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

• Project/Area Number: 17K07187
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor biology
• Research Institution: Miyagi 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: ¥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)

Research Products

• [Journal Article] Divergent metabolic responses dictate vulnerability to NAMPT inhibition in ovarian cancer (2020)
  • 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
  • Peer Reviewed
• [Journal Article] Novel activating KRAS mutation candidates in lung adenocarcinoma (2020)
  • 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
  • Peer Reviewed
• [Journal Article] Loss of protein phosphatase 6 in mouse keratinocytes enhances K-ras G12D -driven tumor promotion (2018)
  • 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
  • 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
  • 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
  • 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
  • Peer Reviewed / Open Access
• [Journal Article] Cysteinyl-tRNA synthetase governs cysteine polysulfidation and mitochondrial bioenergetics (2017)
  • 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
  • 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 proteins (2017)
  • 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
  • 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
  • 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
  • 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
  • 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
• [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
• [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
• [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
  • 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
  • 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
  • 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
  • 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
• [Presentation] 肺神経内分泌腫瘍（NET）における治療標的候補としてのPkm1 (2017)
  • 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
• [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
• [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
• [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