Exploratory study for identifying EMT-associated genes as novel therapeutics for lung cancer

• Project/Area Number: 23591145
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Nagoya University
• Principal Investigator: MITSUO Sato 名古屋大学, 医学部附属病院, 講師 (70467281)
• Co-Investigator(Kenkyū-buntansha): MASASHI Kondo 名古屋大学, 大学院医学系研究科, 准教授 (00378077)
• Project Period (FY): 2011 – 2013
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2011: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 肺癌 / マイクロRNA / 上皮間葉細胞転換 / EMT / 肺がん / 細胞周期 / アポトーシス / 国際情報交換 / 不死化正常気管支細胞 / ｐ53 / KRAS / EGFR / p53

Research Abstract

We evaluated the potential of miR-221 and miR222 as novel therapeutics for lung cancer. These microRNAs are shown to induce epithelial to mesenchymal transition (EMT) in normal mammary epithelial cells. Upon introduction of miR-221 or miR222, immortalized normal human bronchial epithelial cells underwent morphological changes, suggestive of EMT, in association with expression changes in EMT-associated genes. miR-221 and miR222 promoted growth in several lung cancer cell lines but suppressed in other cell lines. Cell cycle and apoptosis analyses revealed that growth suppressive effects by miR-221 and miR-221 occur through S-phase arrest and/or apoptosis. These data suggested the potential of miR-221 and miR222 as novel therapeutics for lung cancer.

Research Products

• [Journal Article] IMELESS is overexpressed in lung cancer and its expression correlates with poor patient survival. (2013)
  • Author(s): Yoshida K, Sato M, Hase T, Elshazley M, Yamashita R, Usami N, Taniguchi T, Yokoi K, Nakamura S, Kondo M, Girard L, Minna JD, Hasegawa Y.
  • Journal Title: Cancer Sci. Volume: 104 Issue: 2 Pages: 171-7
  • DOI: 10.1111/cas.12068
  • Peer Reviewed
• [Journal Article] Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations. (2013)
  • Author(s): Sato M, Larsen JE, Lee W, Sun H, Shames DS, Dalvi MP, Ramirez RD, Tang H, DiMaio JM, Gao B, Xie Y, Wistuba II, Gazdar AF, Shay JW, Minna JD
  • Journal Title: Mol Cancer Res Volume: 11 Issue: 6 Pages: 638-650
  • DOI: 10.1158/1541-7786.mcr-12-0634-t
  • Peer Reviewed
• [Journal Article] NeuroD1 regulates survival and migration of neuroendocrine lung carcinomas via signaling molecules TrkB and NCAM. (2013)
  • Author(s): Osborne JK, Larsen JE, Shields MD, Gonzales JX, Shames DS, Sato M, Kulkarni A, Wistuba II, Girard L, Minna JD, Cobb MH
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 110 Issue: 16 Pages: 6524-9
  • DOI: 10.1073/pnas.1303932110
  • Peer Reviewed
• [Journal Article] NeuroD1 regulation of migration accompanies the differential sensitivity of neuroendocrine carcinomas to TrkB inhibition. (2013)
  • Author(s): Osborne JK, Larsen JE, Gonzales JX, Shames DS, Sato M, Wistuba II, Girard L, Minna JD, Cobb MH.
  • Journal Title: Oncogenesis. Volume: 2 Issue: 8 Pages: e63-e63
  • DOI: 10.1038/oncsis.2013.24
  • Peer Reviewed
• [Journal Article] Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations. (2013)
  • Author(s): Sato M, Larsen JE, Lee W, Sun H, Shames DS, Dalvi MP, Ramirez RD, Tang H, Dimaio JM, Gao B, Xie Y, Wistuba II, Gazdar AF, Shay JW, Minna JD
  • Journal Title: Mol Cancer Res Volume: in press
  • Peer Reviewed
• [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 Issue: S3 Pages: 634-645
  • DOI: 10.1245/s10434-011-2142-0
  • 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 Issue: 12 Pages: 2820-31
  • DOI: 10.1002/ijc.27598
  • Peer Reviewed
• [Journal Article] Oncogenic KRAS-induced epiregulin overexpression contributes to aggressive phenotype and is a promising therapeutic target in non-small-cell lung cancer. (2012)
  • Author(s): Sunaga N, Kaira K, Imai H, Shimizu K, Nakano T, Shames DS, Girard L, Soh J, Sato M, Iwasaki Y, Ishizuka T, Gazdar AF, Minna JD, Mori M.
  • Journal Title: Oncogene Volume: 印刷中 Issue: 34 Pages: 4034-4042
  • DOI: 10.1038/onc.2012.402
  • Peer Reviewed
• [Journal Article] Emerging evidence of Epithelial-to-Mesenchymal Transition in lung carcinogenesis. (2012)
  • Author(s): Sato M, Shames DS, Hasegawa Y.
  • Journal Title: Respirology. Volume: 印刷中 Issue: 7 Pages: 1048-1059
  • DOI: 10.1111/j.1440-1843.2012.02173.x
  • Peer Reviewed
• [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: 印刷中
  • Peer Reviewed
• [Journal Article] Pivotal role of epithelial cell adhesion molecule in the survival of lung cancer cells (2011)
  • Author(s): Hase T, et al
  • Journal Title: Cancer Sci Volume: 102 Issue: 8 Pages: 1493-1500
  • DOI: 10.1111/j.1349-7006.2011.01973.x
  • Peer Reviewed
• [Presentation] Why, when and how to test for EGFR (2014)
  • Author(s): 佐藤光夫
  • Organizer: 第33回フィリピン呼吸器学会
  • Place of Presentation: フィリピン、マニラ
  • Year and Date: 2014-03-08
  • Invited
• [Presentation] Why, When and How to Test for EGFR (2014)
  • Author(s): Mitsuo Sato
  • Organizer: フィリピン呼吸器学会
  • Place of Presentation: フィリピン、マニラ
  • Invited
• [Presentation] 時計遺伝子Bmal1ノックダウンはアポトーシスと細胞老化を介して肺癌細胞の増殖を抑制する (2013)
  • Author(s): 山下良、佐藤光夫、長谷川好規, ら
  • Organizer: 第54回日本肺癌学会
  • Place of Presentation: ホテルニューオータニ、東京都千代田区
  • Year and Date: 2013-11-21
• [Presentation] 時計遺伝子Bmal1 ノックダウンはアポトーシスと細胞老化を介して肺癌細胞の増殖を抑制する (2013)
  • Author(s): 山下 良、佐藤 光夫、長谷川 好規ら
  • Organizer: 第54 回日本肺癌学会総会
  • Place of Presentation: ホテルニューオータニ東京(東京都、千代田区）
• [Presentation] THE COMBINATION OF FIVE CHANGES (TELOMERASE, P16/RB BYPASS, P53 KNOCKDOWN, KRASV12, C-MYC) TOGETHERWITH SERUM-INDUCED EPITHELIAL MESENCHYMAL TRANSITION PROGRESSES NORMAL HUMAN BRONCHIAL EPITHELIAL CELLS TO FULL MALIGNANCY (2012)
  • Author(s): Mitsuo Sato, Jill E. Larsen, Woochang Lee, David Shames, Ignacio I. Wistuba, Adi F. Gazdar3, Jerry W. Shay, John D. Minna, Masashi Kondo, Yoshinori Hasegawa
  • Organizer: 第5回アジア太平洋肺癌会議
  • Place of Presentation: Hilton Fukuoka Sea Hawkホテル、福岡市
  • Year and Date: 2012-11-28
• [Presentation] "THE COMBINATION OF FIVE CHANGES (TELOMERASE, P16/RB BYPASS, P53 KNOCKDOWN, KRASV12, C-MYC) TO- GETHER WITH SERUM-INDUCED EPITHELIAL MESENCHYMAL TRANSITION PROGRESSES NORMAL HUMAN BRONCHIAL EPITHELIAL CELLS TO FULL MALIGNANCY " (2012)
  • Author(s): Sato M, Larsen J, Lee W, Shames D, Ignacio I. Gazdar W, Shay J, Minna D, Kondo M, Hasegawa Y.
  • Organizer: 5th APLCC (Asian Pacific Lung Cancer Congress)
  • Place of Presentation: Fukuoka Japan
• [Presentation] TIMELESS IS OVEREXPRESSED IN LUNG CANCER AND ITS KNOCKDOWN INDUCES APOPTOSIS AND CHEMOSENSITI- ZATION IN LUNG CANCER CELLS (2012)
  • Author(s): Yoshida K, Sato M, Hase T, Momen Elshazley, Yamashita R, Usami N, Taniguchi T, Yokoi K, Kondo M,Girard L, Minna J, Hasegawa Y
  • Organizer: 5th APLCC (Asian Pacific Lung Cancer Congress)
  • Place of Presentation: Fukuoka Japan
• [Presentation] Transient but not stable ZEB1 knockdown dramatically inhibits growth of malignant pleural mesothelioma cells (2011)
  • 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
  • Organizer: 第14回世界肺癌学会
  • Place of Presentation: オランダ、アムステルダム
  • Year and Date: 2011-07-04
• [Presentation] Transient but Not Stable ZEB1 Knockdown Dramatically Inhibits Growth of Malignant Pleural Mesothelioma Cells: Implication of EpCAM Up-regulation Induced by ZEB1 Knockdown (2011)
  • Author(s): M. Horio, M. Sato, Y. Takeyama, T. Hase, E. Momen, K. Yoshida, Y. Sekido, M. Kondo, A.F. Gazdar, J.D. Minna, Y. Hasegawa
  • Organizer: 第14回世界肺がん学会
  • Place of Presentation: オランダ、アムステルダム
• [Book] Micro RNA in Regenerative Medicine (2014)
  • Author(s): Mitsuo Sato, David S. Shames, Yoshinori Hasegawa
  • Publisher: Elsevier (in press)
• [Book] Chapter 34: miRNAs in Transitions: EMT, MET, and EndoMT (2014)
  • Author(s): Mitsuo Sato, David S. Shames, Yoshinori Hasegawa
  • Publisher: Elsevier