2021 Fiscal Year Final Research Report
Roles of super-enhancers in patient-derived prostate cancer cells and xenografts.
| Project/Area Number |
20K21667
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| Research Category |
Grant-in-Aid for Challenging Research (Exploratory)
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| Allocation Type | Multi-year Fund |
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| Review Section |
Medium-sized Section 56:Surgery related to the biological and sensory functions and related fields
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| Research Institution | Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology |
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Principal Investigator |
Inoue Satoshi 地方独立行政法人東京都健康長寿医療センター(東京都健康長寿医療センター研究所), 東京都健康長寿医療センター研究所, 研究部長 (40251251)
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| Co-Investigator(Kenkyū-buntansha) |
堀江 公仁子 埼玉医科大学, 医学部, 教授 (90261982)
市川 智彦 千葉大学, 大学院医学研究院, 教授 (20241953)
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| Project Period (FY) |
2020-07-30 – 2022-03-31
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| Keywords | 患者由来がんモデル / スーパーエンハンサー / 転写制御 / 前立腺がん |
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| Outline of Final Research Achievements |
Androgen receptor (AR) targeted therapies are useful for prostate cancer patients. AR signaling inhibitors are effective, however, tumors often evade this treatment and transform to AR-negative prostate cancer. We previously reported that AR signaling is enhanced by a collaborative transcription factor OCT1. Here, we performed chromatin immunoprecipitation sequencing in patient-derived castration-resistant AR-negative prostate cancer models to identify genes regulated by OCT1 combining with superenhancer analysis. A group of genes associated with neural precursor cell proliferation was significantly enriched, and we focused on neural gene PFN2. PFN2 is highly expressed in human AR-negative prostate cancer tissues. Knockdown of PFN2 by siRNAs significantly inhibited migration of AR-negative prostate cancer cells, as well as tumor growth in vivo. We identified an OCT1-target gene in AR-negative prostate cancer using patient-derived models, superenhancer and clinicopathologial analyses.
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| Free Research Field |
老年医学
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| Academic Significance and Societal Importance of the Research Achievements |
高齢男性の健康上の大きな問題となっている前立腺がんについて、実臨床に近いモデルの確立は未だ不十分であり、病態解明と薬剤開発の面でバリアとなってきた。本研究は最新の培養技術を応用して患者由来の臨床検体からPDC培養系を確立し、治療抵抗性を獲得した独自のがん細胞培養系とそのマウス移植腫瘍PDCXあるいは直接移植したPDXモデルを確立し、その応用として新しい病態メカニズムと創薬に繋げることができた。
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