2018 Fiscal Year Final Research Report

Development of novel markers for drug screening and descovery of mechanism to neuroendocrine differentiation in castration resistant prostate cancer

Research Project

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Project/Area Number	16K11008
Research Category	Grant-in-Aid for Scientific Research (C)
Allocation Type	Multi-year Fund
Section	一般
Research Field	Urology
Research Institution	Yamaguchi University
Principal Investigator	MATSUMOTO Hiroaki 山口大学, 医学部附属病院, 講師 (60610673)
Co-Investigator(Kenkyū-buntansha)	山本義明山口大学, 医学部附属病院, 助教 (30593298) 清木誠山口大学, 大学院医学系研究科, 教授 (50226619) 松山豪泰山口大学, 大学院医学系研究科, 教授 (70209667)
Project Period (FY)	2016-04-01 – 2019-03-31
Keywords	去勢抵抗性前立腺癌 / 3Dオルガノイド / 神経内分泌癌 / YAP / ARHGAP29
Outline of Final Research Achievements	We will continue to establish passage technology and functional analysis for preparation of 3D organoids from prostate cancer specimens. In addition, immunostaining of YAP and ARHGAP29 showed significant correlation with clinical factors, pathological factors and prognosis using specimens of radical prostatectomy. In cell line analysis, expression of ARHGAP29 downstream of YAP is predominantly upregulated in PC3 and significantly downregulated in LNCaP, and knocking down ARHGAP29 in PC3 significantly suppresses cell proliferation and reduces invasiveness. And phosphorylation of YAP was promoted. Conversely, over-expression of ARHGAP29 in LNCaP promoted cell proliferation and significantly enhanced infiltration ability. Moreover, the phosphorylation of Cofilin was increased by knockdown of ARHGAP29 in PC3 and the mechanism of acquisition of malignant traits via the YAP-ARHGAP29-Cofilin pathway was elucidated in prostate cancer.
Free Research Field	泌尿器科腫瘍
Academic Significance and Societal Importance of the Research Achievements	本研究により特にホルモン非依存性前立腺癌においてYAP-ARHGAP29経路の悪性形質獲得へのメカニズムの一端が解明され、それらが新たな前立腺癌の悪性度や予後を予測するバイオマーカーとなる可能性が示唆された。またYAPやARHGAP29をターゲットとした創薬開発は去勢抵抗性前立腺癌の新たな治療戦略となる可能性があり、社会的意義は十分に高いものと思われる。今後3Dオルガノイドを用いた解明がさらに加われば、動物実験を回避し、直接個人でのオーダーメイド医療に道が開けると思われ、臨床的意義は極めて高い。