Integrated approach for identification of tumor-suppressive microRNAs and clinical application to miRNA-based therapy for cancers

• Project/Area Number: 23390077
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KOZAKI Ken-ichi 東京医科歯科大学, 難治疾患研究所, 准教授 (50270715)
• Co-Investigator(Kenkyū-buntansha): 稲澤 譲治 東京医科歯科大学, 難治疾患研究, 教授 (30193551)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2013: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2012: ¥5,850,000 (Direct Cost: ¥4,500,000、Indirect Cost: ¥1,350,000); Fiscal Year 2011: ¥7,930,000 (Direct Cost: ¥6,100,000、Indirect Cost: ¥1,830,000)
• Keywords: 癌 / microRNA / 癌抑制遺伝子 / DNAメチル化異常 / 分子腫瘍学 / 治療ゲノム学 / 機能ゲノム学

Research Abstract

The aim of this study is to identify tumor-suppressive microRNAs (miRNAs) and their direct targets, which potentially contribute to the development of clinical application to miRNA-based therapy for cancers. Actually, in this study, three tumor-suppressive miRNAs, one EMT-suppressive miRNA, and their direct targets were identified through our integrated approach using function- and methylation-based screenings. Moreover, we demonstrated here the great potential of double-stranded RNAs (dsRNA) mimicking sequences of tumor-suppressive miRNAs to be applied to miRNA-based therapy for cancers.

Research Products

• [Journal Article] The Impact of miRNA-Based Molecular Diagnostics and Treatment of NRF2-Stabilized Tumors (2014)
  • Author(s): Yamamoto, S., Inoue, J., Kawano, T., Kozaki, K., Omura, K. and Inazawa, J.
  • Journal Title: Mol. Cancer Res. Volume: 12 Pages: 58-68
  • Peer Reviewed
• [Journal Article] The impact of miRNA-based molecular diagnostics and treatment of NRF2-stabilized tumors. (2014)
  • Author(s): Yamamoto S, Inazawa J, et al.
  • Journal Title: Mol Cancer Res. Volume: 12 Issue: 1 Pages: 58-68
  • DOI: 10.1158/1541-7786.mcr-13-0246-t
  • Peer Reviewed
• [Journal Article] miR-655 is an EMT-suppressive microRNA targeting ZEB1 and TGFBR2 (2013)
  • Author(s): Harazono, Y., Muramatsu, T., Endo, H., Uzawa, N., Kawano, T., Harada, K., Inazawa, J. and Kozaki, K.
  • Journal Title: PLOS ONE Volume: 8
  • Peer Reviewed
• [Journal Article] The tumor-suppressive miR-497-195 cluster targets multiple cell-cycle regulators in hepatocellular carcinoma (2013)
  • Author(s): Furuta, M., Kozaki, K., Tanimoto, K., Tanaka, S., Arii, S., Shimamura, T., Niida, A., Miyano, S. and Inazawa, J
  • Journal Title: PLOS ONE Volume: 8
  • Peer Reviewed
• [Journal Article] Potential of tumor-suppressive miR-596 targeting LGALS3BP as a therapeutic agent in oral cancer (2013)
  • Author(s): Endo, H., Muramatsu, T., Furuta, M., Uzawa, N., Pimkhaokham, A., Amagasa, T., Inazawa, J. and Kozaki, K.
  • Journal Title: Carcinogenesis Volume: 34 Pages: 560-569
  • Peer Reviewed
• [Journal Article] The Tumor-suppressive mir-497-195 cluster targets multiple cell-cycle regulators in hepatocellular carcinoma. (2013)
  • Author(s): Furuta M
  • Journal Title: PLoS One Volume: 8 Issue: 3 Pages: e60155-e60155
  • DOI: 10.1371/journal.pone.0060155
  • Peer Reviewed
• [Journal Article] miR-655 is an EMT-suppressive microRNA targeting ZEB1 and TGFBR2. (2013)
  • Author(s): Harazono Y, Inazawa J, et al.
  • Journal Title: PLoS One. Volume: 8 Issue: 5 Pages: e62757-e62757
  • DOI: 10.1371/journal.pone.0062757
  • Peer Reviewed
• [Journal Article] Potential of tumor-suppressive miR-596 targeting LGALS3BP as a therapeutic agent in oral cancer. (2013)
  • Author(s): Endo H, Inazawa J, et al.
  • Journal Title: Carcinogenesis. Volume: 34 Issue: 3 Pages: 560-9
  • DOI: 10.1093/carcin/bgs376
  • Peer Reviewed
• [Journal Article] Tumor-suppressive microRNA silenced by tumor-specific DNA hypermethylation in cancer cells (2012)
  • Author(s): Kozaki, K. and Inazawa, J
  • Journal Title: Cancer Sci. Volume: 103 Pages: 837-845
  • Peer Reviewed
• [Journal Article] Integrative array-based approach identifies MZB1 as a frequently methylated putative tumor-suppressor in hepatocellular carcinoma (2012)
  • Author(s): Matsumura, S., Imoto, I., Kozaki, K., Matsui, T., Muramatsu, T., Furuta, M., Tanaka, S., Sakamoto, M., Arii, S. and Inazawa, J.
  • Journal Title: Clin. Cancer Res. Volume: 18 Pages: 3541-3551
  • Peer Reviewed
• [Journal Article] SIX1 promotes epithelial-mesenchymal transition in colorectal cancer through ZEB1 activation (2012)
  • Author(s): Ono, H., Imoto, I., Kozaki, K., Tsuda, H., Matsui, T., Kurasawa, Y., Muramatsu, T., Sugihara, K. and Inazawa, J.
  • Journal Title: Oncogene Volume: 31 Pages: 4923-4934
  • Peer Reviewed
• [Journal Article] Stabilization of phenotypic plasticity through mesenchymal-specific DNA hypermethylation in cancer cells (2012)
  • Author(s): Kurasawa, Y., Kozaki, K., Pimkhaokham, A., Muramatsu, T., Ono, H., Ishihara, T., Uzawa, N., Imoto, I., Amagasa, T. and Inazawa, J.
  • Journal Title: Oncogene Volume: 31 Pages: 1963-1974
  • Peer Reviewed
• [Journal Article] Integrative array-based approach identifies MZB1 as a frequently methylated putative tumor suppressor in hepatocellular carcinoma (2012)
  • Author(s): Matsumura S, Imoto I, Kozaki K, Matsui T, Muramatsu T, Furuta M, Tanaka S, Sakamoto M, Arii S, Inazawa J
  • Journal Title: Clin Cancer Res Volume: 18 Issue: 13 Pages: 3541-51
  • DOI: 10.1158/1078-0432.ccr-11-1007
  • Peer Reviewed
• [Journal Article] Tumor-suppressive microRNA silenced by tumor-specific DNA hypermethylation in cancer cells. (2012)
  • Author(s): Kozaki K., et al.
  • Journal Title: Cancer Sci. Volume: 103 Issue: 5 Pages: 837-845
  • DOI: 10.1111/j.1349-7006.2012.02236.x
  • Peer Reviewed
• [Journal Article] SIX1 promotes epithelial-mesenchymal transition in colorectal cancer through ZEB1 activation (2012)
  • Author(s): Ono H, Imoto I, Kozaki K, Tsuda H, Matsui T, Kurasawa Y, Muramatsu T, Sugihara K, Inazawa J
  • Journal Title: Oncogene Volume: 31 Issue: 47 Pages: 4923-4934
  • DOI: 10.1038/onc.2011.646
  • Peer Reviewed
• [Journal Article] Tumor-suppressive microRNA silenced by tumor-specific DNA hypermethylation in cancer cells (2012)
  • Author(s): Kozaki, K., et al
  • Journal Title: Cancer Sci. Volume: (Epub ahead of print)
  • Peer Reviewed
• [Journal Article] The HECT-type ubiquitin ligase ITCH targets lysosomal-associated protein multispanning transmembrane 5 (LAPTM5) and prevents LAPTM5-mediated cell death (2011)
  • Author(s): Ishihara, T., Inoue, J., Kozaki, K., Imoto, I. and Inazawa, J.
  • Journal Title: J. Biol. Chem. Volume: 286 Pages: 44086-44094
  • Peer Reviewed
• [Journal Article] miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer (2011)
  • Author(s): Tsuruta, T., Kozaki, K., Uesugi, A., Furuta, M., Hirasawa, A., Imoto, I., Susumu, N., Aoki, D. and Inazawa, J.
  • Journal Title: Cancer Res Volume: 71 Pages: 6450-6462
  • Peer Reviewed
• [Journal Article] The tumor suppressive microRNA miR-218 targets the mTOR component Rictor and inhibits AKT phosphorylation in oral cancer (2011)
  • Author(s): Uesugi, A., Kozaki, K., Tsuruta, T., Furuta, M., Morita, K., Imoto, I., Omura, K. and Inazawa, J.
  • Journal Title: Cancer Res. Volume: 71 Pages: 5765-5778
  • Peer Reviewed
• [Journal Article] Stabilization of phenotypic plasticity through mesenchymal-specific DNA hypermethylation in cancer cells (2011)
  • Author(s): Kurasawa Y
  • Journal Title: Oncogene Volume: 12.31(15) Issue: 15 Pages: 1963-74
  • DOI: 10.1038/onc.2011.373
  • Peer Reviewed
• [Journal Article] HECT-type ubiquitin ligase ITCH targets lysosomal- associated protein multispanningtransmembrane 5 (LAPTM5) and prevents LAPTM5-mediated cell death (2011)
  • Author(s): Ishihara T, Inoue J, Kozaki K, Imoto I, Inazawa J
  • Journal Title: J Biol Chem Volume: 286 Issue: 51 Pages: 44086-94
  • DOI: 10.1074/jbc.m111.251694
  • Peer Reviewed
• [Journal Article] miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer (2011)
  • Author(s): Tsuruta T, Inazawa J, et al
  • Journal Title: Cancer Res Volume: 71 Issue: 20 Pages: 6450-6462
  • DOI: 10.1158/0008-5472.can-11-0364
  • Peer Reviewed
• [Presentation] Function-based screening of EMT-suppressive microRNA in cancer cells. Symposium X "Targeting Cancer Stem Cells and EMT" (2013)
  • Author(s): Kozaki, K.
  • Organizer: 2013 SNUCRI & SNUCH Cancer Symposium
  • Place of Presentation: Jeju, Korea)
  • Year and Date: 2013-05-04
  • Invited
• [Presentation] Function-based screening of EMT-suppressive microRNA by CDH1/E-cadherin-promoter activity. Symposia "MicroRNA for cancer therapy and diagnosis" (2013)
  • Author(s): Kozaki, K. and Inazawa, J.
  • Organizer: 72st Annual Meeting of Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] Function-based screening of EMT-suppressive microRNA by CDH1/E-cadherin-promoter activity. (2013)
  • Author(s): Kozaki, K. and Inazawa, J.
  • Organizer: 72st Annual Meeting of Japanese Cancer Association
  • Place of Presentation: Yokohama
• [Presentation] Function-based screening of EMT-suppressive microRNA in cancer cells. (2013)
  • Author(s): Kozaki K.
  • Organizer: 2013 SNUCRI & SNUCH Cancer Symposium
  • Place of Presentation: Jeju, Korea
  • Invited
• [Presentation] DNA過剰メチル化異常により発現抑制される癌抑制遺伝子型microRNA (2012)
  • Author(s): 小崎健一
  • Organizer: お茶の水がん学アカデミア第82回集会
  • Place of Presentation: 東京・順天堂大学
  • Year and Date: 2012-03-21
• [Presentation] Methylation-based screening of tumor-suppressive microRNAs in cancer cells. Symposia "Recent progress of non-coding RNA and cancer" (2012)
  • Author(s): Kozaki, K., Endo, H. and Inazawa, J.
  • Organizer: 71st Annual Meeting of Japanese Cancer Association
  • Place of Presentation: Sapporo
• [Presentation] DNA過剰メチル化により発現抑制される癌抑制遺伝子型microRNAの機能的スクリーニング (2011)
  • Author(s): 小崎健一, 他
  • Organizer: 日本人類遺伝学会第56回大会・第11回東アジア人類遺伝学会
  • Place of Presentation: 幕張
  • Year and Date: 2011-11-10
• [Presentation] Function-based screening of tumor-suppressive microRNAs silenced by DNA hypermethylation in cancer cells (2011)
  • Author(s): Kozaki, K., et al
  • Organizer: 70th Annual Meeting of Japanese Cancer Association
  • Place of Presentation: Nagoya
  • Year and Date: 2011-10-04
• [Presentation] DNA 過剰メチル化により発現抑制される癌抑制遺伝子型microRNA の機能的スクリーニング. シ ンポ ジ ウ ム1「small RNA と疾患」 (2011)
  • Author(s): 小崎健一,稲澤譲治
  • Organizer: 日本人類遺伝学会 第56回大会・第11回 東アジア人類遺伝学会
  • Place of Presentation: 幕張
• [Presentation] Function-based screening of tumor-suppressive microRNAs silenced by DNA hypermethylation in cancer cells. Symposia "Cancer epigenetics : Breakthroughs in basic research and clinical applications" (2011)
  • Author(s): Kozaki, K. and Inazawa, J
  • Organizer: 70th Annual Meeting of Japanese Cancer Association
  • Place of Presentation: Nagoya
• [Presentation] Methylation-based screening of tumor-suppressive microRNAs in cancer cells.
  • Author(s): Kozaki K.
  • Organizer: 71st Annual Meeting of Japanese Cancer Association
  • Place of Presentation: Sapporo
• [Book] 肝細胞癌の 早期診断; 画像と分子マーカー、肝細胞癌関連 microRNA. 肝細胞癌の早期診断;画像と分子マーカー (2012)
  • Author(s): 小崎健一,古田繭子,井本逸勢,稲澤譲治
  • Publisher: アークメディア社
• [Book] 肝細胞癌の早期診断；画像と分子マーカー, (監・編集) 有井滋樹, 松井 修 (2012)
  • Author(s): 小崎健一
  • Publisher: (株) アークメディア社
• [Book] 肝細胞癌の早期診断;画像と分子マーカー,(監・編集)有井滋樹,松井修 (2012)
  • Author(s): 小崎健一, 他
  • Publisher: (株)アークメディア社
• [Remarks] 東京医科歯科大学 難治疾患研究所 分子細胞遺伝分野
  • URL: http://aqua.tmd.ac.jp/ResDB/DispRsch/dsp_resdata.php?id=1694&la=ja
• [Remarks] KALEN
  • URL: http://kaken.nii.ac.jp/d/r/50270715
• [Remarks] ReaD&Researchmap
  • URL: http://researchmap.jp/read0203939/
• [Remarks] 東京医科歯科大学 難治疾患研究所 分子細胞遺伝学
  • URL: http://www.tmd.ac.jp/mri/cgen/framepage.htm
• [Remarks] 東京医科歯科大学ホームページ 研究情報データベース
  • URL: http://aqua.tmd.ac.jp/ResDB/DispRsch/dsp_resdata.php?id=1694&la=ja
• [Patent(Industrial Property Rights)] 癌の検出方法および癌抑制剤 (2012)
  • Inventor(s): 稲澤譲治,小崎健一,井本逸勢
  • Industrial Property Rights Holder: 富士フィルム株式会社,国立大学法人東京医科歯科大学
  • Industrial Property Rights Type: 特許
  • Acquisition Date: 2012-10-26
• [Patent(Industrial Property Rights)] 癌の検出方法および癌抑制剤 (2012)
  • Inventor(s): 稲澤譲治,小崎健一,井本逸勢
  • Industrial Property Rights Holder: 富士フィルム株式会社,国立大学法人東京医科歯科大学
  • Industrial Property Rights Type: 特許
  • Acquisition Date: 2012-05-22
  • Overseas
• [Patent(Industrial Property Rights)] 癌の検出方法および癌抑制剤 (2011)
  • Inventor(s): 稲澤譲治, 小崎健一, 井本逸勢
  • Industrial Property Rights Holder: 富士フィルム株式会社,国立大学法人東京医科歯科大学
  • Industrial Property Rights Type: 特許
  • Acquisition Date: 2011-04-27
  • Overseas