2014 Fiscal Year Annual Research Report
| Project Area | Development of Novel Treatment Strategies Targeting Cancer Stem Cells |
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| Project/Area Number |
22130005
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
田中 真二 東京医科歯科大学, 医歯学総合研究科, 教授 (30253420)
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| Co-Investigator(Kenkyū-buntansha) |
森 正樹 大阪大学, 医学(系)研究科(研究院), 教授 (70190999)
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| Project Period (FY) |
2010-04-01 – 2015-03-31
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| Keywords | 癌 / 外科 / 再生医学 / トランスレーショナルリサーチ / シグナル伝達 / プロテアソーム / 細胞周期 / 代謝 |
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| Outline of Annual Research Achievements |
本課題では、幹細胞のプロテアソーム非依存性（田中）と細胞周期特性（森・石井）の二つのアプローチに基づいて癌幹細胞を可視化し、生体内の動態解明と創薬展開を図るのが目的である。
田中は本研究課題によって作成した幹細胞性可視化トランスジェニックマウスを用いて膵発癌メカニズムを解析した。その結果、acinar to ductal metaplasia (ADM)によって一過性に幹細胞性が変化し、かつKRASシグナルが一時的に亢進することを見出した。次に膵特異的KRAS変異マウスPdx-1-Cre：LSL-KrasG12Dと掛け合わせて解析を進めた。KRAS変異マウスではADMによる幹細胞性変化が持続することを見出し、KRASシグナル、Cyclin D1、NF-kBなどが持続的に亢進した結果 膵癌前駆病変を生じることを明らかにした。以上により膵発癌における幹細胞性変化とKRASシグナルの重要性を明確にし、その持続性が発癌を惹起するという新規メカニズムを解明した。
また森・石井は、癌幹細胞の細胞周期静止期にある生物学的特徴を明らかにする目的で、生体イメージングによる癌幹細胞可視化を行った。細胞周期をG1期-赤、S/G2/M期-緑でリアルタイムに可視化できるFucci(Fluorescent Ubiquitination-based Cell Cycle Indicator)をヒト消化器癌幹細胞に導入して解析を行った。その結果G1期ではRFPL4Aをはじめ複数の分子が重要であることを明らかにした。またS/G2/M期の制御に関しては、IFNAR2遺伝子をはじめ複数の遺伝子が重要であることを明らかにした。以上により難治性消化器癌の癌幹細胞の根源である分子機構を解明した。
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| Research Progress Status |
26年度が最終年度であるため、記入しない。
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| Strategy for Future Research Activity |
26年度が最終年度であるため、記入しない。
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[Journal Article] DNA methylation at hepatitis B viral integrants is associated with methylation at flanking human genomic sequences.2015
Author(s)
Watanabe Y, Yamamoto H, Oikawa R, Toyota M, Yamamoto M, Kokudo N, Tanaka S, Arii S, Yotsuyanagi H, Koike K, Itoh F.
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Journal Title
Genome Research
Volume: 25(3)
Pages: 328-337
DOI
Peer Reviewed
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[Journal Article] A novel therapeutic combination targeting sequentially Aurora B and Bcl-xL in hepatocellular carcinoma.2015
Author(s)
Matsunaga H, Tanaka S, Aihara A, Ogawa K, Matsumura S, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Arii S, Tanabe M.
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Journal Title
Annals of Surgical Oncology
Volume: in press
Pages: in press
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] RFPL4A increases the G1 population and decreases sensitivity to chemotherapy in human colorectal cancer cells.2015
Author(s)
Naito A, Yamamoto H, Kagawa Y, Naito Y, Okuzaki D, Otani K, Iwamoto Y, Maeda S, Kikuta J, Nishikawa K, Uemura M, Nishimura J, Hata T, Takemasa I, Mizushima T, Ishii H, Doki Y, Mori M, Ishii M.
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Journal Title
J Biol Chem
Volume: 290(10)
Pages: 6326-6337,
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] EpCAM-targeted therapy for human hepatocellular carcinoma.2014
Author(s)
Ogawa K, Tanaka S, Matsumura S, Murakata A, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Tanabe M, Arii S.
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Journal Title
Annals of Surgical Oncology
Volume: 21(4)
Pages: 1314-1322.
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Reduced organic anion transporter expression is a risk factor for hepatocellular carcinoma in chronic hepatitis C patients.2014
Author(s)
Yasui Y, Kudo A, Kurosaki M, Matsuda S, Muraoka M, Tamaki N, Suzuki S, Hosokawa T, Ueda K, Matsunaga K, Nakanishi H, Tsuchiya K, Itakura J, Takahashi Y, Tanaka S, Asahina Y, Enomoto N, Arii S, Izumi N.
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Journal Title
Oncology
Volume: 86(1)
Pages: 53-62
DOI
Peer Reviewed
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[Journal Article] Age-related clinicopathological and molecular features of patients received curative hepatectomy for hepatocellular carcinoma.2014
Author(s)
Katsuta E, Tanaka S, Mogushi K, Matsumura S, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Tanaka H, Tanabe M, Arii S.
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Journal Title
American Journal of Surgery
Volume: 208(3)
Pages: 450-456
DOI
Peer Reviewed / Acknowledgement Compliant
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[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.
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Journal Title
Nature Communications
Volume: 5
Pages: 3591
DOI
Peer Reviewed / Open Access / Acknowledgement Compliant
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[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.
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Journal Title
Br J Cancer
Volume: 111(3)
Pages: 506-514
DOI
Peer Reviewed / Acknowledgement Compliant
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[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.
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Journal Title
Br J Cancer
Volume: 111(8)
Pages: 1572-1580
DOI
Peer Reviewed / Acknowledgement Compliant
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[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, Hirofumi Y, Konno M, Uemura M, Nishimura J, Hata T, Takemasa I, Mizushima T, Nishida N, Kawamoto K, Koseki J, Doki Y, Mori M, Ishii H.
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Journal Title
Cancer Sci
Volume: 105(9)
Pages: 1100-1108
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Identification of chemoradiation-resistant osteosarcoma stem cells using an imaging system for proteasome activity.2014
Author(s)
Tamari K, Hayashi K, Ishii H, Kano Y, Konno M, Kawamoto K, Nishida N, Koseki J, Fukusumi T, Hasegawa S, Ogawa H, Hamabe A, Miyo M, Noguchi K, Seo Y, Doki Y, Mori M, Ogawa K.
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Journal Title
Int J Oncol
Volume: 45(6)
Pages: 2349-2354
DOI
Peer Reviewed / Acknowledgement Compliant
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[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, Gotho N, Yamamoto H, Doki Y, Mori M, Ishii H.
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Journal Title
Proc Natl Acad Sci USA
Volume: 111(43)
Pages: 15526-15531
DOI
Peer Reviewed / Acknowledgement Compliant
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[Journal Article] Interferon-α acts on the S/G2/M phases to induce apoptosis in the G1 phase of an IFNAR2-expressing hepatocellular carcinoma cell line.2014
Author(s)
Maeda S, Wada H, Naito Y, Nagano H, Simmons S, Kagawa Y, Naito A, Kikuta J, Ishii T, Tomimaru Y, Hama N, Kawamoto K, Kobayashi S, Eguchi H, Umeshita K, Ishii H, Doki Y, Mori M, Ishii M.
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Journal Title
J Biol Chem
Volume: 289(34)
Pages: 23786-23795
DOI
Peer Reviewed / Acknowledgement Compliant
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[Presentation] A preclinical study of EpCAM-targeted therapy for human hepatocellular carcinoma with stem cell features.2014
Author(s)
Tanaka S, Ogawa K, Matsumura S, Aihara A, Ban D, Ochiai T, Irie T, Kudo A, Arii S, Tanabe M.
Organizer
65th Annual Meeting of the American Association for the Study of Liver diseases
Place of Presentation
Boston, USA
Year and Date
2014-11-10 – 2014-11-10
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[Presentation] Preclinical studies of EpCAM-targeted therapy for human hepatocellular carcinoma with specific inhibition of stem cell features.2014
Author(s)
Tanaka S, Ogawa K, Murakata A, Mogushi K, Matsumura S, Aihara A, Ban D, Ochiai T, Irie T, Kudo A, Nakamura N, Tanaka H, Arii S, Tanabe M.
Organizer
105th Annual Meeting of the American Association for Cancer Research
Place of Presentation
San Diego, USA
Year and Date
2014-04-06 – 2014-04-06
