Ppp6c deletion promotes mutated RAS-initiated tumor formation in keratinocytes.

• Project/Area Number: 16K19745
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Miyagi Prefectural Hospital Organization Miyagi Cancer Center
• Principal Investigator: INOUE Yui 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, 共同研究員 (30750442)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: プロテインホスファターゼ / Kras / 皮膚腫瘍学

Outline of Final Research Achievements

To assess effects of PP6 loss on activated K-ras-induced tumorigenesis in keratinocytes, we established K14-CreERtam/LSL-K-rasG12D/Ppp6cflox/flox mice (exhibiting epidermal-specific tamoxifen-inducible K-rasG12D expression plus Ppp6c deficiency) and K14-CreERtam/LSL-K-rasG12D mice (which showed only epidermal-specific tamoxifen-inducible K-rasG12D expression). Ten independent 4HT-treated K14-CreERtam/LSL-K-rasG12D/Ppp6cflox/flox mice developed lip tumors. Microscopic analysis of lip tumor tissue from the mouse indicated hyperkeratotic papillomatous proliferative lesions. It is noteworthy that a region of squamous cell carcinoma in situ (CIS) sacrificed between days 16 to 20. To examine lip epidermis growth, we measured tissue thickness at 4, 8 and 12 days after 4HT injection. The ratio of lip thickness of K14-CreERtam/LSL-K-rasG12D/Ppp6cflox/flox to that of K14-CreERtam/LSL-K-rasG12D mice was 2.3, 24 and 42, at days 4, 8 and 12, respectively.

Research Products

• [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] 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] 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
• [Presentation] Functional analysis of the pyruvate kinase M(Pkm) isoforms by transformation experiments of mouse lungs epithelia cells (2016)
  • Author(s): 佐藤卓、坂本良美、野村美有樹、井上維、盛田麻美、田中遼太、渡邊利雄、佐藤郁郎、島礼、岡田克典、田沼延公
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: 神奈川県・横浜市
  • Year and Date: 2016-10-06
• [Presentation] 遺伝子改変肺上皮細胞を用いた形質転換実験による、代謝酵素Pkmの機能解析 (2016)
  • Author(s): 佐藤卓、坂本良美、野村美有樹、井上維、盛田麻美、田中遼太、渡邊利雄、佐藤郁郎、島礼、岡田克典、田沼延公
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 宮城県・仙台市
  • Year and Date: 2016-09-25
• [Presentation] Pyruvate kinase Mの両isoformを欠損するマウスの解析 (2016)
  • Author(s): 田中遼太、小河穂波、井上維、山下洋二、三浦康、河合賢郎、佐藤郁郎、渡邊利雄、島礼、田沼延公
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 宮城県・仙台市
  • Year and Date: 2016-09-25
• [Presentation] 発がんプロモーターオカダ酸の標的、PP6の皮膚がん抑制遺伝子としての意義 (2016)
  • Author(s): 島礼、黒沢是之、小河穂波、桃井勇貴、井上維、田沼延公、渡邊利雄
  • Organizer: 第89回日本生化学会大会
  • Place of Presentation: 宮城県・仙台市
  • Year and Date: 2016-09-25