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Functional analysis of PHLDA3, a repressor of Akt, to elucidate the mechanism of neuroendocrine tumor development

Research Project

Project/Area Number 17H03587
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Tumor biology
Research InstitutionNational Cancer Center Japan

Principal Investigator

Ohki Rieko  国立研究開発法人国立がん研究センター, 研究所, 独立ユニット長 (70356252)

Co-Investigator(Kenkyū-buntansha) 小嶋 基寛  国立研究開発法人国立がん研究センター, 臨床開発センター, ユニット長 (30338470)
平岡 伸介  国立研究開発法人国立がん研究センター, 中央病院, 科長 (40276217)
森実 千種  国立研究開発法人国立がん研究センター, 中央病院, 医長 (50501871)
山田 正三  (財)冲中記念成人病研究所, その他部局等, 研究員 (80260131)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥17,940,000 (Direct Cost: ¥13,800,000、Indirect Cost: ¥4,140,000)
Fiscal Year 2019: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000)
Fiscal Year 2018: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2017: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Keywords神経内分泌腫瘍 / Akt / PHLDA3 / がん抑制遺伝子 / がん遺伝子Akt / PHLDA3遺伝子 / p53 / 遺伝子 / がん
Outline of Final Research Achievements

We found that the PHLDA3 gene encodes a suppressor of the oncogene Akt and is a tumor suppressor of lung / pancreatic NET. Moreover, it was shown that cases with loss of PHLDA3 function in lung / pancreatic NET are highly malignant and the patients have poorer prognosis. Based on these findings, we tackled the following three issues. 1. Analysis of PHLDA3 gene abnormality in various NET samples, comprehensive whole exon sequence analysis, RNA-seq analysis. 2. Preparation of pancreatic NET / pituitary / thyroid NET model animals useful for preclinical studies and establishment of pancreatic NET cell lines. 3. Analysis of the relationship between PHLDA3 gene abnormalities and patient prognosis and therapeutic drug response.

Academic Significance and Societal Importance of the Research Achievements

本研究成果は、組織を超えたNET 共通のがん抑制メカニズムの解明につながるものであり、今後さらに研究を進めることで、希少がんであるNET の本態解明とそれに続く創薬や治療法の開発が加速すると予想される。

Report

(2 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • Research Products

    (13 results)

All 2020 2019 Other

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 6 results,  Open Access: 3 results) Presentation (5 results) (of which Invited: 3 results) Remarks (1 results)

  • [Journal Article] Identification and characterization of the binding sequences and target genes of p53 lacking the 1st transactivation domain.2020

    • Author(s)
      Shiori Suzuki, Shuichi Tsutsumi, Yu Chen, Chikako Ozeki, Atsushi Okabe, Tatsuya Kawase, Hiroyuki Aburatani and Rieko Ohki.
    • Journal Title

      Cancer Science

      Volume: 111 Issue: 2 Pages: 451-466

    • DOI

      10.1111/cas.14279

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Nuclear import of IER5 is mediated by a classical bipartite nuclear localization signal and is required for HSF1 full activation2020

    • Author(s)
      Shotaro Yamano, Makoto Kimura, Yu Chen, Naoko Imamoto, Rieko Ohki
    • Journal Title

      Experimental Cell Research

      Volume: 386 Issue: 1 Pages: 111686-111686

    • DOI

      10.1016/j.yexcr.2019.111686

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Non-naturally Occurring Helical Molecules Can Interfere with p53–MDM2 and p53–MDMX Protein–Protein Interactions2019

    • Author(s)
      AozeSu, Siyuan Wang, Akane Sada,Yuko Otani, Luhan Zhai, Xin Liu, Misa Sayama, Rieko Ohki and Tomohiko Ohwada.
    • Journal Title

      Chemical and Pharmaceutical Bulletin

      Volume: 67 Issue: 10 Pages: 1139-1143

    • DOI

      10.1248/cpb.c19-00501

    • NAID

      130007722045

    • ISSN
      0009-2363, 1347-5223
    • Year and Date
      2019-10-01
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Overall Shape Constraint of Alternating /-Hybrid Peptides Containing Bicyclic Proline.2019

    • Author(s)
      Siyuan Wang, Yuko Otani, Luhan Zhai, Aoze Su, Masayuki Nara, Masatoshi Kawahata, Kentaro Yamaguchi, Akane Sada, Rieko Ohki, Tomohiko Ohwada.
    • Journal Title

      Organic Letters

      Volume: 21 Issue: 19 Pages: 7813-7817

    • DOI

      10.1021/acs.orglett.9b02799

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Recommendation of long-term and systemic management according to the risk factors in rectal NETs patients.2019

    • Author(s)
      Kojima M, Chen Y, Ikeda K, Tsukada Y, Takahashi D, Kawano S, Amemiya K, Ito M, Ohki R, Ochiai A.
    • Journal Title

      Sci Rep

      Volume: 9 Issue: 1 Pages: 2040-2040

    • DOI

      10.1038/s41598-018-37707-z

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IER5 Is a p53-Regulated Activator of HSF1 That Contributes to Promotion of Cancer.2019

    • Author(s)
      Tatsuya Kawase, Yu Chen, Rieko Ohki.
    • Journal Title

      Heat Shock Proteins

      Volume: 17 Pages: 253-272

    • DOI

      10.1007/978-3-030-03952-3_13

    • ISBN
      9783030039516, 9783030039523
    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] 膵神経内分泌腫瘍のゲノム異常とプレシジョン・メディシンへの応用.2019

    • Author(s)
      大木理恵子
    • Journal Title

      肝胆膵

      Volume: 79 Pages: 1135-114

    • Related Report
      2019 Annual Research Report
  • [Presentation] p53が制御する新規の神経内分泌腫瘍抑制経路の解明2019

    • Author(s)
      大木 理恵子
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] 知られざるp53の肖像~最も有名ながん抑制遺伝子p53の新機能~2019

    • Author(s)
      大木 理恵子
    • Organizer
      第32回モロシヌス研究会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] p53が制御する新規の神経内分泌腫瘍抑制経路の解明2019

    • Author(s)
      大木 理恵子
    • Organizer
      第42回日本分子生物学会年会
    • Related Report
      2019 Annual Research Report
    • Invited
  • [Presentation] PHLDA3遺伝子とMEN1遺伝子による膵臓神経内分泌腫瘍抑制機構の解明2019

    • Author(s)
      陳 ヨ、大木理恵子
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] 分泌性タンパク質p53PAD7とHippoシグナル経路による増殖抑制機構の解明2019

    • Author(s)
      滝川 雅大、大木理恵子
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Remarks] 基礎腫瘍学ユニットホームページ

    • URL

      https://www.ncc.go.jp/jp/ri/division/fundamental_oncology/index.html

    • Related Report
      2019 Annual Research Report

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Published: 2017-04-28   Modified: 2021-02-19  

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