Nuclear translocation mechanism of MALT1 and oral carcinoma cell invasion

• Project/Area Number: 18K09542
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 57020:Oral pathobiological science-related
• Research Institution: The Nippon Dental University
• Principal Investigator: Kazushi IMAI 日本歯科大学, 生命歯学部, 教授 (10328859)
• Co-Investigator(Kenkyū-buntansha): 冨山 希美 (美原希美) 日本歯科大学, 生命歯学部, 助教 (00803264) ; 千葉 忠成 日本歯科大学, 生命歯学部, 准教授 (60350138)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2018: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: MALT1 / 口腔癌 / ドメイン / プロモーター / 浸潤

Outline of Final Research Achievements

In normal oral epithelium, mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) is expressed in the basal epithelial cells, and the expression is rapidly disappeared in an aggressive subset of oral carcinomas. However, mechanisms of the subcellular localization and the loss of expression are unknown.
This study demonstrated that caspase-like domain of MALT1 translocates the protein into nucleus and the death domain suppresses cell proliferation. In regard to the regulation of expression, binding of NF-κB subunit RELA to the core promoter region (+402~+501) was a primary cause for loss of the gene expression.

Academic Significance and Societal Importance of the Research Achievements

口腔癌細胞はMALT1を核に発現することで高度悪性形質を抑制し、予後不良な口腔癌では発現が低下する。本研究課題では、第１にMALT1はカスパーゼ様ドメイン依存性に核移行したデスドメインにより細胞増殖を抑制すること、第２に+402~+501のサイレンサー領域にNF-kBサブユニットRELAが結合することで遺伝子発現が負に制御されることが判明した。
口腔癌は頭頸部で最も発生頻度が高い悪性腫瘍であるが、患者予後は十分に改善されたとは言えない。予後の改善には新たな治療法を確立する必要がる。本研究で得られた成果は口腔癌進行の新たな分子機構を示すものであり、将来的に新規治療法の開発につながる可能性をもつ。

Research Products

• [Journal Article] NF-kB subunit RELA suppression of mucosa-associated lymphoi tissue lymphoma tranlocation protein 1 expression in oral carcinoma cells (2021)
  • Author(s): Takaomi Nozawa, Nozomi Mihara-Tomiyama, Tadashige Chiba, Kazushi Imai
  • Journal Title: Biochemistry and Biophysical Research Communications Volume: 542 Pages: 24-28
  • Peer Reviewed
• [Journal Article] Domain structures of mucosa-associated lymphoid tissue lymphoma translocation 1 protein for nuclear translocation in oral carcinoma cells and the proliferation inhibition (2020)
  • Author(s): H Hayashi, T Chiba, N Mihara-Tomiyama, T Negishi, Y Kodama, H Sakashita, K Imai
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 522 Issue: 3 Pages: 799-804
  • DOI: 10.1016/j.bbrc.2019.11.171
  • Peer Reviewed / Open Access
• [Presentation] 口腔癌細胞におけるMALT1核移行ドメインの解析 (2019)
  • Author(s): 林宏泰、千葉忠成、冨山希美、今井一志、坂下英明
  • Organizer: 第73回NPO法人日本口腔科学会学術集会