Search for diagnostic markers and molecular-targeted compounds for the treatment of malignant mesothelioma

• Project/Area Number: 19K08668
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53030:Respiratory medicine-related
• Research Institution: Aichi Medical University
• Principal Investigator: Hosokawa Yoshitaka 愛知医科大学, 医学部, 教授 (60229193)
• Co-Investigator(Kenkyū-buntansha): 太田 明伸 愛知医科大学, 医学部, 講師 (30438048)
• 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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 悪性胸膜中皮腫 / ゲノム編集技術 / 癌抑制遺伝子 / 診断マーカー / 遺伝子編集技術 / cDNAマイクロアレイ / 胸膜中皮腫 / 阻害剤

Outline of Research at the Start

本研究では、申請者が樹立した癌抑制遺伝子ノックアウト細胞株を利用して、中皮腫の増殖・進展に関わる細胞内分子および浸潤・転移を阻害する化合物を同定し、新規診断マーカーや新規治療薬の候補分子を探索することを目的とする。将来的には中皮腫に対する効果的な診断法・治療法を開発することを目指す。

Outline of Final Research Achievements

Malignant pleural mesothelioma (MPM) is an aggressive malignancy of the pleura that is currently incurable due to the lack of an effective early diagnostic method and specific medication. To understand how these mutations contribute to MPM tumor growth, we generated NF2-knockout and NF2/p16 double-knockout (DKO) cell clones using human mesothelial cell lines. cDNA microarray analysis, quantitative PCR and western blot analyses showed upregulation of fibroblast growthfactor receptor 2 (FGFR2) and CD24, respectively, in NF2-knockout and NF2/p16 double-knockout (DKO) cell clones. These results strongly indicate the potential use of FGFR2 and CD24 as prognostic markers as well as novel diagnostic and therapeutic targets for MPM.

Academic Significance and Societal Importance of the Research Achievements

悪性胸膜中皮腫はアスベスト曝露に関連して発症し、発病までの期間は約20-30年と長期に渡り、中皮腫患者の死亡者数は10万人を超えると予測されている。多くは進行した状態で診断され、化学療法や免疫チェックポイント阻害薬の併用療法が行われているが、その効果は極めて限定的である。本研究では、胸膜中皮細胞を用いて癌抑制遺伝子ノックアウト株を作成し、新規診断マーカーや新規治療薬の候補分子を探索することを目的とした。今回、新規診断マーカーとしてFGF受容体2およびCD24を同定し、阻害化合物としてセルレニンを発見した。悪性胸膜中皮腫の治療状況の現状を鑑みて、今回の発見の社会的意義は大きいと考えられる。

Research Products

• [Journal Article] PBK Enhances Cellular Proliferation With Histone H3 Phosphorylation and Suppresses Migration and Invasion With CDH1 Stabilization in Colorectal Cancer (2022)
  • Author(s): Koshino Akira、Nagano Aya、Ota Akinobu、Hyodo Toshinori、Ueki Akane、Komura Masayuki、Sugimura-Nagata Akane、Ebi Masahide、Ogasawara Naotaka、Kasai Kenji、Hosokawa Yoshitaka、Kasugai Kunio、Takahashi Satoru、Inaguma Shingo
  • Journal Title: Frontiers in Pharmacology Volume: 12 Pages: 772926-772935
  • DOI: 10.3389/fphar.2021.772926
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Correction of a CD55 mutation to quantify the efficiency of targeted knock-in via flow cytometry (2022)
  • Author(s): Rahman Md. Lutfur、Hyodo Toshinori、Hasan Muhammad Nazmul、Mihara Yuko、Karnan Sivasundaram、Ota Akinobu、Tsuzuki Shinobu、Hosokawa Yoshitaka、Konishi Hiroyuki
  • Journal Title: Molecular Biology Reports Volume: - Issue: 7 Pages: 6241-6248
  • DOI: 10.1007/s11033-022-07422-0
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Experimental strategies to achieve efficient targeted knock-in via tandem paired nicking (2021)
  • Author(s): Rahman Md. Lutfur、Hyodo Toshinori、Karnan Sivasundaram、Ota Akinobu、Hasan Muhammad Nazmul、Mihara Yuko、Wahiduzzaman Md、Tsuzuki Shinobu、Hosokawa Yoshitaka、Konishi Hiroyuki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 1-13
  • DOI: 10.1038/s41598-021-01978-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD52 is a novel target for the treatment of FLT3-ITD-mutated myeloid leukemia (2021)
  • Author(s): Karnan Sivasundaram、Hanamura Ichiro、Uchino Kaori、Murakami Satsuki、Wahiduzzaman Md、Quang Vu Lam、Rahman Md Lutfur、Hasan Muhammad Nazmul、Hyodo Toshinori、Konishi Hiroyuki、Tsuzuki Shinobu、Yoshikawa Kazuhiro、Suzuki Susumu、Ueda Ryuzo、Ejiri Masayuki、Hosokawa Yoshitaka、Takami Akiyoshi
  • Journal Title: Cell Death Discovery Volume: 7 Issue: 1 Pages: 1-10
  • DOI: 10.1038/s41420-021-00446-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Flow cytometry-based quantification of targeted knock-in events in human cell lines using a GPI-anchor biosynthesis gene <i>PIGP</i> (2021)
  • Author(s): Rahman Md.?Lutfur、Hyodo Toshinori、Hasan Muhammad?Nazmul、Mihara Yuko、Karnan Sivasundaram、Ota Akinobu、Tsuzuki Shinobu、Hosokawa Yoshitaka、Konishi Hiroyuki
  • Journal Title: Bioscience Reports Volume: 41 Issue: 12
  • DOI: 10.1042/bsr20212231
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Identification of CD24 as a potential diagnostic and therapeutic target for malignant pleural mesothelioma (2020)
  • Author(s): KarnanS, Ota A, Murakami H, Rahman ML, Hasan MN, Wahiduzzaman MD, Hanamura I, Vu LQ, Inoko A, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y.
  • Journal Title: Cell Death Discovery Volume: 18 Issue: 1 Pages: 127-139
  • DOI: 10.1038/s41420-020-00364-1
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Establishment and characterization of CRISPR/Cas9-mediated NF2-/- human mesothelial cell line: Molecular insight into fibroblast growth factor receptor 2 in malignant pleural mesothelioma. (2019)
  • Author(s): Wahiduzzaman M, Karnan S, Ota A, Hanamura I, Murakami H, Inoko A, Rahman ML, Hyodo T, Konishi H, Tsuzuki S, Hosokawa Y.
  • Journal Title: Cancer Science Volume: 110 Pages: 180-193
  • Peer Reviewed / Open Access