Identification of molecular mechanisms how TILR regulates apoptosis in lung cancer

• Project/Area Number: 19K07679
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: Kajino Taisuke 愛知県がんセンター(研究所), 分子診断TR分野, 主任研究員 (50723673)
• Project Period (FY): 2019-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); 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); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: TP53 / lncRNA / 肺がん / DNA損傷応答 / miR-20a / miRNA / p53

Outline of Research at the Start

タンパク質をコードしないnon-coding RNAはその長さから大きくmiRNAとlncRNAに分けられるが、その機能は大きく異なる。近年、肺癌におけるmiRNAとlncRNAの重要性を示唆する報告が増加する一方で、複雑なmiRNAとlncRNAの制御機構ならびにその標的遺伝子に関しては不明な点が多く残されている。本研究ではmiR-20aによるlncRNAの制御と、そのlncRNAの機能を解明し、複雑な癌の制御機構を解明することを目的とする。

Outline of Final Research Achievements

Non-coding RNAs have integral regulatory roles in numerous functions related to lung cancer development. Previously, we identified novel lncRNA, termed TILR (TP53-inhibiting lncRNA), which was found to suppress p53 expression and tumor cell growth. In this research, we aimed to reveal the molecular mechanisms how TILR regulates p53 in lung cancer. We performed the proteomic search to identify TILR-binding protein(s) as well as transcriptomic analysis to find the pathways which are regulated by TILR. Our data demonstrated that TILR was also shown to suppress p53 expression in a post-transcriptional manner, as well as via a positive feedback loop involving p53 and Fanconi anemia pathway genes. These results indicated that TILR constitutively inhibits p53 expression to maintain p53 transcriptional activity at a level sufficiently low for avoidance of spurious apoptosis induction.

Academic Significance and Societal Importance of the Research Achievements

本研究において我々は、肺がん細胞の生存に必須の働きをするlncRNA、TILRの機能解析を行った。TILR結合タンパク質の探索および網羅的な遺伝子発現プロファイルの解析を通じ、TILRがp53タンパク質の発現を抑制するlncRNAであることを明らかにした。さらに、TILRの発現抑制とDNA損傷応答誘発剤処理により、p53の活性化を著しく誘導することを見出した。以上の結果から、本研究において我々が明らかにしたTILRによるp53の発現制御機構は、新たな肺がんの治療の提案に繋がることと期待される。

Research Products

• [Journal Article] Long non-coding RNA TILR constitutively represses TP53 and apoptosis in lung cancer (2023)
  • Author(s): Iwai Mika、Kajino Taisuke、Nakatochi Masahiro、Yanagisawa Kiyoshi、Hosono Yasuyuki、Isomura Hisanori、Shimada Yukako、Suzuki Motoshi、Taguchi Ayumu、Takahashi Takashi
  • Journal Title: Oncogene Volume: 42 Issue: 5 Pages: 364-373
  • DOI: 10.1038/s41388-022-02546-w
  • Peer Reviewed
• [Journal Article] Inhibition of HSP90 destabilizes receptor tyrosine kinase ROR1 in lung adenocarcinoma. (2021)
  • Author(s): Khaledian B, Taguchi A, Shin-ya, K, Kondo-Ida L, Kagaya N, Suzuki M, Kajino T, Yamaguchi T, Shimada Y, Takahashi T.
  • Journal Title: Cancer Sci. Volume: 112 Issue: 3 Pages: 1225-1234
  • DOI: 10.1111/cas.14786
  • Peer Reviewed / Open Access
• [Presentation] A novel long non-coding RNA, TILR, suppresses the apoptosis by inhibiting p53 expression. (2020)
  • Author(s): Kajino T, Takahashi T
  • Organizer: 第79回日本癌学会学術総会
  • Int'l Joint Research / Invited