嫌気性微小環境に応答する難治性消化器癌幹細胞の新しい転写制御機構の解明と創薬応用

• Project Area: Integrative Research on Cancer Microenvironment Network
• Project/Area Number: 25112708
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Osaka University
• Principal Investigator: 石井 秀始 大阪大学, 医学(系)研究科(研究院), 特任教授(常勤) (10280736)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000); Fiscal Year 2014: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000); Fiscal Year 2013: ¥3,770,000 (Direct Cost: ¥2,900,000、Indirect Cost: ¥870,000)
• Keywords: 癌 / ゲノム / 発現制御 / 薬学 / 臨床

Outline of Annual Research Achievements

癌微小環境の新しい研究:治療抵抗性癌幹細胞内pyruvate kinase[PKM2]の『非代謝性機能』が関わる新しい癌悪性化機構の解明と創薬応用を明確な出口戦略として設定するために、PKM2の代謝性機能から『非代謝性機能』に注目して研究を進めた。前年度に引き続き今年度は解糖系酵素の非代謝性機能に注目してPKM2の下流でエピゲノムの同体を分子論的に究明した。微小環境に応答する難治性消化器癌の分子病態を究明し、革新的な創薬のための基盤を構築した。【創薬】2つの創薬標的(核移行・核内）のうち、この段階では核移行に焦点を当てて、Cell Imaging Systemでsemi-HTS(High-Throughput-Screening)した。【核内転写制御】核内PKM2複合対が結合するDNA配列をゲノムワイドで明らかにし、データベースと照合して核内PKM2下流の遺伝子を同定した。【創薬】核内PKM2が標的プロモーター結合の人工的制御をPOCとして、阻害剤、デコイをスクリーニングした。以上より難治癌の転移に関わる癌代謝とエピゲノムの関連性を分子論的に究明した。

Research Progress Status

26年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

26年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] Ultra-sensitive liquid biopsy of circulating extracellular vesicles using ExoScreen. (2014)
  • Author(s): Yoshioka Y, Kosaka N, Konishi Y, Ohta H, Okamoto H, Sonoda H, Nonaka R, Yamamoto H, Ishii H, Mori M, Furuta K, Nakajima T, Hayashi H, Sugisaki H, Higashimoto H, Kato T, Takeshita F, Ochiya T.
  • Journal Title: Nat. Commun. Volume: 5 Pages: 3591-3591
  • DOI: 10.1038/ncomms4591
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] LZTS1 downregulation confers paclitaxel resistance and is associated with worse prognosis in breast cancer. (2014)
  • Author(s): Lovat, F., Ishii, H., Schiappacassi, M., Fassan, M., Barbareschi, M., Galligioni, E., Gasparini, P., Baldassarre, G., Croce, CM., Vecchione, A.
  • Journal Title: Oncotarget Volume: 5 Pages: 970-977
  • Peer Reviewed
• [Journal Article] CD10 as a novel marker of therapeutic resistance and cancer stem cells in head and neck squamous cell carcinoma. (2014)
  • Author(s): Fukusumi T, Ishii H, Konno M, Yasui T, Nakahara S, Takenaka Y, Yamamoto Y, Nishikawa S, Kano Y, Ogawa H, Hasegawa S, Hamabe A, Haraguchi N, Doki Y, Mori M, Inohara H.
  • Journal Title: Br. J. Cancer Volume: 111(3) Pages: 506-514
  • DOI: 10.1038/bjc.2014.289
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] MicroRNA-1246 expression associated with CCNG2-mediated chemoresistance and stemness in pancreatic cancer. (2014)
  • Author(s): Hasegawa S, Eguchi H, Nagano H, Konno M, Tomimaru Y, Wada H, Hama N, Kawamoto K, Kobayashi S, Nishida N, Koseki J, Nishimura T, Gotoh N, Ohno S, Yabuta N, Nojima H, Mori M, Doki Y, Ishii H.
  • Journal Title: B.r J. Cancer Volume: 111 Pages: 1572-1580
  • DOI: 10.1038/bjc.2014.454
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Combined evaluation of hexokinase 2 and phosphorylated pyruvate dehydrogenase-E1α in invasive front lesions of colorectal tumors predicts cancer metabolism and patient prognosis. (2014)
  • Author(s): Hamabe, A. Yamamoto, H. Konno, M. Uemura, M. Nishimura, J. Hata, T. Takemasa, I. Mizushima, T. Nishida, N. Kawamoto, K. Koseki, J. Doki, Y. Mori, M. Ishii, H.
  • Journal Title: Cancer Sci. Volume: 105 Pages: 1100-1108
  • DOI: 10.1111/cas.12487
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Role of pyruvate kinase M2 in transcriptional regulation leading to epithelial-mesenchymal transition. (2014)
  • Author(s): Hamabe, A. Konno, M. Tanuma, N. Shima, H. Tsunekuni, K. Kawamoto, K. Nishida, N. Koseki, J. Mimori, K. Gotoh, N. Yamamoto, H. Doki, Y. Mori, M. Ishii, H.
  • Journal Title: Proc Natl Acad Sci U S A. Volume: 111 Pages: 15526-15531
  • DOI: 10.1073/pnas.1407717111
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cancer Stem Cells of the Digestive System. (2014)
  • Author(s): Colvin, S. H., Nishida, N., Koseki, J., Konno, M., Kawamoto, K., Tsunekuni, K., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Jpn. J. Clin. Oncol. Volume: 44 Pages: 1141-1149
  • DOI: 10.1093/jjco/hyu146
  • Peer Reviewed
• [Journal Article] SSEA-3 as a novel amplifying cancer cell surface marker in colorectal cancers. (2013)
  • Author(s): Suzuki, Y., Haraguchi, N., Takahashi, H., Uemura, M., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Ishii, H., Doki, Y., Mori, M., Yamamoto, H.
  • Journal Title: Int. J. Oncol Volume: 42 Pages: 161-167
  • DOI: 10.3892/ijo.2012.1713
  • Peer Reviewed
• [Journal Article] Depletion of JARID1B induces cellular senescence in human colorectal cancer. (2013)
  • Author(s): Ohta, K., Haraguchi, N., Kano, Y., Kagawa, Y., Konno, M., Nishikawa, S., Hamabe, A., Hasegawa, S., Ogawa, H., Fukusumi, T., Uemura, M., Nishimura, J., Hata, T., Takemasa, I., Nishimura, T., Noguchi, Y., Ozaki, M., Kudo, T., Sakai, D., Satoh, T., Fukami, M., Ishii, M., Yamamoto, H., Doki, Y., Mori, M., Ishii, H.
  • Journal Title: Int. J. Oncol. Volume: 42 Pages: 1212-1218
  • DOI: 10.3892/ijo.2013.1799
  • Peer Reviewed
• [Journal Article] Jumonji/Arid1b (Jarid1b) protein modulates human esophageal cancer cell growth (2013)
  • Author(s): Kano, Y., Konno, M., Ohta, K., Haraguchi, N., Nishikawa, S., Kagawa, Y., Hamabe, A., Hasegawa, S., Ogawa, H., Fukusumi, T., Noguchi, Y., Ozaki, M., Kudo, T., Sakai, D., Satoh, T., Ishii, M., Mizohata, E., Inoue, T., Mori, M., Doki, Y., Ishii, H.
  • Journal Title: Molecular and Clinical Oncology Volume: 1 Pages: 753-757
  • DOI: 10.3892/mco.2013.127
  • Peer Reviewed
• [Journal Article] Effect of in vivo administration of reprogramming factors in the mouse liver. (2013)
  • Author(s): 6） Tomokuni, A., Eguchi, H., Hoshino, H., Dewi, DL., Nishikawa, S., Kano, Y., Miyoshi, N., Tojo, A., Kobayashi, S., Gotoh, N., Hinohara, K., Fusaki, N., Saito, T., Suemizu, H., Wada, H., Kobayashi, S., Marubashi, S., Tanemura, M., Doki, Y., Mori, M.,et.al.
  • Journal Title: Oncol Lett. Volume: 6 Pages: 323-328
  • DOI: 10.3892/ol.2013.1418
  • Peer Reviewed
• [Journal Article] Aldehyde dehydrogenasehigh gastric cancer stem cells are resistant to chemotherapy. (2013)
  • Author(s): Nishikawa, S., Konno, M., Hamabe, A., Hasegawa, S., Kano, Y., Ohta, K., Fukusumi, T., Sakai, D., Kudo, T., Haraguchi, N., Satoh, T., Takiguchi, S., Mori, M., Doki,Y., Ishii, H.
  • Journal Title: Int J Oncol. Volume: 42 Pages: 1437-1442
  • DOI: 10.3892/ijo.2013.1837
  • Peer Reviewed
• [Journal Article] CD49f-positive cell population efficiently enriches colon cancer-initiating cells. (2013)
  • Author(s): Haraguchi, N., Ishii, H., Mimori, K., Ohta, K., Uemura, M., Nishimura, J., Hata, T., Takemasa, I., Mizushima, T., Yamamoto, H., Doki, Y., Mori, M.
  • Journal Title: Int J Oncol. Volume: 43 Pages: 425-430
  • DOI: 10.3892/ijo.2013.1955
  • Peer Reviewed
• [Presentation] Innovative drug discovery for intractable cancer stem cells (2014)
  • Author(s): 石井秀始
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場(大阪）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 難治性消化器癌に対する革新的治療法 (2014)
  • Author(s): 石井秀始、土岐祐一郎、森正樹
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] 創薬標的としての癌幹細胞エピゲノム代謝 (2014)
  • Author(s): 石井秀始
  • Organizer: 第73回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2014-09-25 – 2014-09-27
• [Presentation] Innvovative Medicine for Gastrointestinal Cancer Stem Cells (2014)
  • Author(s): 石井秀始
  • Organizer: 第52回日本癌治療学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川)
  • Year and Date: 2014-08-28 – 2014-08-30
• [Presentation] 難治性消化器癌に対する革新的医療技術の創出 (2013)
  • Author(s): 石井秀始、土岐 祐一郎、森 正樹
  • Organizer: 第72回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] 癌幹細胞研究の現状と展望 (2013)
  • Author(s): 石井秀始
  • Organizer: 第23回日本サイトメトリー学会学術集会
  • Place of Presentation: 日本医科大学橘桜会館（東京都）