がん組織における高―中酸素分圧下での新規ＨＩＦ活性化メカニズムの機能解析

• Project Area: Integrative Research on Cancer Microenvironment Network
• Project/Area Number: 23112505
• 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: The University of Tokyo
• Principal Investigator: 坂本 毅治 東京大学, 医科学研究所, 助教 (70511418)
• Project Period (FY): 2011-04-01 – 2013-03-31
• Project Status: Completed (Fiscal Year 2012)
• Budget Amount: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2012: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2011: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000)
• Keywords: マクロファージ / HIF / 転移 / Mint3 / がん / 低酸素

Outline of Annual Research Achievements

がん組織は正常組織と接する比較的酸素分圧の高い領域から腫瘍内部の壊死領域のような激しい低酸素の領域まで幅広い酸素分圧を呈す特異な微小環境にある。細胞の酸素分圧センサーとして低酸素応答性転写因子Hypoxia Inducible Factor (HIF) があり、がん組織で重要な役割を果たしていることが知られているが、高-中酸素分圧下での活性制御については不明である。そこで本研究では申請者らが新規に同定した高-中酸素分圧下でのHIF活性因子Mint3のがん組織での役割を解明することで、がん組織内の高-中酸素分圧下におけるHIFの活性化がどのようにがん細胞やがん間質細胞の機能を制御しがんの悪性化に影響するかを明らかにする。
がん間質構成細胞におけるMint3の機能を明らかにするため、Mint3欠損マウスと乳がんモデルマウスMMTV-PyMTマウスを交配させ解析を行った。その結果、Mint3欠損マウスでは肺へのがん転移が有意に低下していることが明らかとなった。またMint3欠損マウスにメラノーマ細胞株B16F10を尾静脈移植した際にも肺転移が有意に低下しており、マクロファージ特異的Mint3欠損マウスでも同様の結果が得られたことから、マクロファージのMint3ががん転移に関わることが明らかとなった。さらなる解析でMint3によるがん転移の促進は転移初期でのがん細胞の血管外遊走に関わることが明らかとなった。

Research Progress Status

24年度が最終年度であるため、記入しない。

Strategy for Future Research Activity

24年度が最終年度であるため、記入しない。

Research Products

• [Journal Article] MT1-MMP plays a critical role in henatopoiesis by regulating HIF-mediated chemo-/cytokine gene transcription within niche cells. (2012)
  • Author(s): Chiemi Nishida, Kaori Kusubata, Yoshihiko Tashiro, Ismael Gritli, Aki Sato, Makiko Ohki-Koizumi, Yohei Morita, Makoto Nagano, Takeharu Sakamoto, Naohiko Koshikawa, Takahiro Kuchimaru, Shinae Kizaka-Kondoh, Motoharu Seiki, Hiromitsu Nakauchi, Beate Heissig, and Koichi Hattori.
  • Journal Title: Blood Volume: 119 Issue: 23 Pages: 5404-5416
  • DOI: 10.1182/blood-2011-11-390849
  • Peer Reviewed
• [Journal Article] Genetic screening of new genes responsible for cellular adaptation to hypoxia using a genome-wide shRNA library. (2012)
  • Author(s): Yoshino S, Hara T, Weng JS, Takahashi Y, Seiki M, Sakamoto T.
  • Journal Title: PLoS One. Volume: 7(4) Issue: 4 Pages: e35590-e35590
  • DOI: 10.1371/journal.pone.0035590
  • Peer Reviewed
• [Journal Article] Genetic screening of new genes responsible for cellular adaptation to hypoxia using a genome-wide shRNA library (2012)
  • Author(s): Yoshino S, Hara T, Weng JS, Takahashi Y, Seiki M, Sakamoto T
  • Journal Title: PLoS ONE Volume: (印刷中)
  • Peer Reviewed
• [Journal Article] Genetic dissection of proteolytic and non-proteolytic contributions of MT1-MMP to macrophage invasion. (2011)
  • Author(s): Hara T, Mimura K, Seiki M, Sakamoto T.
  • Journal Title: Biochem Biophys Res Commun. Volume: 23;413(2) Issue: 2 Pages: 277-81
  • DOI: 10.1016/j.bbrc.2011.08.085
  • Peer Reviewed
• [Journal Article] Deletion of the Mint3/Apba3 gene in mice abrogates macrophage functions and increases resistance to lipopolysaccharide-induced septic shock (2011)
  • Author(s): Hara T, Mimura K, Abe T, Shioi G, Seiki M, Sakamoto T.
  • Journal Title: J Biol Chem. Volume: 16;286(37) Issue: 37 Pages: 32542-51
  • DOI: 10.1074/jbc.m111.271726
  • Peer Reviewed
• [Journal Article] Targeting the Warburg effect that arises in tumor cells expressing membrane type-1 matrix (2011)
  • Author(s): Sakamoto T, Niiya D, Seiki M
  • Journal Title: metalloproteinase. Volume: J Biol Chem 22;286(16) Issue: 16 Pages: 14691-704
  • DOI: 10.1074/jbc.m110.188714
  • Peer Reviewed
• [Presentation] Mint3 promotes tumor malignancy in cancer and stromal cells (2013)
  • Author(s): Takeharu Sakamoto, Toshiro Hara, Motoharu Seiki
  • Organizer: Ninth AACR-Japanese Cancer Association Joint Conference
  • Place of Presentation: Maui, HI, USA
  • Invited
• [Presentation] Mint3 is a new molecular target for metastasis suppression (2012)
  • Author(s): Takeharu Sakamoto, Motoharu Seiki
  • Organizer: The 16th JFCR-ISCC
  • Place of Presentation: 東京
  • Year and Date: 2012-01-25
• [Presentation] 新規HIF活性化因子・Mint3の生体における機能の解析 (2012)
  • Author(s): 坂本 毅治、原 敏朗、清木 元治
  • Organizer: 第85回日本生化学会大会
  • Place of Presentation: 福岡
  • Invited
• [Presentation] Crosstalk between mTOR and MT1-MMP via Mint3 Induces Post-translational Activation of HIF-1 (2012)
  • Author(s): 坂本毅治、Weng Jane, 原敏朗、芳野聖子、清木元治
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Deletion of the Mint3 Gene in Mice Abrogates Macrophage Functions and Increases Resistance to Cancer Metastasis (2012)
  • Author(s): 原敏朗、坂本毅治、清木元治
  • Organizer: 第35回日本分子生物学会年会
  • Place of Presentation: 福岡
• [Presentation] Mint3 deficiency abrogates macrophage functios and suppresses tumor metastasis (2012)
  • Author(s): Toshiro Hara, Kohei Mimura, Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] The analysis of stromal Mint3 that promotes tumor malignancy (2012)
  • Author(s): Jane Weng, Toshiro Hara, Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Mint3 promotes tumor malignancy in cancer and stromal cells (2012)
  • Author(s): Takeharu Sakamoto, Toshiro Hara, Motoharu Seiki
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
  • Invited
• [Presentation] A novel E3 ligase, RNF126, regulates the metabolic fate of pyrubate during normoxia and tumor growth (2012)
  • Author(s): Seiko Yoshino, Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第71回日本癌学会学術総会
  • Place of Presentation: 札幌
• [Presentation] Ubiquitin ligase RNF126 serves as a gate keeper from glycolysis to oxidative phosphorylation and regulates tumor growth (2011)
  • Author(s): Seiko Yoshino, Takeharu Sakamoto Motoharu Seiki
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 神奈川
  • Year and Date: 2011-12-15
• [Presentation] Targeting the Warburg effect that arises in tumor cells expressing membrane type-1 matrix metalloprotease (2011)
  • Author(s): Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 神奈川
  • Year and Date: 2011-12-15
• [Presentation] Mint3 in tumor stromal cells promotes tumor metastasis (2011)
  • Author(s): Kouhei Mimura, Toshiro Hara, Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 神奈川
  • Year and Date: 2011-12-14
• [Presentation] Analysis of the regulatory mechanism of HIF-1 activation by Mint3 during normoxia (2011)
  • Author(s): Jane S.Weng, Takeharu Sakamoto Motoharu Seiki
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 神奈川
  • Year and Date: 2011-12-14
• [Presentation] Deletion of the Mint3/Apba3 Gene in Mice Abrogates Macrophage Functions and Increases Resistance to Lipopolysaccharide-induced Septic Shock (2011)
  • Author(s): Toshiro Hara, Kouhei Mimura, Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第34回日本分子生物学会年会
  • Place of Presentation: 神奈川
  • Year and Date: 2011-12-14
• [Presentation] Mint3/APBA3 regulating HIF-1 activation in macrophages play a critical role in LPS-induced septic shock in a mouse model (2011)
  • Author(s): Toshiro Hara, Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知
  • Year and Date: 2011-10-05
• [Presentation] ZF21, a novel focal adhesion-related protein, promotes cancer cell invasion (2011)
  • Author(s): Makoto Nagano, Daisuke Hoshino, Takeharu Sakamoto, Rika Okihara, Motomi Konishi, Naohiko Koshikawa, Toshifumi Akizawa, Motoharu Seiki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知
  • Year and Date: 2011-10-05
• [Presentation] Ubiquitin ligase RNF126 serves as a gate keeper from glycolysis to oxidative phosphorylation and regulates tumor growth (2011)
  • Author(s): Seiko Yoshino, Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知
  • Year and Date: 2011-10-04
• [Presentation] Targeting the Warburg effect that arises in tumor cells expressing membrane type-1 matrix metalloprotease (2011)
  • Author(s): Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知
  • Year and Date: 2011-10-04
• [Presentation] Analysis of the regulatory mechanism of HIF-1 activation by Mint3 during normoxia (2011)
  • Author(s): Jane S.Weng, Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知
  • Year and Date: 2011-10-04
• [Presentation] Mint3 in tumor stromal cells promotes tumor metastasis (2011)
  • Author(s): Kouhei Mimura, Toshiro Hara, Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 愛知
  • Year and Date: 2011-10-03
• [Presentation] Deletion of the Mint3 gene in mice abrogates macrophage functions and increases resistance to cancer metastasis (2011)
  • Author(s): 原敏朗、三村耕平、坂本毅治、清木元治
  • Organizer: 平成23年度がん若手研究者ワークショップ
  • Place of Presentation: 長野
  • Year and Date: 2011-09-02
• [Presentation] Ring finger protein 126, RNF126, is a new E3 ubiquitin ligase that serves as a gate keeper from glycolysis to oxidative phosphorylation and regulates tumor growth (2011)
  • Author(s): 芳野聖子、坂本毅治、清木元治
  • Organizer: 平成23年度がん若手研究者ワークショップ
  • Place of Presentation: 長野
  • Year and Date: 2011-09-01
• [Presentation] MT1-MMP/Mint3は通常酸素下でHIF-1を活性化しマクロファージおよび癌細胞の解糖系を亢進させる (2011)
  • Author(s): Takeharu Sakamoto, Motoharu Seiki
  • Organizer: 日本がん分子標的治療学会第15回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2011-06-25
• [Book] がんの浸潤・転移第20章細胞外マトリックス(ECM) (2011)
  • Author(s): 坂本毅治・清木元治
  • Publisher: 南山堂
• [Remarks] 東京大学医科学研究所腫瘍細胞社会学分野HP
  • URL: http://www.motoharu-seiki.com/
• [Remarks]
  • URL: http://www.motoharu-seiki.com/