: 2015-06-05
• [Book] Renal Cell Carcinoma - Molecular Features and Treatment Updates(分担執筆, Chapter 2; Hereditary Renal Cell Carcinoma) (2017)
  • Author(s): Baba M, Schmidt LS, Linehan WM
  • Total Pages: 64
  • Publisher: Springer
• [Book] Year Book of RCC 2016 (分担執筆,がんの不均一性と進化・進展) (2017)
  • Author(s): 馬場理也、江藤正俊
  • Total Pages: 11
  • Publisher: メディカルビュー社
• [Book] 実験医学 (分担執筆, 腎がん発生の分子メカニズムー腎がん研究からわかってきたがんの病態基盤ー) (2016)
  • Author(s): 馬場理也
  • Total Pages: 6
  • Publisher: 羊土社
• [Remarks]
  • URL: http://researchmap.jp/7000016636/
• [Remarks]
  • URL: http://ircms.kumamoto-u.ac.jp/publications/2016/06/loss-of-folliculin-disrupts-hematopoietic-stem-cell-quiescence-and-homeostasis-resulting-in-bone-mar-1.html
• [Remarks]
  • URL: http://ircms.kumamoto-u.ac.jp/