Novel strategy for the treatment of highly malignant tumors

• Project/Area Number: 18K07040
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Kitagawa Masanobu 東京医科歯科大学, 大学院医歯学総合研究科, 教授 (10177834)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: DNA損傷 / MCM2 / apoptosis / 腫瘍 / 悪性腫瘍の治療 / NA損傷 / アポトーシス

Outline of Final Research Achievements

We have clarified the prominent enhancement of DNA-damage induced apoptosis in highly malignant tumor cells that showed strong expression of MCM2. To confirm the effect of MCM2 expression on the induction of DNA-damage induced apoptosis, we analyzed the apoptosic nature of highly malignant tumor cells after DNA-damage. As a result, we could show the strong expression of MCM2 in highly malignant tumors and the apoptosis-sensitive character of these tumors after DNA-damage.

Academic Significance and Societal Importance of the Research Achievements

通常とは全く異なる新たな経路で p53 依存性アポトーシスシグナルが増強されていることが明らかになった。またin vitro の実験系を用いてこの現象の機序を徹底解明したところ、新たな apoptosis 誘導経路に関わる MCM2minochromosome maintenance protein 2） の作用機構の全貌を解明することができた。細胞株を用いた in vitro 実験系やマウスモデルを用いた in vivo 実験でMCM2高発現腫瘍にはDNA損傷に伴う強い apoptosdis 誘導が認められ、今後の治療開発を考える上で有用であると考えられた。

Research Products

• [Journal Article] Fatty acid beta oxidation enzyme HADHA is a novel potential therapeutic target in malignant lymphoma. (2020)
  • Author(s): Yamamoto K, Abe S, Honda A, Hashimoto J, Aizawa Y, Ishibashi S, Takemura T, Hanagata N, Yamamoto M, Miura O, Kurata M, Kitagawa M.
  • Journal Title: Lab Invest Volume: 100. Issue: 3 Pages: 359-362
  • DOI: 10.1038/s41374-019-0318-6
  • Peer Reviewed
• [Journal Article] CRISPR screening identifies M1AP as a new MYC regulator with a promoter-reporter system (2020)
  • Author(s): Yamamoto Akiko、Kurata Morito、Onishi Iichiroh、Sugita Keisuke、Matsumura Miwa、Ishibashi Sachiko、Ikeda Masumi、Yamamoto Kouhei、Kitagawa Masanobu
  • Journal Title: PeerJ Volume: 8 Pages: e9046-e9046
  • DOI: 10.7717/peerj.9046
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Expression of cathepsins B, D and K in thymic epithelial tumours (2020)
  • Author(s): Yamaguchi Naoko、Tomaru Utano、Kiuchi Takayuki、Ishizu Akihiro、Deguchi Takahiro、Otsuka Noriyuki、Tanaka Satoshi、Marukawa Katsuji、Matsuno Yoshihiro、Kitagawa Masanobu、Kasahara Masanori
  • Journal Title: Journal of Clinical Pathology Volume: 74 Issue: 2 Pages: 84-90
  • DOI: 10.1136/jclinpath-2020-206551
  • Peer Reviewed
• [Journal Article] Biological activity is not suppressed in mid-shaft stress fracture of the bowed femoral shaft unlike in “typical” atypical subtrochanteric femoral fracture: A proposed theory of atypical femoral fracture subtypes (2020)
  • Author(s): Oh Yoto、Yamamoto Kouhei、Hashimoto Jun、Fujita Koji、Yoshii Toshitaka、Fukushima Kazuyuki、Kurosa Yoshiro、Wakabayashi Yoshiaki、Kitagawa Masanobu、Okawa Atsushi
  • Journal Title: Bone Volume: 137 Pages: 115453-115453
  • DOI: 10.1016/j.bone.2020.115453
  • Peer Reviewed / Open Access
• [Journal Article] Histopathologic analysis of signet-ring cell carcinoma in situ in patients with hereditary diffuse gastric cancer. (2020)
  • Author(s): Tsugeno Y, Nakano K, Nakajima T, Namikawa K, Takamatsu M, Yamamoto N, Fujisaki J, Nunobe S, Kitagawa M, Takeuchi K, Kawachi H.
  • Journal Title: Am J Surg Pathol Volume: 44 Issue: 9 Pages: 1204-1212
  • DOI: 10.1097/pas.0000000000001511
• [Journal Article] Clinicopathological characteristics of gastric cancer with carbohydrate antigen 19-9 expression occurring in elderly individuals: an autopsy study. (2020)
  • Author(s): 145.Wang T, Matsuda Y, Nonaka K, Kakizaki M, Ishiwata T, Kanazawa N, Uegaki S, Muramatsu M, Sawabe M, Mori S, Kitagawa M, Arai T.
  • Journal Title: Pathology International Volume: 70 Issue: 2 Pages: 92-100
  • DOI: 10.1111/pin.12882
  • Peer Reviewed / Open Access
• [Journal Article] Subcellular localization of MCM2 protein correlates with the prognosis of clear cell carcinoma of the ovary. (2019)
  • Author(s): 142.Aihemaiti G, Kurata M, Nogawa D, Yamamoto A, Mineo T, Onishi I, Kinowaki Y, Jin X, Miyasaka N, Kitagawa M, YamamotoK.
  • Journal Title: Oncotarget Volume: 9 Issue: 46 Pages: 28213-28225
  • DOI: 10.18632/oncotarget.25613
  • Peer Reviewed
• [Journal Article] Subcellular localization of MCM2 protein correlates with the prognosis of clear cell carcinoma of the ovary. (2019)
  • Author(s): Aihemaiti G, Kurata M, Nogawa D, Yamamoto A, Mineo T, Onishi I, Kinowaki Y, Jin X, Miyasaka N, Kitagawa M, YamamotoK.
  • Journal Title: Oncotarget Volume: in press
  • Peer Reviewed
• [Journal Article] CRISPR/Cas9 library screening for drug target discovery. (2018)
  • Author(s): Kurata M, Yamamoto K, Branden M, Kitagawa M, Largaesapda D.
  • Journal Title: J Hum Genetics Volume: 63 Issue: 2 Pages: 179-186
  • DOI: 10.1038/s10038-017-0376-9
• [Journal Article] Glutathione peroxidase 4 overexpression inhibits ROS-induced cell death in diffuse large B-cell lymphoma. (2018)
  • Author(s): Kinowaki Y, Kurata M, Ishibashi S, Ikeda M, Yamamoto M, Miura O, Kitagawa M, Yamamoto K.
  • Journal Title: Lab Invest Volume: 98 Issue: 5 Pages: 609-619
  • DOI: 10.1038/s41374-017-0008-1