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Tumorigenesis due to dysfunction of PP6, a novel target for cancer treatment.

Research Project

Project/Area Number 17K07187
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Tumor biology
Research InstitutionMiyagi Prefectural Hospital Organization Miyagi Cancer Center

Principal Investigator

Shima Hiroshi  地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), がん薬物療法研究部, 部長 (10196462)

Co-Investigator(Kenkyū-buntansha) 佐藤 郁郎  地方独立行政法人宮城県立病院機構宮城県立がんセンター(研究所), ティッシュバンクセンター, 部長 (50225918)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2019: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Keywordsプロテインホスファターゼ / Kras / セリン・スレオニンプロテインホスファターゼ6型 / イニシエーション / プロモーション / 皮膚がん / PP6 / メラノーマ / 発がん
Outline of Final Research Achievements

Here, we address the function of protein phosphatase 6 (PP6) loss on K-ras-initiated tumorigenesis in keratinocytes. To do so, we developed tamoxifen-inducible double mutant (K-rasG12D-expressing and Ppp6c-deficient) mice in which K-rasG12D expression is driven by the cytokeratin 14 (K14) promoter. Doubly-mutant mice showed early onset tumor formation in lip, nipples, external genitalia, anus and palms, and had to be sacrificed by three weeks after induction by tamoxifen, while comparably-treated K-rasG12D-expressing mice did not. HE-staining of lip tumors before euthanasia revealed that all were papillomas, some containing focal squamous cell carcinoma. Immunohistochemical analysis of lip tumor suggested that protein synthesis and survival signals are enhanced in lip tissues of doubly-mutant mice. We also developed melanocyte specific tamoxifen-inducible double mutant (BRAFV600E-expressing and Ppp6c-deficient) mic mice to address the function of PP6 in melanogenesis. (984)

Academic Significance and Societal Importance of the Research Achievements

プロテインキナーゼの異常が発がんの原因となっていることは明らかである。一方で、ホスファターゼが原因となる発がんに関しては研究が遅れていた。申請者は、PP6ホスファターゼ (Ppp6c)遺伝子を 皮膚特異的に欠損するマウスを作製し、DMBA処理や紫外線照射により腫瘍が高率に発生する事を見いだした。本研究は、これまでの研究の継続として、Ppp6cと発がんとの関連を明らかにすることである。(193)

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report

Research Products

(23 results)

All 2020 2018 2017

All Journal Article (11 results) (of which Int'l Joint Research: 3 results,  Peer Reviewed: 11 results,  Open Access: 7 results,  Acknowledgement Compliant: 1 results) Presentation (12 results) (of which Int'l Joint Research: 4 results)

  • [Journal Article] Divergent metabolic responses dictate vulnerability to NAMPT inhibition in ovarian cancer2020

    • Author(s)
      Kudo Kei、Nomura Miyuki、Sakamoto Yoshimi、Ito Shigemi、Morita Mami、Kawai Masaaki、Yamashita Yoji、Ito Kiyoshi、Yamada Hidekazu、Shima Hiroshi、Yaegashi Nobuo、Tanuma Nobuhiro
    • Journal Title

      FEBS Lett.

      Volume: 594 Pages: 1379-1388

    • DOI

      10.1002/1873-3468.13736

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Novel activating KRAS mutation candidates in lung adenocarcinoma2020

    • Author(s)
      Abe Jiro、Tanuma Nobuhiro、Nomura Miyuki、Ito Shin、Kasugai Isao、Sato Ikuro、Tamai Keiichi、Mochizuki Mai、Yamaguchi Kazunori、Shima Hiroshi、Okada Yoshinori、Yasuda Jun
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 522 Pages: 690-696

    • DOI

      10.1016/j.bbrc.2019.11.151

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Loss of protein phosphatase 6 in mouse keratinocytes enhances K-ras G12D -driven tumor promotion2018

    • Author(s)
      Kurosawa Koreyuki、Inoue Yui、Kakugawa Yoichiro、Yamashita Yoji、Kanazawa Kosuke、Kishimoto Kazuhiro、Nomura Miyuki、Momoi Yuki、Sato Ikuro、Chiba Natsuko、Suzuki Mai、Ogoh Honami、Yamada Hidekazu、Miura Koh、Watanabe Toshio、Tanuma Nobuhiro、Tachi Masahiro、Shima Hiroshi
    • Journal Title

      Cancer Science

      Volume: 109 Pages: 2178-2187

    • DOI

      10.1111/cas.13638

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] PKM1 Confers Metabolic Advantages and Promotes Cell-Autonomous Tumor Cell Growth.2018

    • Author(s)
      M Morita, T Sato, M Nomura, Y Sakamoto, Y Inoue, R Tanaka, S Ito, K Kurosawa, K Yamaguchi, Y Sugiura, H Takizaki, Y Yamashita, R Katakura, I Sato, Y Okada, H Watanabe, G Kondoh, et al.
    • Journal Title

      Cancer Cell

      Volume: 12 Pages: 355-367

    • DOI

      10.1016/j.ccell.2018.02.004

    • Related Report
      2018 Research-status Report 2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of protein phosphatase 6 in mouse keratinocytes enhances K-rasG12D-driven tumor promotion.2018

    • Author(s)
      Kurosawa K, Inoue Y, Kakugawa Y, Yamashita Y, Kanazawa K, Kishimoto K, Nomura M, Momoi Y, Sato I, Chiba N, Suzuki M, Ogoh H, Yamada H, Miura K, Watanabe T, Tanuma N, Tachi M, and Shima H
    • Journal Title

      Cancer Science

      Volume: 印刷中

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] Ex vivo model of non-small cell lung cancer using mouse lung epithelial cells.2017

    • Author(s)
      Sato T, Morita M, Tanaka R, Inoue Y, Nomura M, Sakamoto Y, Miura K, Ito S, Sato I, Tanaka N, Abe J, Takahashi S, Kawai M, Sato M, Hippo Y, Shima H, Okada Y, Tanuma N
    • Journal Title

      Oncol Lett

      Volume: 14(6) Pages: 6863-6868

    • DOI

      10.3892/ol.2017.7098

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics2017

    • Author(s)
      Akaike Takaaki、、、Nishida Motohiro(4)、、、、、、Fujii Shigemoto(20)、、、Motohashi Hozumi(26)
    • Journal Title

      Nature Commun

      Volume: 8 Pages: 1-10

    • DOI

      10.1038/s41467-017-01311-y

    • NAID

      120007134656

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Sialidase NEU3 defines invasive potential of human glioblastoma cells by regulating calpain-mediated proteolysis of focal adhesion proteins2017

    • Author(s)
      Takahashi Kohta、Proshin Sergei、Yamaguchi Kazunori、Yamashita Yoji、Katakura Ryuichi、Yamamoto Koji、Shima Hiroshi、Hosono Masahiro、Miyagi Taeko
    • Journal Title

      Biochimica et Biophysica Acta (BBA) - General Subjects

      Volume: 1861 Pages: 2778-2788

    • DOI

      10.1016/j.bbagen.2017.07.023

    • Related Report
      2017 Research-status Report
    • Peer Reviewed
  • [Journal Article] A-kinase anchoring protein BIG3 coordinates oestrogen signalling in breast cancer cells.2017

    • Author(s)
      Yoshimaru T, Ono M, Bando Y, Chen YA, Mizuguchi K, Shima H, Komatsu M, Imoto I, Izumi K, Honda J, Miyoshi Y, Sasa M, Katagiri T
    • Journal Title

      Nature Communications

      Volume: 印刷中 Pages: 15427-15427

    • DOI

      10.1038/ncomms15427

    • NAID

      120006535065

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Journal Article] Drug delivery of oral anti-cancer fluoropyrimidine agents.2017

    • Author(s)
      Miura K, Shima H, Takebe N, Julie R, Satoh K, Kakugawa Y, Satoh M, Kinouchi M, Yamamoto K, Hasegawa Y, Kawai M, Kanazawa K, Fujiya T, Unno M and Katakura R.
    • Journal Title

      Expert Opinion on Drug Delivery

      Volume: 印刷中 Pages: 1-12

    • DOI

      10.1080/17425247.2017.1316260

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Enhanced expression of PKM2 is involved in the gastric cancer development via regulating cancer specific metabolism.2017

    • Author(s)
      Shiroki T, Yokoyama M, Tanuma N, Maejima R, Tamai K, Yamaguchi K, Oikawa T, Noguchi T, Miura K, Fujiya T, Shima H, Sato I, Kamiya N, Hatakeyama M, Iijima K, Shimosegawa T and Satoh K.
    • Journal Title

      Cancer Sci

      Volume: 印刷中 Pages: 931-940

    • DOI

      10.1111/cas.13211

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] プロテインホスファターゼPP6の機能不全は、ケラチノサイトにおいて、変異型K-rasで誘導される腫瘍化を著しく亢進させる2018

    • Author(s)
      岸本和大、金澤孝祐、井上維、田沼延公、島礼
    • Organizer
      生化学会東北支部会
    • Related Report
      2018 Research-status Report
  • [Presentation] 13Cグルコースを使ったマウス個体でのin vivoトレーサー解析2018

    • Author(s)
      田沼延公,、野村美有樹、福原達郎、坂本良美、島礼、本橋ほづみ、紙健次郎
    • Organizer
      生化学会東北支部会
    • Related Report
      2018 Research-status Report
  • [Presentation] 活性型Pkm1-Pkm2ヘテロ複合体の形成2018

    • Author(s)
      野村美有樹、盛田麻美、坂本良美、島礼、田沼延公
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report
  • [Presentation] Loss of protein phosphatase 6 in mouse keratinocytes enhances K-rasG12D-driven tumor promotion.2018

    • Author(s)
      Kosuke Kanazawa, Kazuhiro Kishimoto, Yui Inoue, Koh Miura, Nobuhiro Tanuma, and Hiroshi Shima
    • Organizer
      Mechanisms & Models of Cancer
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Tie2-Cre Induced Tissue Specific Deletion of Ppp6c Caused Abnormal Hematopoiesis during Mouse Embryogenesis.2018

    • Author(s)
      Kato Rika, Ogoh Honami, Kishimoto Ayako, Suzuki Mai, Tanuma Nobuhiro, Shima Hiroshi and Watanabe Toshio
    • Organizer
      ICPP13, Workshop on Frontiers in Phosphatase Research and Drug Discovery
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Tissue Specific Deletion of Protein Phosphatase 6 Catalytic Subunit (Ppp6c) Caused Embryonic lethality and postnatal death.2018

    • Author(s)
      Watanabe Toshio, Kato Rika, Ogoh Honami, Kishimoto Ayako, Suzuki Mai, Tanuma Nobuhiro, and Shima Hiroshi
    • Organizer
      ICPP13, Workshop on Frontiers in Phosphatase Research and Drug Discovery
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Tumor suppressor activity of protein phosphatase 6.2018

    • Author(s)
      Kurosawa Koreyuki, Kakugawa Yoichiro , Tanuma Nobuhiro , Watanabe Toshio, and Shima Hiroshi
    • Organizer
      ICPP13, Workshop on Frontiers in Phosphatase Research and Drug Discovery
    • Related Report
      2018 Research-status Report
    • Int'l Joint Research
  • [Presentation] Ppp6c は、マウス皮膚のがん抑制遺伝子として働く2017

    • Author(s)
      黒沢是之、野村美有樹、角川陽一郎、山下洋二、三浦康、山田秀和、松浦一登、佐藤郁郎、田沼延公、渡邊利雄、島礼
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] 肺神経内分泌腫瘍(NET)における治療標的候補としてのPkm12017

    • Author(s)
      盛田麻美、野村美有樹、坂本良美、佐藤卓、田中遼太、福原達朗、佐藤郁郎、中山敬一、前門戸任、島礼、田沼延公
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] Pkm1 とPkm2 の機能解析-非小細胞肺がん(NSCLC)での検討2017

    • Author(s)
      野村美有樹、佐藤卓、盛田麻美、坂本良美、田中遼太、三浦康、河合賢朗、佐藤郁郎、島礼、田沼延公
    • Organizer
      第76回日本癌学会学術総会
    • Related Report
      2017 Research-status Report
  • [Presentation] [1AT26-15(1P-0063)] 形質膜シアリダーゼNEU3によるEGFRシグナリングの調節機構2017

    • Author(s)
      山本 晃司、高橋 耕太、塩崎 一弘、山口 壹範、島 礼、宮城 妙子
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report
  • [Presentation] [3PT04-01(3P-0454)] オートファジーによるtype 2A protein phosphataseの制御機構の解明2017

    • Author(s)
      藤原 信行、渋谷 周作、坂井 祐介、島 礼、渡邊 利雄、大島 浩子、大島 正伸、齋藤 達哉、審良 静男、永野 浩昭、臼井 達哉、大浜 剛、佐藤 晃一
    • Organizer
      第40回日本分子生物学会年会
    • Related Report
      2017 Research-status Report

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Published: 2017-04-28   Modified: 2021-02-19  

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