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Analysis of p62 nuclear - cytoplasm shuttling in the carcinogenesis of oral cancer

Research Project

Project/Area Number 19H03846
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Review Section Basic Section 57060:Surgical dentistry-related
Research InstitutionUniversity of Tsukuba

Principal Investigator

Toru Yanagawa  筑波大学, 医学医療系, 教授 (10312852)

Co-Investigator(Kenkyū-buntansha) 田渕 克彦  信州大学, 学術研究院医学系, 教授 (20546767)
蕨 栄治  筑波大学, 医学医療系, 講師 (70396612)
山縣 憲司  筑波大学, 医学医療系, 准教授 (00420084)
内田 文彦  筑波大学, 医学医療系, 講師 (70736008)
Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000)
Fiscal Year 2021: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2020: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000)
Fiscal Year 2019: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
Keywordsp62 / シャトリング / 口腔癌 / 口腔がん
Outline of Research at the Start

本研究では、p62の口腔癌の発癌における役割を調べるために、とくにp62の核-細胞質シャトリングに着目し、ゲノム編集を用いてp62の核排出シグナル(NES: Nuclear export signal)に遺伝子操作を加えることによってp62の核排出をON/OFFにできるノックインマウスを製作し、生体内でp62の核移行に障害が起きた際のマウスの発癌の変化の検討と、ヒトの臨床検体の前癌病変におけるp62の局在に異常がないかを免疫組織学的に検討して、p62の核-細胞質シャトリングが口腔癌の発癌において果たしている役割を探る。

Outline of Final Research Achievements

In this study, we analyzed the role of p62 in oral carcinogenesis, focusing on the nuclear-cytoplasmic shuttling of p62 and how the subcellular localization of p62 affects carcinogenesis. When the nuclear efflux function was stopped by leptomycin B treatment, accumulation of p62 in the nucleus was observed. Phenotypic analysis of mice with mutations in the nuclear efflux and nuclear localization signals revealed abnormalities in kidney podcyte cells. In addition, using samples of clinical specimens of leukoplakia, we examined the association between nuclear localization of p62 and clinical indexes and pathological morphology, and proved that it was significantly associated with epithelial dysplasia. From the above, it was inferred that abnormal localization of p62 could be associated with carcinogenesis.

Academic Significance and Societal Importance of the Research Achievements

本研究ではp62という選択的オートファジー(自食作用)を行う物質が口腔癌の発癌にどのように働いているかを、p62の核-細胞質の移動に注目して解析をおこなったところ、核排出シグナルと核局在シグナルに変異を加えたマウスを制作して表現型を解析したところ、核排出シグナルに異常があると細胞に異常を認め、また、前癌病変である白板症との関連を人の病理検体を用いて調べたところ、上皮異形と有意に関連することが証明されたため、p62の細胞内の局在が発癌に重要な役割をしていることが考えられた。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Annual Research Report
  • 2019 Annual Research Report
  • Research Products

    (8 results)

All 2022 2021 2020 2019

All Journal Article (7 results) (of which Int'l Joint Research: 4 results,  Peer Reviewed: 7 results,  Open Access: 6 results) Presentation (1 results)

  • [Journal Article] MicroRNA 142-5p promotes tumor growth in oral squamous cell carcinoma via the PI3K/AKT pathway by regulating PTEN2021

    • Author(s)
      Iizumi Seiichiro、Uchida Fumihiko、Nagai Hiroki、Takaoka Shohei、Fukuzawa Satoshi、Kanno Naomi Ishibashi、Yamagata Kenji、Tabuchi Katsuhiko、Yanagawa Toru、Bukawa Hiroki
    • Journal Title

      Heliyon

      Volume: 7 Issue: 10 Pages: e08086-e08086

    • DOI

      10.1016/j.heliyon.2021.e08086

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] IQSEC2 Deficiency Results in Abnormal Social Behaviors Relevant to Autism by Affecting Functions of Neural Circuits in the Medial Prefrontal Cortex2021

    • Author(s)
      Mehta Anuradha、Shirai Yoshinori、Kouyama-Suzuki Emi、Zhou Mengyun、Yoshizawa Takahiro、Yanagawa Toru、Mori Takuma、Tabuchi Katsuhiko
    • Journal Title

      Cells

      Volume: 10 Issue: 10 Pages: 2724-2724

    • DOI

      10.3390/cells10102724

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Essential role of autophagy in protecting neonatal haematopoietic stem cells from oxidative stress in a p62-independent manner2021

    • Author(s)
      Nomura Naho、Ito Chiaki、Ooshio Takako、Tadokoro Yuko、Kohno Susumu、Ueno Masaya、Kobayashi Masahiko、Kasahara Atsuko、Takase Yusuke、Kurayoshi Kenta、Si Sha、Takahashi Chiaki、Komatsu Masaaki、Yanagawa Toru、Hirao Atsushi
    • Journal Title

      Scientific Reports

      Volume: 11 Issue: 1 Pages: 1666-1679

    • DOI

      10.1038/s41598-021-81076-z

    • Related Report
      2021 Annual Research Report 2020 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Loss of p62 impairs bone turnover and inhibits PTH-induced osteogenesis.2020

    • Author(s)
      Agas D, Amaroli A, Lacava G, Yanagawa T, Sabbieti MG.
    • Journal Title

      J Cell Physiol.

      Volume: 235 Issue: 10 Pages: 7516-7529

    • DOI

      10.1002/jcp.29654

    • Related Report
      2020 Annual Research Report 2019 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Gender difference in development of steatohepatitis in <i>p62/Sqstm1 and Nrf2</i> double-knockout mice2020

    • Author(s)
      Watahiki T, Okada K, Warabi E, Nagaoka T, Suzuki H, Ishige K, Yanagawa T, Takahashi S, Mizokami Y, Tokushige K, Ariizumi SI, Yamamoto M, Shoda J
    • Journal Title

      Experimental Animals

      Volume: 69 Issue: 4 Pages: 395-406

    • DOI

      10.1538/expanim.20-0028

    • NAID

      130007938666

    • ISSN
      0007-5124, 1341-1357, 1881-7122
    • Related Report
      2020 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Association between p62 expression and clinicopathological characteristics in oral leukoplakia.2019

    • Author(s)
      T. Yoshida, T. Terabe, H. Nagai, F. Uchida, S. Hasegawa, T. Nagao, S. Miyabe, N. Ishibashi‐Kanno, K. Yamagata, E. Warabi, M. Gosho, T. Yanagawa, H. Bukawa
    • Journal Title

      Clinical and Experimental Dental Research

      Volume: 5 Issue: 4 Pages: 389-397

    • DOI

      10.1002/cre2.193

    • NAID

      120007133181

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] SQSTM1/p62 promotes mitochondrial ubiquitination independently of PINK1 and PRKN/parkin in mitophagy.2019

    • Author(s)
      Yamada T, Dawson TM, Yanagawa T, Iijima M, Sesaki H.
    • Journal Title

      Autophagy

      Volume: 15 Issue: 11 Pages: 2012-2018

    • DOI

      10.1080/15548627.2019.1643185

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] オートファジー選択的基質p62/Sqstm1の細胞質-核間シャトリング異常はポドサイト障害を引き起こす2022

    • Author(s)
      蕨 栄治、Ning Baoshuo、布施谷 清香、森戸 直記、臼井 俊明、 柳川 徹、水野 聖哉、川西 邦夫、高橋 智
    • Organizer
      第6回ポドサイト研究会
    • Related Report
      2021 Annual Research Report

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Published: 2019-04-18   Modified: 2023-01-30  

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