Identification of Diagnostic Markers for Malignant Mesothelioma Using Innovative Mass Spectrometry

• Project/Area Number: 17H04059
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Human pathology
• Research Institution: The Tazuke Kofukai (2020); Kyoto University (2017-2019)
• Principal Investigator: Tsuruyama Tatsuaki 公益財団法人田附興風会, 医学研究所 第1研究部, 研究員 (00303842)
• Co-Investigator(Kenkyū-buntansha): 吉澤 明彦 京都大学, 医学研究科, 准教授 (80378645) ; 平塚 拓也 京都大学, 医学研究科, 特定講師 (90641639)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000); Fiscal Year 2020: ¥3,120,000 (Direct Cost: ¥2,400,000、Indirect Cost: ¥720,000); Fiscal Year 2019: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2018: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2017: ¥6,240,000 (Direct Cost: ¥4,800,000、Indirect Cost: ¥1,440,000)
• Keywords: 悪性中皮腫 / 質量分析 / タンパク質 / バイオマーカー / 中皮腫 / FFPE / 呼吸器・縦隔

Outline of Final Research Achievements

We extracted proteins from 24 tissue sections collected from epithelioid malignant pleural mesothelioma (EMPM) and normal mesothelial cells (NM). The abundance of individual proteins in each tissue sample was assessed using liquid chromatography-mass spectrometry (LC/MS). RhoA, a highly susceptible mutation locus, were significantly higher in EMPM than in NM tissues. Besides, endoplasmic reticulum related proteins, including vigilin and redox-oxidation control proteins including PRDX4, and ubiquitin E3 ligase, were significantly higher in EMPM than in NM tissues. Immunohistochemistry (IHC) of 93 MM (epithelioid, 71 cases; sarcomatoid, 13 cases; biphasic, 9 cases), 64 lung adenocarcinoma (LAC), 60 lung squamous cell carcinoma (LSC), and 14 NM tissues was performed. RhoA and vigilin revealed positivity of EMPM, and PRDX4 and ubiquitin E3 ligase were positive in most MMs and the majority of LAC and LSC. This profiling suggests that the stress-induced reaction relates to MM pathogenesis.

Academic Significance and Societal Importance of the Research Achievements

悪性中皮腫の腫瘍発生に関する病因はいまだ明確でなく、その早期診断マーカーや治療の早期開発が強く望まれている。今回の研究で、活性酸素、プロテアソーム、小胞体ストレスに関するタンパク質の発現の増加が悪性中皮腫で顕著であり、その腫瘍発生のメカニズムの概観が可能になった。また治療法開発についても酸化ストレス、プロテアソーム、小胞体ストレスの関連分子を標的としたあらたな方法の開発の有効性を示唆している。

Research Products

• [Int'l Joint Research] ハイデルベルグ大学(ドイツ)
  • Country Name: GERMANY
  • Counterpart Institution: ハイデルベルグ大学
• [Journal Article] Hierarchical Cluster and Region of Interest Analyses Based on Mass Spectrometry Imaging of Human Brain Tumours (2020)
  • Author(s): Hiratsuka Takuya、Arakawa Yoshiki、Yajima Yuka、Kakimoto Yu、Shima Keisuke、Yamazaki Yuzo、Ikegami Masahiro、Yamamoto Takushi、Fujiwake Hideshi、Fujimoto Koichi、Yamada Norishige、Tsuruyama Tatsuaki
  • Journal Title: Scientific Reports Volume: 10 Pages: 5757
  • DOI: 10.1038/s41598-020-62176-8
  • Peer Reviewed
• [Journal Article] Human Atrial Natriuretic Peptide in Cold Storage of Donation After Circulatory Death Rat Livers: An Old but New Agent for Protecting Vascular Endothelia? (2019)
  • Author(s): Nigmet Y, Hata K, Tamaki I, Okamura Y, Tsuruyama T, Miyauchi H, Kusakabe J, Tajima T, Hirao H, Kubota T, Inamoto O, Yoshikawa J, Goto T, Tanaka H, Uemoto S.
  • Journal Title: Transplantation Volume: 103 Pages: 512-521
  • DOI: 10.1097/TP.0000000000002552
  • Peer Reviewed
• [Journal Article] Arid1a is essential for intestinal stem cells through Sox9 regulation. (2019)
  • Author(s): Hiramatsu Y, Fukuda A, Ogawa S, Goto N, Ikuta K, Tsuda M, Matsumoto Y, Kimura Y, Yoshioka T, Takada Y, Maruno T, Hanyu Y, Tsuruyama T, Wang Z, Akiyama H, Takaishi S, Miyoshi H, Taketo MM, Chiba T, Seno H.
  • Journal Title: Proceedings of the National Academy of Sciences of the United States of America Volume: 116 Pages: 1704-1713
  • DOI: 10.1073/pnas.1804858116
  • Peer Reviewed
• [Journal Article] Mass spectrometry imaging of mitochondrial and sarcomeric proteins in acute cardiac infarction tissue. (2018)
  • Author(s): Yajima Y, Hiratsuka T, Kakimoto Y, Ogawa S, Shima K, Yamazaki Y, Yoshikawa K, Tamaki K, Tsuruyama T.
  • Journal Title: Scientific reports Volume: 8 Pages: 7493
  • DOI: 10.1038/s41598-018-25817-7
  • Peer Reviewed / Open Access
• [Journal Article] Laminin 511 is a target antigen in autoimmune pancreatitis. (2018)
  • Author(s): Shiokawa M, Kodama Y, Sekiguchi K, Kuwada T, Tomono T, Kuriyama K, Yamazaki H, Morita T, Marui S, Sogabe Y, Kakiuchi N, Matsumori T, Mima A, Nishikawa Y, Ueda T, Tsuda M, Yamauchi Y, Sakuma Y, Maruno T, Uza N, Tsuruyama T, Mimori T, Seno H, Chiba T.
  • Journal Title: Science Translational Medicine Volume: 10 Pages: 0997
  • DOI: 10.1126/scitranslmed.aaq0997
  • Peer Reviewed / Open Access
• [Journal Article] Human Sox4 facilitates the development of CXCL13-producing helper T cells in inflammatory environments. (2018)
  • Author(s): Yoshitomi H, Kobayashi S, Miyagawa-Hayashino A, Okahata A, Doi K, Nishitani K, Murata K, Ito H, Tsuruyama T, Haga H, Matsuda S, Toguchida J.
  • Journal Title: Nature Communication Volume: 9 Pages: 3762
  • DOI: 10.1038/s41467-018-06187-0.9
  • Peer Reviewed
• [Presentation] 質量イメージングによる膠芽腫と転移性肺腫瘍の鑑別 (2020)
  • Author(s): 鶴山竜昭、平塚拓也
  • Organizer: 日本病理学会
• [Presentation] グリオブラストーマ、転移性脳腫瘍の質量分析イメージング (2019)
  • Author(s): 鶴山竜昭、平塚拓也
  • Organizer: 臨床病理 (0047-1860)67巻補冊 Page197(2019.10)
• [Presentation] ホルマリン固定組織を用いた質量分析イメージングによる超急性心筋梗塞領域の可視化 (2019)
  • Author(s): 平塚拓也、鶴山竜昭
  • Organizer: 日本病理学会会誌(0300-9181)108巻1号 Page326(2019.04)
• [Presentation] 質量分析イメージングによる心筋梗塞バイオマーカー探索 (2018)
  • Author(s): 鶴山竜昭
  • Organizer: 臨床検査医学会
• [Book] Histology "Novel Techniques in Histologic Research: Morphometry and Mass Spectrometry Imaging" (2018)
  • Author(s): Tsuruyama T, Hiratsuka T
  • Total Pages: 13
  • Publisher: IntechOpen
  • ISBN: 978-1-78984-971-4