Exploring a molecular mechanism governing the metabolism to repress cancer progression depending on genetic backgrounds

• Project/Area Number: 18K07235
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Nagasaki University
• Principal Investigator: YAMAMOTO Kazuo 長崎大学, 医歯薬学総合研究科(医学系), 准教授 (70255123)
• 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: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2019: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 細胞サイズ / ミトコンドリア / がん / 代謝 / タンパク質合成 / 癌抑制遺伝子 / 翻訳制御

Outline of Final Research Achievements

A gene called Largen is ubiquitously expressed in most types of cells with low level, but increases cell size by modulating cellular mitochondrial content and ATP production upon over expression. To elucidate the relationships between mitochondrial activity and cancer onset/development, we investigated the effect of Largen-over expression in two different mouse models for leukemia caused by the distinct genetic disorders. The over expression of Largen extended the life span in one model mouse system, but had no effect on another one. The investigator found that the metabolic profiles and the rate of protein synthesis were altered in the cells derived from individual mouse models. The effect of Largen-over expression was also different in these models. A metabolome analysis revealed that particular metabolic pathways were activated by Largen-over expression.

Academic Significance and Societal Importance of the Research Achievements

上記の研究成果から、白血病という病気が、最終的にT細胞の無秩序な増殖を理由とする病態であっても、その先駆けとなる遺伝子の変異が異なると、細胞内における代謝に対して異なる影響を及ぼし、異なる経緯で増殖に至っていることが分かる。従って、 Largen過剰発現に感受性の高い代謝経路を特定し、それぞれの遺伝子変異による白血病モデルにおける代謝にどう関わっているかを明らかにすることで、これまでとは全く異なる観点からの治療薬・治療法の開発につながると期待される。さらに他の発癌モデルにも研究を適用することで、より一般的な疾病の克服に発展させることも考えられる。

Research Products

• [Journal Article] Geranylgeranylacetone decreases the production of hepatitis B virus‐related antigen by comprehensive downregulation of mRNA transcription activity (2021)
  • Author(s): Haraguchi Masafumi、Miuma Satoshi、Yamamoto Kazuo、Nakao Yasuhiko、Ichikawa Tatsuki、Kanda Yasuko、Sasaki Ryu、Fukushima Masanori、Akazawa Yuko、Miyaaki Hisamitsu、Nakao Kazuhiko
  • Journal Title: Journal of Gastroenterology and Hepatology Volume: - Issue: 7 Pages: 1-9
  • DOI: 10.1111/jgh.15394
  • Peer Reviewed
• [Journal Article] An inhibitor of Krüppel-like factor 5 suppresses peritoneal fibrosis in mice. (2021)
  • Author(s): Muta K, Nakazawa Y, Obata Y, Inoue H, Torigoe K, Nakazawa M, Abe K, Furusu A, Miyazaki M, Yamamoto K, Koji T, Nishino T
  • Journal Title: Perit Dial Int Volume: - Issue: 4 Pages: 394-403
  • DOI: 10.1177/0896860820981322
  • Peer Reviewed / Open Access
• [Journal Article] Hexapeptide derived from prothymosin alpha attenuates cisplatin-induced acute kidney injury. (2020)
  • Author(s): Torigoe K, Obata Y, Torigoe M, Oka S, Yamamoto K, Koji T, Ueda H, Mukae H, Nishino T
  • Journal Title: Clin Exp Nephrol Volume: 24 Issue: 5 Pages: 411-419
  • DOI: 10.1007/s10157-019-01843-1
  • Peer Reviewed / Open Access
• [Journal Article] Differential levels of regulatory T-cells and T-helper-17 cells in women with early and advanced endometriosis (2019)
  • Author(s): Khan KN, Yamamoto K, Fujishita A, Muto H, Koshiba A, Kuroboshi H, Saito S, Teramukai S, Nakashima M, Kitawaki J.
  • Journal Title: J Clin Endocrinol Metab. Volume: May 1 Issue: 10 Pages: 4715-4729
  • DOI: 10.1210/jc.2019-00350
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Association between FOXP3+ regulatory T-cells and occurrence of peritoneal lesions in women with ovarian endometrioma and dermoid cysts (2019)
  • Author(s): Khan KN, Yamamoto K, Fujishita A, Koshiba A, Kuroboshi H, Sakabayashi S, Teramukai S, Nakashima M, Kitawaki J.
  • Journal Title: Reprod Biomed Online Volume: Jan 31 Issue: 6 Pages: 857-869
  • DOI: 10.1016/j.rbmo.2019.01.011
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Intracellular redox status controls spherogenicity, an in vitro cancer stem cell marker, in thyroid cancer cell lines (2018)
  • Author(s): Shimamura Mika、Yamamoto Kazuo、Kurashige Tomomi、Nagayama Yuji
  • Journal Title: Experimental Cell Research Volume: 370 Issue: 2 Pages: 699-707
  • DOI: 10.1016/j.yexcr.2018.07.036
  • Peer Reviewed / Open Access