Investigation of epigenetic mechanisms regulating the development and biological properties of malignant mesothelioma

• Project/Area Number: 26460444
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Hyogo Medical University
• Principal Investigator: Tsujimura Tohru 兵庫医科大学, 医学部, 教授 (20227408)
• Co-Investigator(Kenkyū-buntansha): 鳥井 郁子 兵庫医科大学, 医学部, 准教授 (70207661) ; 佐藤 鮎子 兵庫医科大学, 医学部, 講師 (20419823) ; 篠原 義康 兵庫医科大学, 医学部, 助教 (60723509) ; 工藤 朝雄 兵庫医科大学, 医学部, ポストドクター (60709781)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 悪性中皮腫 / エピジェネティクス / 細胞増殖 / EZH2

Outline of Final Research Achievements

In malignant mesothelioma, EZH2 is highly expressed and BAP1 mutation is observed. Suppression of EZH2 expression in mesothelioma cells by RNA interfering method decreased their proliferation, motility, and tumorigenic ability, but could not induce tumorigenesis even when EZH2 was highly expressed in mesothelial cells. The EZH2 high expression group of malignant mesothelioma patients had a poorer prognosis than the EZH2 low expression group. Although high expression of EZH2 alone is insufficient for tumorigenesis of mesothelial cells, the prognosis of malignant mesothelioma patients is thought to be involved in EZH2-controlled growth and invasion related molecules.
Although BAP1 mutation is considered to be a useful molecular marker for diagnosing epithelioid mesothelioma, further investigation is required on the biological function of BAP1 in malignant mesothelioma.

Research Products

• [Journal Article] Immunohistochemical detection of MTAP and BAP1 protein loss for mesothelioma diagnosis: Comparison with 9p21 FISH and BAP1 immunohistochemistry. (2017)
  • Author(s): Hida T, Hamasaki M, Matsumoto S, Sato A, Tsujimura T, Kawahara K, Iwasaki A, Okamoto T, Oda Y, Honda H, Nabeshima K.
  • Journal Title: Lung Cancer Volume: 104 Pages: 98-105
  • DOI: 10.1016/j.lungcan.2016.12.017
  • Peer Reviewed
• [Journal Article] Usefulness of p16/CDKN2A fluorescence in situ hybridization and BAP1 immunohistochemistry for the diagnosis of biphasic mesothelioma. (2016)
  • Author(s): Wu D, Hiroshima K, Yusa T, Ozaki D, Koh E, Sekine Y, Matsumoto S, Nabeshima K, Sato A, Tsujimura T, Yamakawa H, Tada Y, Shimada H, Tagawa M.
  • Journal Title: Annals of Diagnostic Pathology Volume: 26 Pages: 31-37
  • Peer Reviewed
• [Journal Article] High-density array-CGH with targeted NGS unmask multiple noncontiguous minute deletions on chromosome 3p21 in mesothelioma. (2016)
  • Author(s): Yoshikawa Y, Emi M, Hashimoto-Tamaoki T, Ohmuraya M, Sato A, Tsujimura T, Hasegawa S, Nakano T, Nasu M, Pastorino S, Szymiczek A, Bononi A, Tanji M, Pagano I, Gaudino G, Napolitano A, Goparaju C, Pass HI, Yang H, Carbone M.
  • Journal Title: Proc Natl Acad Sci U S A Volume: 113 Issue: 47 Pages: 13432-13437
  • DOI: 10.1073/pnas.1612074113
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] BAP1 immunohistochemistry and p16 FISH results in combination provide higher confidence in malignant pleural mesothelioma diagnosis: ROC analysis of the two tests. (2016)
  • Author(s): Hida T, Hamasaki M, Matsumoto S, Sato A, Tsujimura T, Kawahara K, Iwasaki A, Okamoto T, Oda Y, Honda H, Nabeshima K.
  • Journal Title: Pathol Int Volume: 66 Issue: 10 Pages: 563-570
  • DOI: 10.1111/pin.12453
  • Peer Reviewed
• [Journal Article] Low homozygous/high heterozygous deletion status by p16 FISH correlates with a better prognostic group than high homozygous deletion status in malignant pleural mesothelioma. (2016)
  • Author(s): Hamasaki M, Matsumoto S, Abe S, Hamatake D, Kamei T, Hiroshima K, Kawahara K, Sato A, Tsujimura T, Nakatani Y, Yoshida Y, Iwasaki A, Nabeshima K.
  • Journal Title: Lung Cancer Volume: 99 Pages: 155-161
  • DOI: 10.1016/j.lungcan.2016.07.011
  • Peer Reviewed
• [Journal Article] Trimodality strategy for treating malignant pleural mesothelioma: results of a feasibility study of induction pemetrexed plus cisplatin followed by extrapleural pneumonectomy and postoperative hemithoracic radiation (Japan Mesothelioma Interest Group 0601 Trial) (2016)
  • Author(s): Hasegawa S, Okada M, Tanaka F, Yamanaka T, Soejima T, Kamikonya N, Tsujimura T, Fukuoka K, Yokoi K, Nakano T.
  • Journal Title: Int J Clin Oncol Volume: 21 Issue: 3 Pages: 523-530
  • DOI: 10.1007/s10147-015-0925-1
  • Peer Reviewed / Open Access
• [Journal Article] Deletion status of p16 in effusion smear preparation correlates with that of underlying malignant pleural mesothelioma tissue. (2015)
  • Author(s): Hida T, Matsumoto S, Hamasaki M, Kawahara K, Tsujimura T, Hiroshima K, Kamei T, Taguchi K, Iwasaki A, Oda Y, Honda H, Nabeshima K.
  • Journal Title: Cancer Sci Volume: 106 Issue: 11 Pages: 1635-1641
  • DOI: 10.1111/cas.12769
  • Peer Reviewed
• [Journal Article] Frequent genomic rearrangements of BRCA1 associated protein-1 (BAP1) gene in Japanese malignant mesothelioma-characterization of deletions at exon level. (2015)
  • Author(s): Emi M et al
  • Journal Title: J Hum Genet Volume: 60 Issue: 10 Pages: 647-649
  • DOI: 10.1038/jhg.2015.91
  • Peer Reviewed
• [Journal Article] p16/CDKN2A FISH in Differentiation of Diffuse Malignant Peritoneal Mesothelioma From Mesothelial Hyperplasia and Epithelial Ovarian Cancer. (2015)
  • Author(s): Ito T, Hamasaki M, Matsumoto S, Hiroshima K, Tsujimura T, Kawai T, Shimao Y, Marutsuka K, Moriguchi S, Maruyama R, Miyamoto S, Nabeshima K.
  • Journal Title: Am J Clin Pathol Volume: 143 Issue: 6 Pages: 830-838
  • DOI: 10.1309/ajcpoatj9l4gcgda
  • Peer Reviewed / Open Access
• [Journal Article] Biallelic germline and somatic mutations in malignant mesothelioma: multiple mutations in transcription regulators including mSWI/SNF genes. (2015)
  • Author(s): Yoshikawa Y, Sato A, Tsujimura T, Otsuki T, Fukuoka K, Hasegawa S, Nakano T, Hashimoto-Tamaoki T.
  • Journal Title: Int J Cancer Volume: 136 Issue: 3 Pages: 560-571
  • DOI: 10.1002/ijc.29015
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LIM-domain protein AJUBA suppresses malignant mesothelioma cell proliferation via Hippo signaling cascad (2014)
  • Author(s): Tanaka I, Osada H, Fujii M, Fukatsu A, Hida T, Horio Y, Kondo Y, Sato A, Hasegawa Y, Tsujimura T, Sekido Y
  • Journal Title: Oncogene Volume: 34 Issue: 1 Pages: 73-83
  • DOI: 10.1038/onc.2013.528
  • Peer Reviewed / Open Access
• [Journal Article] Significant increase in circulating tumour cells in pulmonary venous blood during surgical manipulation in patients with primary lung cancer. (2014)
  • Author(s): Hashimoto M, Tanaka F, Yoneda K, Takuwa T, Matsumoto S, Okumura Y, Kondo N, Tsubota N, Tsujimura T, Tabata C, Nakano T, Hasegawa S.
  • Journal Title: Interact Cardiovasc Thorac Surg Volume: 18 Issue: 6 Pages: 775-783
  • DOI: 10.1093/icvts/ivu048
  • Peer Reviewed / Open Access
• [Presentation] Utility of liquid-based cytology in the diagnosis of malignant pleural mesothelioma (2016)
  • Author(s): Tsujimura T, Sato A, Shinohara Y, Sumida A, Nakanishi T, Sato G, Ishida M, Torii Y, Shimizu S.
  • Organizer: The 19th International Congress of Cytology
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-05-30
  • Int'l Joint Research
• [Presentation] Clinical, cytological, and molecular biological approaches to the diagnosis of early mesothelioma (2016)
  • Author(s): Tsujimura T, Sato A, Shinohara Y, Sumida A, Hasegawa S, Nakano T.
  • Organizer: The 19th International Congress of Cytology
  • Place of Presentation: パシフィコ横浜（横浜）
  • Year and Date: 2016-05-30
  • Int'l Joint Research
• [Presentation] 悪性胸膜中皮腫における液状化検体細胞診の有用性の検討 (2016)
  • Author(s): 佐藤鮎子, 篠原義康, 清水重喜, 隅田安由美, 中野孝司, 長谷川誠紀, 鍋島一樹, 辻村 亨
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-05-13
• [Presentation] 悪性中皮腫細胞株におけるオートファジーの役割 (2016)
  • Author(s): 篠原義康, 佐藤鮎子, 隅田安由美, 辻村 亨
  • Organizer: 第105回日本病理学会総会
  • Place of Presentation: 仙台国際センター（仙台）
  • Year and Date: 2016-05-12
• [Presentation] Relationship of PD-L1 Expression and Prognosis in Epithelioid Mesothelioma (2016)
  • Author(s): Tsujimura T, Kudo T, Shinohara Y, Sato A, Shimizu S, Daimon T, Hasegawa S, Nakano T.
  • Organizer: 13th International Conference of the International Mesothelioma Interest Group
  • Place of Presentation: Birmingham, UK
  • Year and Date: 2016-05-03
  • Int'l Joint Research
• [Presentation] 増加する悪性中皮腫診断のスキルアップを目指して 中皮細胞の機能と形態から診断のカギを探る 中皮腫診断の現状と将来 (2015)
  • Author(s): 辻村亨, 佐藤鮎子, 篠原義康, 工藤朝雄, 今橋祐喜, 清水重喜, 鍋島一樹, 長谷川誠紀, 中野孝司
  • Organizer: 第56回日本臨床細胞学会総会（春期大会）
  • Place of Presentation: 松江（くにびきメッセ・松江テルサ）
  • Year and Date: 2015-06-12
• [Book] 細胞診ガイドライン4 呼吸器・胸腺・体腔液・リンパ節／2015年版 (2015)
  • Author(s): 辻村亨
  • Total Pages: 270
  • Publisher: 金原出版㈱
• [Book] 石綿関連疾患の病理とそのリスクコミュニケーション (2015)
  • Author(s): 清水重喜、鳥井郁子、佐藤鮎子、辻村亨
  • Total Pages: 300
  • Publisher: 篠原出版新社