Ppp6c functions as a tumor suppressor in skin carcinogenesis.

• Project/Area Number: 18K16043
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53050:Dermatology-related
• 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): 2018-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: プロテインホスファターゼ / Kras / Braf / メラノーマ / 皮膚腫瘍 / PP6 / 触媒サブユニット / ケラチノサイト / メラノサイト

Outline of Final Research Achievements

Recent DNA sequencing screens relevant to human cancer highlight the importance of PP6 in tumorigenesis. Somatic mutation of Ppp6c is reported in 20% of skin basal cell carcinoma, and 10% of malignant melanoma. Here, we examined the effect of Ppp6c loss on K-ras-induced proliferation in the context of keratinocyte tumorigenesis. We showed that Ppp6c deficiency enhances K-rasG12D-dependent tumor promotion. Nextly,
in order to analyze Ppp6c function in melanomagenesis, melanocyte specific inducible mutant mice which have BRAF(V600E) and Ppp6c loss were developed. The data using these mice suggested that loss of function of Ppp6c enhanced BRAF(V600E) initiated melanomagenesis in mice.

Academic Significance and Societal Importance of the Research Achievements

マウス皮膚２段階発がん実験で、貝毒オカダ酸が、皮膚がん腫瘍プロモーターとして働くことは、27年前に藤木博士により報告された。前後して、オカダ酸が脱リン酸化酵素の阻害剤であることが、高井博士により報告された。これらは、「皮膚がんにおいて、未同定の脱リン酸化酵素が、がん抑制作用を持つこと」を示唆していた。しかし、その脱リン酸化酵素は未同定のままだった。(174)

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
• [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] 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