Stress response of cancer cells and its research for intractable cancer therapy

• Project/Area Number: 15K08300
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pathological medical chemistry
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: KITAJIMA Shigetaka 東京医科歯科大学, 難治疾患研究所, 教授 (30186241)
• Co-Investigator(Renkei-kenkyūsha): KAWAUCHI Junya 東京医科歯科大学, 難治疾患研究所, 助教 (20544498)
• Research Collaborator: INOUE Makoto 東京医科歯科大学, 医歯学総合大学院, 大学院生 ; EDAGAWA Makoto 九州大学, 医学研究院, 大学院生 ; UCHIDA Yohei 東京医科歯科大学, 難治疾患研究所, 研究補助員
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2017: ¥650,000 (Direct Cost: ¥500,000、Indirect Cost: ¥150,000); Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2015: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
• Keywords: 難治がん / ストレス応答 / Wnt / p53 / ATF3 / がん遊走浸潤 / ストレス応答遺伝子 / システムズ解析 / ストレス応答転写因子 / Wntシグナル / がん浸潤抑制 / MMP / TIMP / がん抑制 / がん細胞遊走浸潤

Outline of Final Research Achievements

Aberrant signaling of Wnt pathway and p53 inactivation is one of major genetic hallmarks of human colorectal cancer. At the same time, stress response to DNA damage is deeply involved in susceptibility of cancer cells to DNA damage. In this study, we performed system analysis of DNA damage response of double knockout MEF of p53 and stress response gene ATF3, and clearly identified gene clusters of p53 targets positively or negatively regulated by ATF3. We further showed that ATF3 gene contains atypical TCF4 binding motif at its very proximal promoter and is a direct target of b-catenin binding in human HCT116 colorectal cancer cells. Using genetically hemi-targeted HCT116 cells with wild or mutant b-catenin allele, we demonstrated that ATF3 plays role of suppressing cancer cell invasion and migration. ATF3 could be a target for chemotherapy and prevention of human colon cancer.

Research Products

• [Journal Article] The stress response gene ATF3 is a direct target of the Wnt/β-catenin pathway and inhibits the invasion and migration of HCT116 human colorectal cancer cells. (2018)
  • Author(s): Inoue M, Uchida Y, Edagawa M, Hirata M, Mitamura J, Miyamoto D, Taketani K, Sekine S, Kawauchi J, Kitajima S.
  • Journal Title: PLOSONE Volume: 10 Issue: 7 Pages: 18-18
  • DOI: 10.1371/journal.pone.0194160
  • Peer Reviewed / Open Access
• [Journal Article] ATF3 hyper-induced during Japanese encephalitis virus infection negatively regulates the antiviral signalling in neuronal cells in the absence of type1 interferons. (2017)
  • Author(s): Vikas S, Dhurjhoti S, Parashar D, Manish S, Utsav S, Kitajima S, Manjula K, Chowdhury S, Sudhanshu V.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 8789-8789
  • DOI: 10.1038/s41598-017-08584-9
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] ATF3 deficiency in chondrocytes alleviates osteoarthritis development. (2016)
  • Author(s): Iezaki T, Ozaki K, Fukasawa K, Inoue M, Kitajima S, Muneta T, Takeda S, Fujita H, Onishi Y, Horie T, Yoneda Y, Takarada T, Hinoi E.
  • Journal Title: J Pathol. Volume: 239(4) Issue: 4 Pages: 426-437
  • DOI: 10.1002/path.4739
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] ATF3 controls proliferation of osteoclast precursor and bone remodeling. (2016)
  • Author(s): Fukasawa K, Park G, Iezaki T, Horie T, Kanayama T, Ozaki K, Onishi Y, Takahata Y, Yoneda Y, Takarada T, Kitajima S, Vacher J, Hinoi E.
  • Journal Title: Sci Rep. Volume: 6 Issue: 1 Pages: 30918-30918
  • DOI: 10.1038/srep30918
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Remarks] 東京医科歯科大学難治疾患研究所遺伝生化学
  • URL: http://www.tmd.ac.jp/mri/bgen/message.html
• [Remarks] 東京医科歯科大学難治疾患研究所遺伝生化ホームページ
  • URL: http://www.tmd.ac.jp/mri/bgen/open.html