Analysis of the role of ASC as a regulator of metastatic phenotype

• Project/Area Number: 26460272
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General anatomy (including histology/embryology)
• Research Institution: Shinshu University
• Principal Investigator: FUJII Chifumi 信州大学, 学術研究院医学系, 助教 (10361982)
• Co-Investigator(Renkei-kenkyūsha): TANIGUCHI Shun'ichiro 信州大学, 医学部, 特任教授 (60117166) ; HIDA Shigeaki 名古屋市立大学, 大学院薬学研究科, 教授 (10345762)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 細胞運動 / 浸潤突起 / ASC / インフラマソーム / 細胞骨格

Outline of Final Research Achievements

Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) has been reported a pro-apoptotic molecule that is epigenetically silenced in several human cancers. However, the role of ASC in the regulation of tumor progression remains elusive. To determine the effect of ASC depletion in cancer cells, ASC was stably knocked down in B16BL6, a murine melanoma cell line. ASC suppression increased the motility of B16BL6 cells and augmented invasiveness. Invadopodia formation and Src phosphorylation level were enhanced in ASC-knockdown cells as well. Since caspase-8 has been reported to enhance cellular migration by Tyr380 phosphorylation via Src, we examined Tyr380 phosphorylation of caspase-8 in ASC-knockdown cells and found it to be elevated. Moreover, ASC ablation increased pulmonary metastasis in mice after intravenous injection of B16BL6 cells. Our findings indicate that ASC suppresses cancer metastasis via the modulation of the Src-caspase-8 signaling pathway.

Research Products

• [Journal Article] ASC induces apoptosis via activation of caspase-9 by enhancing gap junction-mediated intercellular communication. (2017)
  • Author(s): Kitazawa M, Hida S, Fujii C, Taniguchi S, Ito K, Matsumura T, Okada N, Sakaizawa T, Kobayashi A, Takeoka M, and Miyagawa SI
  • Journal Title: PLoS One Volume: 12 Issue: 1 Pages: e0169340-e0169340
  • DOI: 10.1371/journal.pone.0169340
  • Peer Reviewed / Open Access
• [Journal Article] Novel role of ASC as a regulator of metastatic phenotype. (2016)
  • Author(s): Okada N1, Fujii C1,2, Matsumura T, Kitazawa M, Okuyama R, Taniguchi S, and Hida S (1: Contributed equally, 2: Corresponding author)
  • Journal Title: Cancer Medicine Volume: 5 Issue: 9 Pages: 2487-2500
  • DOI: 10.1002/cam4.800
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] NFkB2 gene as anoble candidate epidemiologically responding to interval walking training. (2015)
  • Author(s): Zhang Y, Hashimoto S, Fujii C, Hida S, Ito K, Matsumura T, Sakaizawa T, Morikawa M, Masuki S, Nose H, Higuchi K, Nakajima K, Taniguchi S
  • Journal Title: Int. J. Sports. Med. Volume: in press Issue: 09 Pages: 769-775
  • DOI: 10.1055/s-0035-1547221
  • Peer Reviewed / Open Access
• [Presentation] Novel role of ASC as a regulator of metastatic phenotype (2016)
  • Author(s): 岡田なぎさ、藤井千文、松村富穂、北沢将人、谷口俊一郎、肥田重明、宇原久、奥山隆平
  • Organizer: 第41回研究皮膚科学会年次学術大会
  • Place of Presentation: 仙台国際センター（仙台市）
  • Year and Date: 2016-12-09
• [Presentation] インフラマソーム構成因子ASCの細胞運動における役割 (2016)
  • Author(s): 藤井千文、松村富穂、肥田重明、岡田なぎさ、谷口俊一郎
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（横浜市）
  • Year and Date: 2016-10-06
• [Presentation] ヒト肺癌の悪性形質獲得におけるASCの役割 (2015)
  • Author(s): 境澤隆夫、松村富穂、藤井千文、肥田重明、谷口俊一郎
  • Organizer: 第24回日本がん転移学会学術集会・総会
  • Place of Presentation: 大阪府大阪市シティプラザ大阪
  • Year and Date: 2015-07-23
• [Presentation] ASCによるがん細胞転移能の制御機構の解析 (2014)
  • Author(s): 藤井千文、松村富穂、肥田重明、谷口俊一郎
  • Organizer: 日本がん転移学会学術集会
  • Place of Presentation: 金沢市文化ホール・金沢ニューグランドホテル（石川県金沢市）
  • Year and Date: 2014-07-10 – 2014-07-11
• [Presentation] The roles of ASC in cancer cell metastasis (2014)
  • Author(s): Chifumi Fujii, Tomio Matsumura, Takao Sakaizawa, Shigeaki Hida, Shun'ichiro Taniguchi
  • Organizer: 15th International Biennial Congress Metastasis Research Society
  • Place of Presentation: Heidelberg（ドイツ）
  • Year and Date: 2014-06-28 – 2014-07-01