Analysis of the cancer suppressor gene Ppp6c, which is frequently mutated in skin UV-induced cancer.

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K17365
• 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: Kato Hiroyuki 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 (90770347)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: メラノーマ / マウス発がん実験 / PP6 / BRAF / 紫外線

Outline of Final Research Achievements

According to the TCGA database, mutations in PPP6C are found in approximately 10% of tumors from melanoma patients, where they coexist with BRAF and NRAS mutations. To assess PP6 function in melanoma carcinogenesis, we generated mice in which we could specifically induce BRAF (V600E) expression and delete Ppp6c in melanocytes. In these mice, melanoma susceptibility following UVB irradiation exhibited the following pattern: Ppp6c semi-deficient > Ppp6c wild-type > Ppp6c-deficient tumor types. Next-generation sequencing of Ppp6c heterozygous and wild-type melanoma tumors revealed that all harbored Trp53 mutations. Analysis of cell lines derived from either Ppp6c heterozygous or wild-type melanoma tissues showed that both formed tumors in nude mice, but Ppp6c heterozygous tumors grew faster than those from the wild-type line. We conclude that in the presence of BRAF (V600E) expression and UV-induced Trp53 mutation, Ppp6c haploinsufficiency promotes tumorigenesis.

Free Research Field

がん抑制遺伝子、発がん実験、皮膚がん

Academic Significance and Societal Importance of the Research Achievements

日光に曝露されたメラノーマ症例の12％でプロテインホスファターゼ6（PP6）をコードするPpp6cの変異があり、BRAFまたはNRAS変異を有する組織にのみ同定された。今回の研究成果により、世界で初めて、Ppp6cが新規のメラノーマ抑制遺伝子であるという証明をすることができた。本研究の成果であるメラノーマモデルマウスを用いることで、新規のメラノーマ治療の開発が期待できる。