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Mechanism of multidrug resistance acquisition by transcriptional regulators involved in lung cancer metastasis

Research Project

Project/Area Number 20K22717
Research Category

Grant-in-Aid for Research Activity Start-up

Allocation TypeMulti-year Fund
Review Section 0801:Pharmaceutical sciences and related fields
Research InstitutionTakasaki University of Health and Welfare

Principal Investigator

ZHANG XIEYI  高崎健康福祉大学, 薬学部, 博士研究員 (60878510)

Project Period (FY) 2020-09-11 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywords上皮間葉転換 / 薬物排出系トランスポーター / 足場タンパク / SNAIファミリー / がん転移 / 転写調節因子 / 肺がん / HCC827肺がん細胞
Outline of Research at the Start

薬物排出系トランスポーターは,がん細胞の多剤耐薬化に関与するタンパクとして知られており,足場タンパクによって細胞膜上に固定されている. 転写調節因子は、がんの転移に伴う上皮間葉転換を促進するだけでなく、特定の足場タンパクの発現量を上昇させ、薬物排出系トランスポーターの膜発現を促進することにより、その活性上昇(多剤耐性化) に関与している。本研究では、肺がん細胞および肺がん患者から採取した検体を用いて、薬物排出系トランスポーターの発現量や活性にはどの転写調節因子が関与し、その作用はどの足場タンパクを介した間接的なものなのか、あるいは足場タンパクを介さない直接的なものなのかを網羅的に明らかにする。

Outline of Final Research Achievements

Multidrug resistance-associated protein 2 (MRP2) is a drug efflux transporter involved in multidrug resistance in cancer. In the present study, we determined whether the transcriptional regulator Slug is involved in MRP2 activity. mRNA and protein expression levels of MRP2 in Slug-transfected HCC827 lung cancer cells were significantly higher compared to Mock. The intracellular uptake of CDCF and SN-38 levels in Slug-transfected HCC827 cells were significantly decreased compared to Mock cells. Furthermore, there was a high correlation between Slug and MRP2 mRNA expression levels in lung cancer patients. This study demonstrates that Slug plays a regulatory role in MRP2 expression and function.

Academic Significance and Societal Importance of the Research Achievements

P-糖タンパク質(P-gp)や乳がん耐性タンパク質(BCRP)、多剤耐性タンパク質2(MRP2)は細胞膜上に局在して薬物を細胞外に排出するトランスポーター(ETPs) であり、がんの多剤耐性に関与している。今までにがんの多剤耐性を抑制する目的でP-gpの阻害薬の開発が進められてきたが、他の手段を用いて多剤耐性を抑制する研究はほとんど行われていない。本研究は、肺がん細胞および肺がん臨床検体において、転写調節因子Slugが足場タンパク質を介さずに直接MRP2の発現量増強に寄与している可能性を見出した。この研究結果より、転写調節因子発現の制御から多剤耐性の制御できる医薬品の創製が期待された。

Report

(3 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • Research Products

    (11 results)

All 2022 2021 2020

All Journal Article (4 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 4 results,  Open Access: 2 results) Presentation (7 results) (of which Int'l Joint Research: 4 results)

  • [Journal Article] Imaging modalities for monitoring acute therapeutic effects after near-infrared photoimmunotherapy in vivo2022

    • Author(s)
      Xieyi Zhang, Takahito Nakajima, Kenta Mizoi, Yoshito Tsushima, Takuo Ogihara
    • Journal Title

      Journal of Biophotonics

      Volume: 15 Issue: 1

    • DOI

      10.1002/jbio.202100266

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] A lightweight 0.25 mm lead equivalence protective apron for shielding radiological technologists from radiation exposure during single-photon emission computed tomography in nuclear medicine2022

    • Author(s)
      Takao Kanzaki, Tetsuya Higuchi, Xieyi Zhang, Yasuyuki Takahashi, Makoto Sakai, Yoshito Tsushima
    • Journal Title

      Radioprotection

      Volume: - Issue: 2 Pages: 143-148

    • DOI

      10.1051/radiopro/2022006

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Correlations of mRNA Levels among Efflux Transporters, Transcriptional Regulators, and Scaffold Proteins in Non-Small-Cell Lung Cancer2021

    • Author(s)
      Xieyi Zhang, Wangyang Liu, Kazue Edaki, Yuta Nakazawa, Hiroki Kamioka, Atsushi Fujita, Ryoichi Onozato, Misa Iijima, Shigeru Tsuchida, Takahiro Arai, Yukiyoshi Fujita, Kenta Mizoi, Takuo Ogihara
    • Journal Title

      Canadian Journal of Infectious Diseases and Medical Microbiology

      Volume: - Pages: 4005327-4005327

    • DOI

      10.1155/2021/4005327

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effect of metformin on <sup>18</sup>F-fluorodeoxyglucose uptake and positron emission tomographic imaging2021

    • Author(s)
      Xieyi Zhang, Takuo Ogihara, Min Zhu, Dolgormaa Gantumur, Yang Li, Kenta Mizoi, Hiroki Kamioka, Yoshito Tsushima
    • Journal Title

      The British Journal of Radiology

      Volume: 95 Issue: 1130 Pages: 20200810-20200810

    • DOI

      10.1259/bjr.20200810

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Presentation] CYP3A4阻害薬の薬物相互作用マトリックス表の作成と副作用発現リスクの解析2021

    • Author(s)
      Furuya Shinnosuke, Xieyi Zhang, kenta Mizoi, Takuo Ogihara
    • Organizer
      第4回群馬県薬学大会
    • Related Report
      2021 Annual Research Report
  • [Presentation] Effect of pimozide accumulation by P-glycoprotein (P-gp) inhibition on hERG channel on cardiomyocytes2021

    • Author(s)
      Keisuke Takahashi, Misaki Ishii, Hiroki Morishita, Masa-aki Ito, Xieyi Zhang, Hiroki Kamioka, Kenta Mizoi, Kentaro Yano, Takuo Ogihara
    • Organizer
      日本薬剤学会第36年会
    • Related Report
      2021 Annual Research Report
  • [Presentation] A lightweight 0.25 mm lead equivalence protective apron for shielding radiological technologists from radiation exposure during single-photon emission computed tomography (SPECT)2021

    • Author(s)
      Takao Kanzaki, Tetsuya Higuchi, Xieyi Zhang, Yasuyuki Takahashi, Makoto Sakai, Hirotaka Shimada, Takayuki Suto, Yoshito Tsushima
    • Organizer
      Progress in Radiology 2021
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The role of scaffold proteins in regulating P-gp expression during epithelial-mesenchymal transition in lung cancer2021

    • Author(s)
      Xieyi Zhang, Hiroki Kamioka, Yuta Nakazawa, Kazue Edaki, Kenta Mizoi, Takuo Ogihara
    • Organizer
      日本薬物動態学会第36回年会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The role of transcriptional factors and scaffold proteins in mediating MRP2 expression in lung cancer cells2021

    • Author(s)
      Yuta Nakazawa, Xieyi Zhang, Kazue Edaki, Kenta Mizoi, Takuo Ogihara
    • Organizer
      日本薬物動態学会第36回年会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The effect of P-gp mediated pharmacokinetic interactions on pimozide hERG channel inhibition2021

    • Author(s)
      Hiroki Morishita, Keisuke Takahashi, Misaki Ishii, Masaaki Ito, Xieyi Zhang, Kenta Mizoi, Kentaro Yano, Takuo Ogihara
    • Organizer
      日本薬物動態学会第36回年会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Physiological roles of ERM proteins in supporting membrane expression of efflux transporters2020

    • Author(s)
      Xieyi Zhang, Kenta Mizo, Hiroki Kamioka, Kentaro Yano, Takuo Ogihara
    • Organizer
      第5回トランスポーター研究会関東部会
    • Related Report
      2020 Research-status Report

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Published: 2020-09-29   Modified: 2023-01-30  

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