BMP-4 as a new therapeutic target in colorectal cancer

• Project/Area Number: 15K08393
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Experimental pathology
• Research Institution: The University of Tokyo
• Principal Investigator: Ehata Shogo 東京大学, 大学院医学系研究科(医学部), 特任准教授 (90506726)
• Research Collaborator: Yokoyama Yuichiro 東京大学, 大学院医学系研究科, 特任研究員
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: Colorectal cancer / Apoptosis / BMP-4 / Erk MAPK / DUSP5 / 大腸癌 / アポトーシス / Erk / TGF-beta/BMP

Outline of Final Research Achievements

Poor prognoses for colorectal cancer patients with metastatic lesions have driven demand for the development of novel targeted therapies. Here we demonstrate that expression of bone morphogenetic protein 4 (BMP-4) is universally upregulated in human colorectal cancer cells and tissues, resulting in activated BMP signaling. Inhibition of endogenous BMP signaling by the BMP type I receptor inhibitor LDN-193189 elevated expression of the phosphatase DUSP5 in colorectal cancer cells, inducing apoptosis via dephosphorylation of Erk MAPK. Administering LDN-193189 to mice diminished tumor formation of colorectal cancer cells. Our findings suggest inhibition of autocrine BMP-4 as a candidate treatment strategy for colorectal cancer.

Research Products

• [Journal Article] Autocrine BMP-4 Signaling Is a Therapeutic Target in Colorectal Cancer (2017)
  • Author(s): Yokoyama Y, Watanabe T, Tamura Y, Hashizume Y, Miyazono K, Ehata S.
  • Journal Title: Cancer Research Volume: 77 Issue: 15 Pages: 4026-4038
  • DOI: 10.1158/0008-5472.can-17-0112
  • Peer Reviewed / Open Access
• [Journal Article] Whole-Body Profiling of Cancer Metastasis with Single-Cell Resolution (2017)
  • Author(s): Kubota Shimpei I.、Takahashi Kei、Nishida Jun、Morishita Yasuyuki、Ehata Shogo、Tainaka Kazuki、Miyazono Kohei、Ueda Hiroki R.
  • Journal Title: Cell Reports Volume: 20 Issue: 1 Pages: 236-250
  • DOI: 10.1016/j.celrep.2017.06.010
  • Peer Reviewed / Open Access
• [Journal Article] RNA-binding motif protein 47 inhibits Nrf2 activity to suppress tumor growth in lung adenocarcinoma (2016)
  • Author(s): Sakurai T, Isogaya K, Sakai S, Morikawa M, Morishita Y, Ehata S, Miyazono K, Koinuma D
  • Journal Title: Oncogene Volume: 印刷中 Issue: 38 Pages: 5000-5009
  • DOI: 10.1038/onc.2016.35
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Ras and TGF-β signaling enhance cancer progression by promoting the ΔNp63 transcriptional program (2016)
  • Author(s): Vasilaki E, Morikawa M, Koinuma D, Mizutani A, Hirano Y, Ehata S, Sundqvist A, Kawasaki N, Cedervall J, Olsson AK, Aburatani H, Moustakas A, Miyazono K, Heldin CH.
  • Journal Title: Sci Signal. Volume: 9 Issue: 442
  • DOI: 10.1126/scisignal.aag3232
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] EZH2 promotes progression of small cell lung cancer by suppressing the TGF-β-Smad-ASCL1 pathway (2015)
  • Author(s): Fumihiko Murai, Daizo Koinuma, Aya Shinozaki-Ushiku, Masashi Fukayama, Kohei Miyaozono, Shogo Ehata
  • Journal Title: Cell Discovery Volume: 1 Issue: 1 Pages: 15026-15026
  • DOI: 10.1038/celldisc.2015.26
  • Peer Reviewed / Open Access
• [Presentation] BMP阻害剤を応用した大腸がんの分子標的治療 (2017)
  • Author(s): 江幡正悟、横山雄一郎、宮園浩平
  • Organizer: 第21回日本がん分子標的治療学会学術集会
• [Presentation] Autocrine bone morphogenetic protein 4 signaling in colorectal cancer as a target for treatment. (2017)
  • Author(s): Ehata S, Yokoyama Y, Watanabe T, Tamura Y, Hashizume Y, Miyazono K.
  • Organizer: FASEB “The TGF-beta Superfamily: Signaling in Development and Disease”
  • Int'l Joint Research
• [Presentation] BMP阻害剤を使用した大腸癌治療の試み (2017)
  • Author(s): 江幡正悟、横山雄一郎、渡邉聡明、田村佑介、宮園浩平
  • Organizer: 第76回日本癌学会総会
• [Presentation] Autocrine BMP-4 accelerates proteasomal degradation of Bim and protects colorectal cancer cells from apoptosis (2016)
  • Author(s): Yuichiro Yokoyama, Shogo Ehata, Toshiaki Watanabe, Kohei Miyazono
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県横浜市）
  • Year and Date: 2016-10-06
• [Presentation] Autocrine BMP-4 is a novel therapeutic target for colorectal cancer (2016)
  • Author(s): Yuichiro Yokoyama, Shogo Ehata, Yasuyuki Morishita, Toshiaki Watanabe, Kohei Miyazono
  • Organizer: 第10回日米癌合同会議
  • Place of Presentation: Maui, United States of America
  • Year and Date: 2016-02-18
  • Int'l Joint Research
• [Presentation] Autocrine BMP-4 accelerates proteasomal degradation of Bim and protects colorectal cancer cells from apoptosis (2015)
  • Author(s): Yuichiro Yokoyama, Shogo Ehata, Toshiaki Watanabe, Kohei Miyazono
  • Organizer: 第74回日本癌学会総会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-10-09
• [Presentation] Autocrine BMP-4 protects colorectal cancer cells from apoptosis through down-regulation of Bim (2015)
  • Author(s): 横山雄一郎、江幡正悟、渡邉聡明、宮園浩平
  • Organizer: 平成27年度がん若手研究者ワークショップ
  • Place of Presentation: 蓼科グランドホテル滝の湯（長野県茅野市）
  • Year and Date: 2015-09-03
• [Presentation] 大腸癌細胞はBMP-4を自己分泌しBimタンパクの分解を促進することでアポトーシスを抑制する (2015)
  • Author(s): 横山雄一郎、江幡正悟、宮園浩平
  • Organizer: 第19回日本がん分子標的治療学会学術集会
  • Place of Presentation: 松山全日空ホテル（愛媛県松山市）
  • Year and Date: 2015-06-12
• [Remarks] 東京大学大学院医学系研究科病因・病理学専攻分子病理学分野 ホームページ
  • URL: http://beta-lab.umin.ac.jp/