Clarification of the multistage carcinogenesis and basis of the innovative therapeutics for Renal Cell Carcinoma

• Project/Area Number: 15H04975
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• 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(Kenkyū-buntansha): 江藤 正俊 九州大学, 大学病院, 教授 (90315078) ; 矢尾 正祐 横浜市立大学, 医学研究科, 教授 (00260787) ; 長嶋 洋治 東京女子医科大学, 医学部, 教授 (10217995) ; 古屋 充子 横浜市立大学, 医学部, 准教授 (10361445)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥16,640,000 (Direct Cost: ¥12,800,000、Indirect Cost: ¥3,840,000); Fiscal Year 2017: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2016: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2015: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 腎細胞癌 / がん抑制遺伝子 / Birt-Hogg-Dube症候群 / 転座型腎細胞癌 / 発がん分子機構 / FLCN / 多段階発癌 / フォワードジェネティクス / マウスモデル / BHD症候群 / 転座腎細胞癌 / ドライバー遺伝子 / 腎がん / 転座腎がん

Outline of Final Research Achievements

In this study, we focused on two kinds of renal cell carcinoma (RCC), BHD associated RCC whose responsible gene is a tumor suppressor FLCN, and Xp11.2 translocation RCC (tRCC) that expresses chimeric TFE3 produced by Xp11.2 translocation. We utilized genetically engineered mice, human RCC tissues and cell lines to study molecular mechanisms for RCC development, identify driver gene mutations, and develop new diagnostic markers or therapeutics for RCC. We clarified that FLCN altered intracellular signaling through the regulation of cellular metabolism. We then demonstrated that chromatin remodeling genes were frequently mutated in BHD associated RCC. We also demonstrated that chimeric TFE3 proteins worked as oncogenic transcription factors by acquiring altered functions. Finally, we identified a diagnostic marker for tRCC and confirmed its efficacy using human tRCC samples.

Research Products

• [Int'l Joint Research] National Cancer Institute(米国)
• [Int'l Joint Research] National University of Singapore(Singapore)
• [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] Folliculin regulates osteoclastogenesis through metabolic regulation (2018)
  • Author(s): Baba M, Endoh M, Ma W, Toyama H, Hirayama A, Nishikawa K, Takubo K, Hano H, Hasumi H, Umemoto T, Hashimoto M ,Irie N, Esumi C, Kataoka M, Nakagata N, Soga T, Yao M, Kamba T, Minami T, Ishii M, Suda T
  • Journal Title: Journal of Bone and Mineral Research Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of variants in chromatin remodeling genes (2018)
  • Author(s): Hasumi H., Furuya M, Tatsuno K, Yamamoto S, Baba M, Hasumi Yukiko, Isono Yasuhiro, Suzuki K, Jikuya R, Otake S, Muraoka K, Osaka K, Hayashi N, Makiyama K, Miyoshi Y, Kondo K, Nakaigawa N, Kawahara T, Izumi K, Teranishi J, Yumura Y, Uemura H, Nagashima Y, Metwalli A.R., Schmidt L.S., Aburatani H, Linehan W.M., Yao M.
  • Journal Title: Human Molecular Genetics Volume: 印刷中
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Splice-site mutation causing partial retention of intron in the FLCN gene in Birt- Hogg-Dube syndrome: a case report (2018)
  • Author(s): Furuya M, Kobayashi H, Baba M, Ito T, Tanaka R, Nakatani Y
  • Journal Title: BMC Medical Genomics Volume: 42 Issue: 1 Pages: 42-42
  • DOI: 10.1186/s12920-018-0359-5
  • Peer Reviewed / Open Access
• [Journal Article] Review of hereditary leiomyomatosis renal cell carcinoma with focus on clinical and pathobiological aspects of renal tumor (2017)
  • Author(s): Kuroda N, Ohe C, Kato I, Furuya M, Baba M, Nagashima Y, Nakatani Y, Murakami I, Zhou M, Michal M, He O, Amin MB
  • Journal Title: Pol J Pathol Volume: 68 Issue: 4 Pages: 284-290
  • DOI: 10.5114/pjp.2017.73920
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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] Xp11.2転座型腎細胞癌で認めるキメラTFE3転写因子の機能解析 (2018)
  • Author(s): 馬場理也、元島崇信、馬文娟、蓮見壽史 黄瑩、佐藤賢文、宮里パオラ、倉橋竜馬、 長嶋洋治、古屋充子、矢尾正祐 尾池雄一、神波大己
  • Organizer: 第106回日本泌尿器科学会総会
• [Presentation] BHD-associated kidney cancer exhibits unique molecular characteristics and a wide variety of mutations in chromatin remodeling genes (2018)
  • Author(s): Jikuya R, Furuya M, Baba M, Aburatani H, Metwalli AR, Schmidt LS, Linehan M, Yao M, Hasumi H
  • Organizer: American Association for Cancer Research Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Characterization of chimeric TFE3 transcription factors found in Xp11.2 translocation renal cell carcinoma (2018)
  • Author(s): Motoshima T, Satou Y, Miyazato P, Hasumin H, Huang Y, Kadomatsu T, Yao M, Nagashima Y, Furuya M, Oike Y, Schmidt L.S., Kamba T, Linehan W.M., Baba M
  • Organizer: American Urological Association Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] The role of hypoxia pathway in TFE3 translocation Renal Cell Carcinoma (RCC) (2018)
  • Author(s): Ma W, Motoshima T, Satou Y, Miyazato P, Hasumi H, Huang Y, Kadomatsu T, Kurahashi R, Nakagata N, Oike Y, Schmidt L.S., Kamba T, Linehan W.M., Baba M
  • Organizer: 2nd Kumamoto IRCMS Symposium
  • Int'l Joint Research
• [Presentation] Essential role of tumor suppressor Flcn in the regulation of cell proliferation and differentiation through metabolism (2018)
  • Author(s): Masaya Baba
  • Organizer: 2nd Kumamoto IRCMS Symposium
  • Int'l Joint Research
• [Presentation] 遺伝性腎癌症候群～その歴史と医学への貢献～ (2017)
  • Author(s): 馬場理也
  • Organizer: 日本生理人類学会第76 回大会
  • Invited
• [Presentation] Characterization of chimeric TFE3 transcription factors found in Xp11.2 translocation renal cell carcinoma (2017)
  • Author(s): Takanobu Motoshima, Hisashi Hasumi, Huang Ying, Yorifumi Sato, Paola Miyazato, Masahiro Yao, Yoji Nagashima, Mitsuko Furuya, Yuchi Oike, Tomomi Kamba, S Schmidt Laura, Lineha W Marston, Masaya Baba
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Presentation] Molecular Characteristics of Renal Cell Carcinomas in Patients with Birt-Hogg-Dube Syndrome (2017)
  • Author(s): Mitsuko Furuya, Hasumi Hisashi, Ikuma Kato, Masaya Baba, Yoji Nagashima, Yasuhiro Iribe, Yukio Nakatani, Masahiro Yao
  • Organizer: The 76th Annual Meeting of the Japanese Cancer Association
• [Presentation] BHD関連腎癌の発癌機構解析 (2017)
  • Author(s): 蓮見壽史、古屋充子、馬場理也、近藤慶一、中井川昇、山本尚吾、辰野健一、油谷浩幸、矢尾正祐
  • Organizer: 第48回腎癌研究会
• [Presentation] Sleeping Beauty transposon mutagenesisによるマウス腎癌関連ゲノム変異の解析 (2017)
  • Author(s): 馬場理也、元島崇信、入江信子、江角千晴、中潟直己、神波大己
  • Organizer: 第48回腎癌研究会
• [Presentation] Xp11転座型腎癌と診断された２症例のレトロスペクティブな解析 (2017)
  • Author(s): 元島崇信、西澤秀和、馬場理也、古屋充子、加藤生真、神波大己
  • Organizer: 第48回腎癌研究会
• [Presentation] Xp11.2転座腎細胞癌における発癌分子機構の解明 (2017)
  • Author(s): 馬場理也、元島崇信、蓮見壽史、黄瑩、Laura S. Schmidt、矢尾正祐、長嶋洋治、古屋充子、尾池雄一、江藤正俊、神波大己、W. Marston Linehan
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] TFE3活性化腎細胞癌の診断補助マーカーの探索と評価 (2017)
  • Author(s): 元島宗信、馬場理也、蓮見壽史、加藤生真、長嶋洋治、黒田直人、高橋 渡、河野吉昭、矢尾正祐、江藤正俊、神波大己、古屋充子
  • Organizer: 第105回日本泌尿器科学会総会
• [Presentation] Clarification of the molecular mechanism for cancer development in Xp11.2 translocation renal cell carcinoma (2017)
  • Author(s): Masaya Baba, Ying Huang, Takanobu Motoshima, Hisashi Hasumi, Mitsuko Furuya, Yukiko Hasumi, Masahiro Yao, Yuichi Oike, Tomomi Kamba, Laura S. Schmidt, W. Marston Linehan
  • Organizer: American Association for Cancer Research Annual Meeting 2017
  • 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] 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] 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] 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, Chapter: Hereditary Renal Cell Carcinoma (2017)
  • Author(s): Masaya Baba, Laura S. Schmidt, W. Marston Linehan
  • Total Pages: 381
  • Publisher: Springer
  • ISBN: 9784431555308
• [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://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://researchmap.jp/7000016636/