2019 Fiscal Year Final Research Report

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

Research Project

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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
Keywords	プロテインホスファターゼ / Kras
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)
Free Research Field	がん抑制遺伝子、発がん
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)