Integrated regulatory mechanism that govern differentiation and survival of driver-mutation-independent lung adenocarcinoma

• Project/Area Number: 18H02634
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Jichi Medical University
• Principal Investigator: niki toshiro 自治医科大学, 医学部, 教授 (90198424)
• Co-Investigator(Kenkyū-buntansha): 萩原 弘一 自治医科大学, 医学部, 教授 (00240705) ; 遠藤 俊輔 自治医科大学, 医学部, 教授 (10245037) ; 佐久間 裕司 札幌医科大学, 医学部, 准教授 (10364514) ; 吉本 多一郎 自治医科大学, 医学部, 非常勤講師 (20634166) ; 松原 大祐 自治医科大学, 医学部, 准教授 (80415554)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,420,000 (Direct Cost: ¥13,400,000、Indirect Cost: ¥4,020,000); Fiscal Year 2020: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2019: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2018: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000)
• Keywords: 肺腺癌 / 分子標的 / 上皮間葉転換 / 細胞分化 / 病理組織

Outline of Final Research Achievements

Non-TRU (terminal respiratory unit)-type lung adenocarcinoma lacks driver mutations, such as EGFR, and consists of cases that show either 1) abnormal gastrointestinal differentiation, or 2) loss of epidermal traits. In this study, we first clarified the significance of two factors, TFF(trefoil factor family)-1 and HNF(hepatocyte nuclear factor) 4α, as novel biomarkers of the former non-TRU-type, and then examined the effect of their knock-down in lung adenocarcinoma with gastrointestinal differentiation. We also obtained data indicating that loss of BRM, often found in the latter non-TRU-type, is causally related to the loss of epidermal differentiation in this group of non-TRU-type lung adenocarcinoma.

Academic Significance and Societal Importance of the Research Achievements

肺腺癌は，ドライバー変異に基づいた治療が行われているが，治療標的の不明な癌が未だ30％ほど残っている．このような症例は，肺のmaster gene TTF-1が陰性で，上皮形質の異常を示すnon-TRU-type腺癌に多い．本研究は，non-TRU-type腺癌の特徴を分子レベルで明らかにしたもので，今後non-TRU-type腺癌の診断と治療戦略を考えるうえで重要な基盤となる基礎研究である．

Research Products

• [Journal Article] CADM1 promotes malignant features of small-cell lung cancer by recruiting 4.1R to the plasma membrane (2021)
  • Author(s): Funaki Toko、Ito Takeshi、Tanei Zen-ichi、Goto Akiteru、Niki Toshiro、Matsubara Daisuke、Murakami Yoshinori
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 534 Pages: 172-178
  • DOI: 10.1016/j.bbrc.2020.11.121
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Reciprocal expression of trefoil factor‐1 and thyroid transcription factor‐1 in lung adenocarcinomas (2020)
  • Author(s): Matsubara Daisuke、Yoshimoto Taichiro、Soda Manabu、Amano Yusuke、Kihara Atsushi、Funaki Toko、Ito Takeshi、Sakuma Yuji、Shibano Tomoki、Endo Shunsuke、Hagiwara Koichi、Ishikawa Shumpei、Fukayama Masashi、Murakami Yoshinori、Mano Hiroyuki、Niki Toshiro
  • Journal Title: Cancer Science Volume: 111 Issue: 6 Pages: 1-13
  • DOI: 10.1111/cas.14403
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] EGFR-independent EGFR-mutant lung adenocarcinoma cells depend on Bcl-xL and MCL1 for survival. (2020)
  • Author(s): Hirai S, Tada M, Yamaguchi M, Niki T, Sakuma Y.
  • Journal Title: Biochem Biophys Res Commun. Volume: 526 Pages: 417-423
  • DOI: 10.1016/j.lungcan.2019.05.014
  • Peer Reviewed
• [Journal Article] BRG1, INI1, and ARID1B Deficiency in Endometrial Carcinoma (2020)
  • Author(s): Kihara Atsushi、Amano Yusuke、Matsubara Daisuke、Fukushima Noriyoshi、Fujiwara Hiroyuki、Niki Toshiro
  • Journal Title: American Journal of Surgical Pathology Volume: 44 Issue: 12 Pages: 1712-1724
  • DOI: 10.1097/pas.0000000000001581
  • Peer Reviewed
• [Journal Article] Survivin knockdown induces senescence in TTF-1-expressing, KRAS-mutant lung adenocarcinomas. (2018)
  • Author(s): Sumi T, Hirai S, Yamaguchi M, Tanaka Y, Tada M, Yamada G, Hasegawa T, Miyagi Y, Niki T, Watanabe A, Takahashi H, Sakuma Y.
  • Journal Title: International Journal of Oncology Volume: 52 Pages: 33-46
  • DOI: 10.3892/ijo.2018.4365
  • Peer Reviewed / Open Access
• [Journal Article] Trametinib downregulates survivin expression in RB1-positive KRAS-mutant lung adenocarcinoma cells. (2018)
  • Author(s): Sumi T, Hirai S, Yamaguchi M, Tanaka Y, Tada M, Niki T, Takahashi H, Sakuma Y.
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 501 Issue: 1 Pages: 253-258
  • DOI: 10.1016/j.bbrc.2018.04.230
  • Peer Reviewed
• [Presentation] Reciprocal expressions of TFF-1 and TTF-1 in lung adenocarcinomas. (2018)
  • Author(s): ３１．Matsubara D, Soda M, Yoshimoto T, Amano Y, Kihara A, Sakuma Y, Endo S, Hagiwara K, Fukayama M, Mano H, Niki T.
  • Organizer: Annual Meeting of American Association for Cancer Research
  • Int'l Joint Research
• [Remarks] 自治医大病理学講座統合病理学部門
  • URL: https://www.jichi.ac.jp/pathol/
• [Remarks] 自治医科大学統合病理学部門ホームページ
  • URL: http://www.jichi.ac.jp/pathol/
• [Remarks] 自治医科大学病理学講座統合病理学部門ホームページ
  • URL: https://www.jichi.ac.jp/pathol/index.html