Analysis of gene module for genomic instability in lung cancer

• Project/Area Number: 18K07193
• 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: Fujita Health University
• Principal Investigator: Niimi Atsuko 藤田医科大学, 医学部, 准教授 (50508984)
• Co-Investigator(Kenkyū-buntansha): 梶野 泰祐 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): 2018-04-01 – 2022-03-31
• Project Status: Completed (Fiscal Year 2021)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: EGFR / ゲノム不安定化 / DNA修復 / POLD4 / DNA損傷 / DSB修復

Outline of Final Research Achievements

POLD4, a factor in DNA replication/repair pathway, is required for the suppression of genomic instability, but the function is largely unknown. We defined POLD4-correlated genes as “POLD4 module” to elucidate the mechanism of EGFR mutation in lung adenocarcinoma. Interestingly, EGFR mutation in patient is negatively correlated with the activity of POLD4 module. RNA-seq datasets analysis showed that EGFR-specific type mutation (delins: complex mutation with deletion and insertion) are frequently observed in low POLD4 module activity group. By using human lung cancer cell lines, we found that the activity of POLD4 module highly correlated with cancer cell survival against cisplatin, which suggest that POLD4 module has a role in DNA repair.

Academic Significance and Societal Importance of the Research Achievements

EGFRは肺腺がんの代表的なドライバー遺伝子であり、その変異発生のメカニズムを明らかにすることで肺腺がん発生の機序を解明できる可能性がある。本研究の結果より、POLD4モジュールの概念を取り入れることでEGFR変異特異的な変異が起きやすい核内環境について新たな情報を得ることができた。また、低POLD4モジュール活性細胞ではシスプラチン感受性が高いことが明らかとなり、将来的にはPOLD4モジュール活性の測定によりプラチナ製剤の感受性予測が可能となる可能性が示唆された。

Research Products

• [Journal Article] CEBPγ facilitates lamellipodia formation and cancer cell migration through CERS6 upregulation (2021)
  • Author(s): Hanxiao Sh, Atsuko Niimi, Toshiyuki Takeuchi, Kazuya Shiogama, Yasuyoshi Mizutani, Taisuke Kajino, Kenichi Inada, Tetsunari Hase, Takahiro Hatta, Hirofumi Shibata, Takayuki Fukui, Toyofumi Fengshi Chen-Yoshikawa, Kazuki Nagano, Takashi Murate, Yoshiyuki Kawamoto, Shuta Tomida, Takashi Takahashi, Motoshi Suzuki
  • Journal Title: Cancer Science Volume: 未定 Issue: 7 Pages: 2770-2780
  • DOI: 10.1111/cas.14928
  • Peer Reviewed / Open Access
• [Presentation] POLD4 pathway is required for repair of CDDP-induced DNA damage (2021)
  • Author(s): 新美敦子、水谷泰嘉、竹内俊幸、鈴木元
  • Organizer: 第80回日本癌学会学術総会
• [Presentation] A suppressor role of POLD4, the smallest subunit of DNA polymerase δ complex, in lung cancer (2020)
  • Author(s): 新美敦子、水谷泰嘉、竹内俊幸、鈴木元
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] CEBPγ and YBX1 regulate lung cancer metastasis via CERS6 expression and lamellipodia formation (2020)
  • Author(s): 石含笑、新美敦子、竹内俊幸、水谷泰嘉、塩竈和也、稲田健一、長谷哲成、長谷川好規、高橋隆、鈴木元
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] DNAポリメラーゼδ複合体サブユニットPOLD4の肺がん発生における役割解析 (2019)
  • Author(s): 新美敦子、岩瀬咲良、竹内俊幸、水谷泰嘉、鈴木元
  • Organizer: 第42回日本分子生物学会年会
• [Presentation] A metastasis protein CERS6 is transcriptionally regulated by miR-101 and YB-1 (2018)
  • Author(s): 石含笑、竹内俊幸、新美敦子、水谷泰嘉、村手隆、高橋隆、鈴木元
  • Organizer: 第77回日本癌学会学術総会
• [Remarks] 藤田医科大学 分子腫瘍学講座
  • URL: http://info.fujita-hu.ac.jp/~motosuzu/index.html