Function of a novel suppressor gene for melanoma development.

• Project/Area Number: 17K16358
• 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: Momoi Yuki 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 (10750440)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: carcinogenesis / プロテインホスファターゼ6型 / メラノーマ / Braf / Kras / プロテインホスファターゼ / 皮膚腫瘍学

Outline of Final Research Achievements

To address the function of protein phosphatase 6 (PP6) loss on K-ras-initiated tumorigenesis in keratinocytes, 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 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 of doubly-mutant versus K-rasG12D mice revealed that cell proliferation and cell size increased approximately two-fold relative to K-rasG12D-expressing mutants, and epidermal thickness of lip tissue greatly increased relative to that seen in K-rasG12D only mice. Ppp6c deficiency enhances K-rasG12D-dependent tumor promotion.

Academic Significance and Societal Importance of the Research Achievements

RAS変異は、ヒトのがんで最も高い頻度で同定される遺伝子変異である。RAS変異をもつ細胞が、他の遺伝子変異を蓄積することでより悪性度の高い腫瘍になると考えられる。一方で変異型RASに対する有効な治療法はいまだ開発されていない。考えられる治療法の1つは、変異型RASの悪性化を制御する因子を標的とした治療法である。本研究成果がそのような治療法の開発に繋がる可能性がある。

Research Products

• [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 Issue: 7 Pages: 2178-2187
  • DOI: 10.1111/cas.13638
  • Peer Reviewed / Open Access
• [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