Analysis of molecular mechanisms of the acquisition of tumor invasiveness

• Project/Area Number: 21370092
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Cell biology
• Research Institution: Hokkaido University
• Principal Investigator: HASHIMOTO Sigeru 北海道大学, 大学院・医学研究科, 准教授 (50311303)
• Project Period (FY): 2009 – 2012
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥18,850,000 (Direct Cost: ¥14,500,000、Indirect Cost: ¥4,350,000); Fiscal Year 2012: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2011: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2010: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2009: ¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
• Keywords: 低酸素 / 細胞浸潤 / 癌転移 / EMT / Arf6 / AMAP1 / GEP100 / 乳癌 / 癌浸潤 / エピジェネティクス / EZH2 / HIF / ポリコームグループ蛋白質群 / ポリコーム群遺伝子

Research Abstract

We have previously shown that the GEP100-Arf6-AMAP1 pathway, activated by receptor tyrosine kinases, is involved in the acquisition of breast cancer invasiveness. Our analyses demonstrate that the activation of GEP100-Arf6-AMAP1 pathway via the c-Met/HGFR signaling is essential for the acquisition of the invasiveness of some breast cancer cells during hypoxia- or TGFss1-induced EMT. Moreover, we found that the expression of some molecules within the GEP100-Arf6-AMAP1 pathway are regulated by hypoxia-inducible factor (HIF) or EZH2, which have shown to be involved in the initiation and maintenance of the stemness in hypoxia.

Research Products

• [Journal Article] Rab5c mediates AMAP1-PRKD2 complexto enhance β1 integrin recycling inEGF-induced cancer invasion (2012)
  • Author(s): Onodera Y., Nam JM., Hashimoto A., Norman JC., Shirato H., Hashimoto S. and Sabe H
  • Journal Title: J.Cell Biol Volume: 197 Issue: 7 Pages: 983-996
  • DOI: 10.1083/jcb.201201065
  • Peer Reviewed
• [Journal Article] Hashimoto A andHashimoto S. ASAP1 (ArfGAP with SH3domain, ankyrin repeat and PH domain 1) (2012)
  • Author(s): Sabe H, Onodera Y
  • Journal Title: Atlas Genet Cytogenet Oncol Haematol
  • URL: http://atlasgeneticsoncology.org/Genes/ASAP1ID44351ch8q24.html
• [Journal Article] GEP100-Arf6-AMAP1-cortactin pathway frequently used in cancer invasion is activated by VEGFR2 to promote angiogenesis (2011)
  • Author(s): Hashimoto A., Hashimoto S., Ando R., Noda K., Ogawa E., Kotani H., Hirose M., Menju T., Morishige M., Manabe T., Toda Y., Ishida S. and Sabe H.
  • Journal Title: PLoS One Volume: 6 Issue: 8 Pages: e23359-e23359
  • DOI: 10.1371/journal.pone.0023359
  • NAID: 120003295085
  • Peer Reviewed
• [Journal Article] Engagement of overexpressed Her2 with GEP100 induces autonomous invasive activities and provides a biomarker for metastases of lung adenocarcinoma (2011)
  • Author(s): Menju T., Hashimoto S., Hashimoto A., Otsuka Y., Handa H., Ogawa E., Toda Y., Wada H., Date H. and Sabe H.
  • Journal Title: PLoS One Volume: 6 Issue: 9 Pages: e25301-e25301
  • DOI: 10.1371/journal.pone.0025301
  • NAID: 120003464637
  • Peer Reviewed
• [Journal Article] The EGFR-GEP100-Arf6-AMAP1 signaling pathway specific to breast cancer invasion and metastasis (2009)
  • Author(s): Sabe H., Hashimoto S., Morishige M., Ogawa E., Hashimoto A., Nam JM., Miura K., Yano H.and Onodera Y.
  • Journal Title: Traffic Volume: 10 Issue: 8 Pages: 982-993
  • DOI: 10.1111/j.1600-0854.2009.00917.x
  • Peer Reviewed
• [Journal Article] The EGFR-GEP100-Arf6-AMAP1 signaling pathway specific to breast cancer invasion and metastasis. (2009)
  • Author(s): Sabe H, Hashimoto S, Morishige M, Ogawa E, Hashimoto A, Nam JM, Miura K, Yano H, Onodera Y.
  • Journal Title: Traffic 10 Pages: 982-993
  • Peer Reviewed
• [Presentation] EZH2 suppresses miR-203expression to promote cancer invasion (2012)
  • Author(s): 橋本茂
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場(福岡県)
  • Year and Date: 2012-12-12
• [Presentation] 低分子量G蛋白質Arf6による細胞運動・極性制御と癌の浸潤・転移 (2012)
  • Author(s): 橋本茂
  • Organizer: 2012年度合同シンポジウム『生命現象の分子レベルでの解明』
  • Place of Presentation: 北海道大学(北海道)
  • Year and Date: 2012-11-16
• [Presentation] Mutant-p53 generatesGEP100-Arf6-AMAP1 pathway to promotebreast cancer cell invasiveness in response toTGFβ1 (2012)
  • Author(s): 橋本あり
  • Organizer: 第71回日本癌学会
  • Place of Presentation: ロイトン札幌(北海道)
  • Year and Date: 2012-09-20
• [Presentation] EZH2-mediated downregulationof miR-203 generates the ARF6-AMAP1pathway pivotal for breast cancer invasiveness, Beatson International Cancer Conference 2012 (2012)
  • Author(s): 杉野弘和
  • Organizer: Membrane dynamics incancer
  • Place of Presentation: Beatson Institute(UK)
  • Year and Date: 2012-07-03
• [Presentation] RTKs-GEP100-Arf6-AMAP1 pathway mediates cancerous EMT in response to mutant p53 and TGFβ1 signaling (2012)
  • Author(s): Hisataka Sabe, Ari Hashimoto, Hirokazu Sugino, Ayumu Yoshikawa, Yutaro Otsuka, Haruka Handa, Sizuka Mito, Hiroki Sato, Jin-Min Nam, Yasuhito Onodera and Shigeru Hashimoto
  • Organizer: 第8回OOTR年次学会
  • Place of Presentation: ウェスティン都ホテル京都（京都市）
• [Presentation] EZH2 regulates breast cancer invasiveness through GEP100-Arf6-AMAP1 signaling pathway (2012)
  • Author(s): Hirokazu Sugino, Shigeru Hashimoto, Ari Hashimoto, Ayumu Yoshikawa, Haruka Handa, Sizuka Mito, Hisataka Sabe
  • Organizer: 第45回日本発生生物学会・第64回日本細胞生物学会合同大会
  • Place of Presentation: 神戸国際会議場（神戸市）
• [Presentation] MUTANT-p53 GENERATES GEP100-Arf6-AMAP1 PATHWAY TO PROMOTE BREAST CANCER CELL INVASIVENESS IN RESPONSE TO TGFβ1 (2012)
  • Author(s): Ari Hashimoto, Shigeru Hashimoto, Ayumu Yoshikawa, Hirokazu Sugino, Haruka Handa, Sizuka Mito, Hiroki Sato, Yutaro Otsuka, Hinako Yoshino, Jin-Min Nam, Yasuhito Onodera and Hisataka Sabe
  • Organizer: 第31回札幌国際がんシンポジウム2012
  • Place of Presentation: 北海道大学（札幌市）
• [Presentation] Mutant-p53 generates GEP100-Arf6-AMAP1 pathway to promote breast cancer cell invasiveness in response to TGFβ1 (2012)
  • Author(s): Ari Hashimoto, Shigeru Hashimoto, Ayumu Yoshikawa, Hirokazu Sugino, Haruka Handa, Sizuka Mito, Hiroki Sato, Yutaro Otsuka, Hinako Yoshino, Jin-Min Nam, Yasuhito Onodera and Hisataka Sabe
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌市）
• [Presentation] EZH2-mediated downregulation of miR-203 generates the Arf6-AMAP1 pathway pivotal for breast cancer invasiveness (2012)
  • Author(s): Hirokazu Sugino,Shigeru Hashimoto, Ari Hashimoto, Yasuhito Onodera, Ayumu Yoshikawa, Yutaro Otsuka, Shizuka Mito, Haruka Handa, Hiroki Sato and Hisataka Sabe
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌市）
• [Presentation] GAB1 links c-Met signaling with GEP100-Arf6-AMAP1 pathway to promote breast cancer invasiveness (2012)
  • Author(s): Ayumu Yoshikawa, Shigeru Hashimoto, Ari Hashimoto, Hirokazu Sugino, Yutaro Otsuka, Shizuka Mito, Haruka Handa and Hisataka Sabe
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: ロイトン札幌（札幌市）
• [Presentation] 低分子量G蛋白質Arf6による細胞運動・極性制御と癌の浸潤・転移 (2012)
  • Author(s): 橋本茂
  • Organizer: 2012年度合同シンポジウム『生命現象の分子レベルでの解明』
  • Place of Presentation: 北海道大学（札幌市）
  • Invited
• [Presentation] EZH2-mediated downregulation of miR-203 generates the ARF6-AMAP1 pathway pivotal for breast cancer invasiveness. (2012)
  • Author(s): H. Sugino, S. Hashimoto, A. Hashimoto, A. Yoshikawa, H. Handa and H. Sabe.
  • Organizer: Beatson International Cancer Conference 2012 "Membrane dynamics in cancer"
  • Place of Presentation: Beatson Institute (UK)
• [Presentation] EZH2 suppresses miR-203 expression to promote cancer invasion (2012)
  • Author(s): Shigeru Hashimoto, Hirokazu Sugino, Ari Hashimoto, Ayumu Yoshikawa, Yutaro Otsuka, Masanao Yoshino, Haruka Handa and Hisataka Sabe
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場（福岡市）
• [Presentation] Mutant-p53 generates the GEP100-Arf6-AMAP1 pathway to be activated by TGFβ1 and receptor tyrosine kinases to promote cancer invasion (2012)
  • Author(s): Ari Hashimoto, Shigeru Hashimoto, Ayumu Yoshikawa et al
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡国際会議場（福岡市）
• [Presentation] Tissue morphogenesis by co-operative regulation of cellular proliferation and migration and diseases due to its breakdown (2012)
  • Author(s): Yasuhito Onodera, Jin-Min Nam, Ari Hashimoto, Mina Bissell, Shigeru Hashimoto, Hisataka Sabe
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡国際会議場（福岡市）
• [Presentation] EZH2 regulates Arf6 activitynecessary for invasiveness of some breastcancer cells under normoxia and hypoxia (2011)
  • Author(s): 橋本茂
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-12-14
• [Presentation] EZH2 regulates Arf6 activation necessary for invasiveness of some breast cancer cells under normoxia and hypoxia (2011)
  • Author(s): 橋本茂
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 2011-12-14
• [Presentation] EZH2 is essential to Arf6 activationnecessary for TGFss1- and hypoxia-induced invasiveness of breast cancer cells (2011)
  • Author(s): 橋本茂
  • Organizer: 第70回日本癌学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-03
• [Presentation] EZH2 is essential to Arf6 activation necessary for TGFβ1-and hypoxiainduced invasiveness of breast cancer cells (2011)
  • Author(s): 橋本茂
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場(愛知県)
  • Year and Date: 2011-10-03
• [Presentation] Arf6 activation under hypoxia andits relationship to invasion, EMT conversion and stemness of breast cancer cells (2010)
  • Author(s): 橋本茂
  • Organizer: 第33回日本分子生物学会年会、第83回日本生化学会大会合同大会
  • Place of Presentation: 神戸ポートアイランド(兵庫県)
  • Year and Date: 2010-12-09
• [Presentation] Arf6 activation under hypoxia and its relationship to invasion, EMT conversion and stemness of breast cancer cells (2010)
  • Author(s): 橋本茂
  • Organizer: BMB2010
  • Place of Presentation: 神戸ポートアイランド(神戸市)
  • Year and Date: 2010-12-09
• [Presentation] Hypoxia-induced invasive activityof breast cancer cells involves Arf6 activation (2010)
  • Author(s): 橋本茂
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(大阪府)
  • Year and Date: 2010-09-24
• [Presentation] Hypoxia-induced invasive activity of breast cancer cells involves Arf6 activation (2010)
  • Author(s): 橋本茂
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪国際会議場(大阪市)
  • Year and Date: 2010-09-24
• [Presentation] 微小環境の変化に連動した癌の浸潤形質獲得の分子機序 (2009)
  • Author(s): 橋本茂
  • Organizer: 特別学術講演会
  • Place of Presentation: 北海道大学(北海道)
  • Year and Date: 2009-09-25
• [Presentation] 微小環境の変化に連動した癌の浸潤形質獲得の分子機序 (2009)
  • Author(s): 橋本茂
  • Organizer: 特別学術講演会
  • Place of Presentation: 北海道大学薬学部臨床薬学講義室(札幌市)
  • Year and Date: 2009-09-25
• [Presentation] 乳がん浸潤形質獲得の分子機序 (2009)
  • Author(s): 橋本茂
  • Organizer: 平成21年度大学院「先端医療トピックス」
  • Place of Presentation: 神戸大学(兵庫県)
  • Year and Date: 2009-06-12
• [Presentation] 乳がん浸潤形質獲得の分子機序 (2009)
  • Author(s): 橋本茂
  • Organizer: 平成21年度大学院「先端医療トピックス」
  • Place of Presentation: 神戸大学医学部B講義室(神戸市)
  • Year and Date: 2009-06-12
• [Book] 乳癌レビュー2012EMT-基礎的観点から (2012)
  • Author(s): 橋本あり、杉野弘和、橋本茂、佐邊壽孝
  • Publisher: メディカルレビュー社
• [Book] 「局所浸潤モデル-がんの浸潤転移に関わる分子装置の解析法」『疾患モデルの作製と利用-がん』 (2012)
  • Author(s): 橋本あり、橋本茂、佐邊壽孝
  • Publisher: エル・アイ・シー(株)
• [Book] 「EMT-基礎的観点から」乳癌レビュー2012 (2012)
  • Author(s): 橋本あり、杉野弘和、橋本茂、佐邊壽孝
  • Total Pages: 7
  • Publisher: メディカルレビュー社
• [Book] 「局所浸潤モデルーがんの浸潤転移に関わる分子装置の解析法」『疾患モデルの作製と利用ーがん』 (2012)
  • Author(s): 橋本あり、橋本茂、佐邊壽孝
  • Total Pages: 11
  • Publisher: 株式会社エル・アイ・シー
• [Book] 乳癌レビュー2012EMT-基礎的観点から (2011)
  • Author(s): 橋本あり、杉野弘和、橋本茂, 佐邊壽孝
  • Total Pages: 7
  • Publisher: メディカルレビュー社
• [Remarks]
  • URL: http://info.coop.hokudai.ac.jp/bunsei/
• [Remarks] 北海道大学 大学院医学研究科 生化学講座 分子生物学分野
  • URL: http://www.hucc.hokudai.ac.jp/~g21001/index.html
• [Remarks]
  • URL: http://info.coop.hokudai.ac.jp/bunsei/index.html