Identification of genetic alterations in malignant mesothelioma and the development of new molecular diagnostic tools

• Project/Area Number: 22300338
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor diagnosis
• Research Institution: Aichi Cancer Center Research Institute
• Principal Investigator: SEKIDO Yoshitaka 愛知県がんセンター(研究所), 分子腫瘍学部, 部長 (00311712)
• Project Period (FY): 2010 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥17,290,000 (Direct Cost: ¥13,300,000、Indirect Cost: ¥3,990,000); Fiscal Year 2012: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2011: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2010: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
• Keywords: 中皮腫 / がん抑制遺伝子 / がん遺伝子 / ゲノム異常 / シグナル伝達 / 癌 / ゲノム

Research Abstract

We identified that the LATS2 gene is a novel tumor suppressor gene of malignant mesothelioma (MM) and that LATS2 is inactivated in around 20% of MM cases. Inactivation of NF2 and/or LATS2 results in dysregulation of the Hippo tumor suppressive signaling cascade in MM cells. We found that Hippo pathway inactivation causes YAP activation and enhances transcription of the cyclin D and CTGF genes, which induces a more malignant phenotype of MM.

Research Products

• [Journal Article] EGCG induces human mesothelioma cell death by inducing reactive oxygen species and autophagy (2013)
  • Author(s): Satoh M, Takemura Y, Hamada H, Sekido Y, Kubota S
  • Journal Title: Cancer Cell Int Volume: 13 Pages: 19-19
  • DOI: 10.1186/1475-2867-13-19
• [Journal Article] Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothelioma cells. (2012)
  • Author(s): Horio M, Sato M, Takeyama Y, Elshazley M, Yamashita R, Hase T, Yoshida K, Usami N, Yokoi K, Sekido Y, Kondo M, Toyokuni S, Gazdar AF, Minna JD, Hasegawa Y
  • Journal Title: Ann Surg Oncol. Volume: 19 Supple3
  • DOI: 10.1245/s10434-011-2142-0
  • Peer Reviewed
• [Journal Article] YAP induces malignant mesothelioma cell proliferation by upregulating transcription of cell cycle promoting genes. (2012)
  • Author(s): Mizuno T, Murakami H, Fujii M, Ishiguro F, Tanaka I, Kondo Y, Akatsuka S, Toyokuni S, Yokoi K, Osada H, Sekido Y
  • Journal Title: Oncogene Volume: 31 Pages: 5117-22
  • DOI: 10.1038/onc.2012.5
  • Peer Reviewed
• [Journal Article] Activated leukocyte cell adhesion molecule (ALCAM) promotes malignant phenotypes of malignant mesothelioma. (2012)
  • Author(s): Ishiguro F, Murakami H, Mizuno T, Fujii F, Kondo Y, Usami N, Yokoi K, Osada H, Sekido Y
  • Journal Title: J Thorac Oncol. Volume: 7 Pages: 890-899
  • DOI: 10.1097/jto.0b013e31824af2db
  • Peer Reviewed
• [Journal Article] TGF-β synergizes with defects in the Hippo pathway to stimulate human malignant mesothelioma growth (2012)
  • Author(s): Fujii M, Toyoda T, Nakanishi H, Yatabe Y, Sato A, Matsudaira Y, Ito H, Murakami H, Kondo Y, Kondo E, Hida T, Tsujimura T, Osada H, Sekido Y.
  • Journal Title: The Journal of Experimental Medicine Volume: VOL.209(3) Pages: 479-494
  • DOI: 10.1084/jem.20111653
  • Peer Reviewed
• [Journal Article] The circadian clock gene BMAL1 is a novel therapeutic target for malignant mesothelioma. (2012)
  • Author(s): Elshazley M, Sato M, Hase T, Yamashita R, Yoshida K, Toyokuni S, Ishiguro F, Osada H, Sekido Y, Yokoi K, Usami N, Shames DS, Kondo M, Gazdar AF, Minna JD, Hasegawa Y
  • Journal Title: Int J Cancer. Volume: 131 Pages: 2820-2831
  • DOI: 10.1002/ijc.27598
  • Peer Reviewed
• [Journal Article] Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer. (2012)
  • Author(s): Liu Y, Izumiya M, Abe K, Ochiai M, Jiang L, Nagai H, Okazaki Y, Murakami H, Sekido Y, Arai E, Kanai Y, Hino O, Takahashi T, Nakagama H, Toyokuni S
  • Journal Title: PLoS ONE Volume: 7
  • DOI: 10.1371/journal.pone.0043403
  • Peer Reviewed
• [Journal Article] Convergent signaling in the regulation of connective tissue growth factor in malignant mesothelioma: TGF-β signaling and defects in the Hippo signaling cascade. (2012)
  • Author(s): Fujii M, Nakanishi H, Toyoda T, Tanaka I, Kondo Y, Osada H, Sekido Y
  • Journal Title: Cell Cycle Volume: 11 Pages: 3373-3379
  • DOI: 10.4161/cc.21397
• [Journal Article] Inactivation of Merlin in malignant mesothelioma cells and the Hippo signaling cascade dysregulation. (2011)
  • Author(s): Sekido Y
  • Journal Title: Pathology International Volume: 61 Pages: 331-344
  • DOI: 10.1111/j.1440-1827.2011.02666.x
  • NAID: 10031185092
• [Journal Article] Induction of tubulin polymerization and apoptosis in malignant mesothelioma cells by a new compound JBIR-23. (2011)
  • Author(s): Hwang JH, Takagi M, Murakami H, Sekido Y, Shin-Ya K
  • Journal Title: Cancer Lett Volume: 300 Pages: 189-96
• [Journal Article] LATS2 is a tumor suppressor gene of malignant mesothelioma. (2011)
  • Author(s): Murakami H, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, Hida T, Kondo Y, Toyokuni S, Osada H, Sekido Y
  • Journal Title: Cancer Res Volume: 71 Pages: 873-83
• [Journal Article] 5-Aminolevulinic acid-induced fluorescence diagnosis of pleural malignant tumor. (2011)
  • Author(s): Ali AH, Takizawa H, Kondo K, Matsuoka H, Toba H, Nakagawa Y, Kenzaki K, Sakiyama S, Kakiuchi S, Sekido Y, Sone S, Tangoku A
  • Journal Title: Lung Cancer Volume: 74 Pages: 48-54
  • DOI: 10.1016/j.lungcan.2011.01.031
• [Journal Article] LATS2 is a tumor suppressor gene of malignant mesothelioma (2011)
  • Author(s): Murakami, et al
  • Journal Title: Cancer Research Volume: 71 Pages: 873-883
  • Peer Reviewed
• [Journal Article] Osteopontin-mediated enhanced hyaluronan binding induces multidrug resistance in mesothelioma cells. (2010)
  • Author(s): Tajima K, Ohashi R, Sekido Y, Hida T, Nara T, Hashimoto M, Iwakami S, Minakata K, Yae T, Takahashi F, Saya H, Takahashi K
  • Journal Title: Oncogene Volume: 29 Pages: 1941-51
  • DOI: 10.1038/onc.2009.478
• [Journal Article] High dose of ascorbic acid induces cell death in mesothelioma cells. (2010)
  • Author(s): Takemura Y, Satoh M, Satoh, K, Hamada H, Sekido Y, Kubota S
  • Journal Title: BBRC Volume: 394 Pages: 249-53
  • DOI: 10.1016/j.bbrc.2010.02.012
• [Presentation] Molecular Abnormalities and Cell Signaling Dysregulation of Malignant Pleural Mesothelioma (2012)
  • Author(s): 関戸好孝
  • Organizer: The 17th Congress of the Asian Pacific Society of Respirology (APSR).
  • Place of Presentation: Hong Kong Convention and Exhibition Centre (香港、中国)
  • Year and Date: 2012-12-15
• [Presentation] 悪性中皮腫におけるHippoシグナリング伝達系異常と遺伝子発現. (2012)
  • Author(s): 関戸好孝
  • Organizer: Japan Mesothelioma Interest Group (JMIG) 2012会議.
  • Place of Presentation: 京都私学会館(京都)
  • Year and Date: 2012-11-17
• [Presentation] Carcinogenesis induced by asbestos exposure and genetic abnormalities in mesothelioma cells. (2012)
  • Author(s): 関戸好孝
  • Organizer: 第50回日本癌治療学会学術総会.
  • Place of Presentation: パシフィコ横浜(横浜)
  • Year and Date: 2012-10-26
• [Presentation] Hippo signaling pathway inactivation in malignant mesothelioma cells. (2012)
  • Author(s): 関戸好孝、田中一大、長田啓隆、藤井万紀子
  • Organizer: 世界中皮腫グループ会議2012 (International Mesothelioma Interest Group: IMIG).
  • Place of Presentation: World Trade Center (ボストン、米国)
  • Year and Date: 2012-09-13
• [Presentation] Dysregulation of signal transduction cascades in malignant mesothelioma cells induces connective tissue growth factor (CTGF) expression. (2011)
  • Author(s): 関戸好孝
  • Organizer: 9th China-Japan Joint Conference of Cancer.
  • Place of Presentation: Oriental Riverside Hotel Shanghai(上海、中国)
  • Year and Date: 2011-12-22
• [Presentation] Dysregulation of signal transduction cascades in malignant mesothelioma cells induces connective tissue growth factor (CTGF) expression (2011)
  • Author(s): 関戸好孝
  • Organizer: 9th China-Japan Joint Conference of Cancer
  • Place of Presentation: Oriental Riverside Hotel Shanghai(上海,中国)
  • Year and Date: 2011-12-22
• [Presentation] 悪性中皮腫における新規がん抑制遺伝子LATS2の同定とYAPがん遺伝子の活性化. (2011)
  • Author(s): 関戸好孝
  • Organizer: 第52回日本肺癌学会.
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2011-11-04
• [Presentation] 悪性中皮腫における新規がん抑制遺伝子LATS2の同定とYAPがん遺伝子の活性化 (2011)
  • Author(s): 関戸好孝
  • Organizer: 第52回日本肺癌学会
  • Place of Presentation: 大阪国際会議場(大阪)
  • Year and Date: 2011-11-04
• [Presentation] 悪性中皮腫の分子病態. (2011)
  • Author(s): 関戸好孝
  • Organizer: 第70回日本癌学会学術総会.
  • Place of Presentation: 名古屋国際会議場(名古屋)
  • Year and Date: 2011-10-05
• [Presentation] 悪性中皮腫におけるHippoシグナル伝達系異常. (2011)
  • Author(s): 関戸好孝
  • Organizer: 第84回日本生化学会大会.
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2011-09-21
• [Presentation] 悪性中皮腫におけるHippoシグナル伝達系異常 (2011)
  • Author(s): 関戸好孝
  • Organizer: 第84回日本生化学会大会
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2011-09-21
• [Presentation] 悪性中皮腫細胞におけるNF2 (マーリン)-Hippoシグナル伝達系の異常. (2010)
  • Author(s): 関戸好孝
  • Organizer: BMB2010.
  • Place of Presentation: 神戸ポートアイランド(神戸)
  • Year and Date: 2010-12-08
• [Presentation] LATS2 is a tumor suppressor gene of malignant mesothelioma. (2010)
  • Author(s): 関戸好孝
  • Organizer: 2nd Workshop on the Hippo Tumor Suppressor Pathway.
  • Place of Presentation: Palazzo Chigi (イタリア・ローマ)
  • Year and Date: 2010-11-05
• [Presentation] Inactivation of LATS2 indicates frequent dysregulation of the Merlin-Hippo signaling pathway in malignant mesothelioma. (2010)
  • Author(s): Sekido Y, Mizuno T, Taniguchi T, Fujii M, Ishiguro F, Fukui T, Akatsuka S, Horio Y, Hida T, Kondo Y, Toyokuni S, Osada H, Murakami H.
  • Organizer: 10th International Conference of International Mesothelioma Interest Group (iMig)
  • Place of Presentation: 京都国際会館(京都)
  • Year and Date: 2010-09-02
• [Presentation] Inactivation of LATS2 indicates frequent dysregulation of the Merlin-Hippo signaling pathway in malignant mesothelioma (2010)
  • Author(s): 関戸好孝, ら
  • Organizer: 第10回世界中皮腫会議(IMIG2010)
  • Place of Presentation: 国立京都国際会館(京都)
  • Year and Date: 2010-09-02
• [Presentation] Hippo signaling pathway inactivation in malignant mesothelioma cells
  • Author(s): 関戸好孝
  • Organizer: iMig (international Mesothelioma interest group）2012 meeting
  • Place of Presentation: Seaport Hotel and World Trade Center（米国 ボストン）
• [Presentation] Carcinogenesis induced by asbestos exposure and genetic abnormalities in mesothelioma cells
  • Author(s): 関戸好孝
  • Organizer: 第50回日本癌治療学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜）
  • Invited
• [Presentation] 悪性中皮腫におけるHippoシグナリング伝達系異常と遺伝子発現
  • Author(s): 関戸好孝
  • Organizer: Japan Mesothelioma Interest Group (JMIG) 2012
  • Place of Presentation: 京都私学会館（京都）
• [Presentation] Molecular Abnormalities and Cell Signaling Dysregulation of Malignant Pleural Mesothelioma
  • Author(s): 関戸好孝
  • Organizer: The 17th Congress of the Asian Pacific Society of Respirology
  • Place of Presentation: Hong Kong Convention and Exhibition Centre (中国、香港)
  • Invited
• [Remarks]
  • URL: http://www.pref.aichi.jp/cancer-center/ri/01bumon/03bunshi_shuyo/index.html
• [Remarks]
  • URL: http://www.pref.aichi.jp/cancer-center/ri/01bumon/03bunshi_shuyo/index.html
• [Remarks]
  • URL: http://www.pref.aichi.jp/cancer-center/400/420/421/421-03.html