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Studies on the function and mutations of DLL3 in small cell lung cancer

Research Project

Project/Area Number 19K23903
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0901:Oncology and related fields
Research InstitutionHokkaido University

Principal Investigator

Furuta Megumi  北海道大学, 大学病院, 医員 (00848765)

Project Period (FY) 2019-08-30 – 2021-03-31
Project Status Completed (Fiscal Year 2020)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
KeywordsDLL3の機能 / 小細胞肺癌 / DLL3 / NOTCH
Outline of Research at the Start

本研究では小細胞肺癌(SCLC)におけるDLL3の機能および遺伝子変異について検討する。我々はSCLCのNotch関連遺伝子の遺伝子変異について検討したところ、DLL3の細胞外ドメインに遺伝子変異を多く認め、その遺伝子変異と予後に相関があったことから、DLL3遺伝子変異細胞株を作成しその機能について解析する。今回の研究でDLL3の機能や遺伝子変異の詳細が明らかになれば予後予測因子や開発中のDLL3をターゲットとした治療の治療効果予測つながると予想される。

Outline of Final Research Achievements

To investigate the role of DLL3 in tumorigenesis in SCLC, we performed loss-of-function and gain-of-function assays using SCLC cell lines. In vitro analysis of cell migration and invasion by transwell assay showed that DLL3 knockdown reduced migration and invasion of SCLC cells, whereas DLL3 overexpression increased these activities. In addition, DLL3 positively regulated SNAI1 expression and knockdown of SNAI1 attenuated the migration and invasion ability of SCLC cells. Moreover, upregulated DLL3 expression induced subcutaneous tumor growth in mouse models. These results indicate that DLL3 promoted tumor growth, migration and invasion in an SCLC model by modulating SNAI1/Snail.

Academic Significance and Societal Importance of the Research Achievements

小細胞肺癌ではNotchのリガンドの一つであるDelta-like protein 3(DLL3)はin vitro、in vivoにおいて腫瘍増殖能、遊走能、浸潤能を促進していた。遊走能、浸潤能促進の機序としてNOTCH1非依存性に上皮間葉転換を誘導に関与する転写因子であるSnailが関与している可能性が考えられた。DLL3を標的とした治療は転移例や再発例において期待されると考えられた。

Report

(3 results)
  • 2020 Annual Research Report   Final Research Report ( PDF )
  • 2019 Research-status Report
  • Research Products

    (1 results)

All 2020

All Journal Article (1 results) (of which Peer Reviewed: 1 results)

  • [Journal Article] Evaluating the immunoproteasome as a potential therapeutic target in cisplatin-resistant small cell and non-small cell lung cancer2020

    • Author(s)
      Shoji T, Kikuchi E, Kikuchi J, Takashima Y, Furuta M, Takahashi H, Tsuji K, Maeda M, Kinoshita I, Dosaka-Akita H, Sakakibara-Konishi J, Konno S
    • Journal Title

      Cancer Chemother Pharmacol

      Volume: in print Issue: 5 Pages: 843-853

    • DOI

      10.1007/s00280-020-04061-9

    • NAID

      120007032615

    • Related Report
      2020 Annual Research Report
    • Peer Reviewed

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Published: 2019-09-03   Modified: 2022-01-27  

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