Functional analysis of new therapeutic target factors for tumorigenesis and recurrence with liver fibrosis
| Project/Area Number |
19K17485
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 53010:Gastroenterology-related
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| Research Institution | Kanazawa University |
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Principal Investigator |
Okada Hikari 金沢大学, 医薬保健学総合研究科, 特任助教 (50788916)
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| Project Period (FY) |
2019-04-01 – 2021-03-31
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| Project Status |
Completed (Fiscal Year 2020)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2020: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Fiscal Year 2019: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
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| Keywords | 肝発がん / 肝線維化 / PKM / NCID / Notch / PKM1 / PKM2 / Notch1 / Jagged1 / 腫瘍成長 / 発癌 / 再発 |
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| Outline of Research at the Start |
肝硬変を背景とした肝細胞癌患者では根治的治療後でも肝細胞癌が高率に再発する。肝細
胞癌の再発抑制が治療上極めて重要な課題である。申請者は、PKM1が肝線維化病態進行に関与し、PKM2は肝細胞癌の腫瘍成長促進に働くと同時にPKLの機能が損失していることを発見した。本研究では、肝疾患病態進行におけるPKMの生理的役割・発現制御機構を解明し、肝線維化及び肝発がん時のPKLの機能損失を正常に回復させることが肝線維化及び肝発がんの新規治療標的になり得るかを動物モデル及び培養実験で検討する。
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| Outline of Final Research Achievements |
The applicant confirmed from the expression analysis that the expression of both PKM1 and PKM2, which are PKM variants, increases with the progression of hepatic fibrosis and the malignancy of hepatocellular carcinoma. PKM1 enhanced hepatic fibrosis by transforming hepatic stellate cells into myofibroblasts. PKM2 was shown to form a complex with the intracellular domain NICD of Notch1 in liver cancer cells. And it was shown that this complex has a role of increasing the malignancy of hepatocellular carcinoma through CSL in the nucleus. From these research results, it was clarified that a therapeutic strategy that inhibits the expression of both PKM1 and PKM2 is more effective than PKM2 alone for the pathological condition of liver carcinogenesis based on liver fibrosis.
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| Academic Significance and Societal Importance of the Research Achievements |
肝硬変を背景とした肝細胞癌患者では、根治的治療後でも肝細胞癌が高率に再発し、再発率は年間約20-25%、5年では70%以上に上ることから肝細胞癌の再発抑制が治療上極めて重要な課題である。そのため、肝線維化・肝硬変による肝発がん機序を解明し、新規治療法につながる基礎研究が重要である。今回の研究成果から、肝線維化病態から肝発がん過程におけるPKM1とPKM2の発現制御機序の一端を解明することができ、肝線維化及び肝発がん・再発に対する新規治療標的の可能性を示せた。
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Report
(3 results)
Research Products
(4 results)
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[Journal Article] Fatty acid-driven modifications in T-cell profiles in non-alcoholic fatty liver disease patients.2020
Author(s)
T Seike, E Mizukoshi, K Yamada, H Okada, M Kitahara, T Yamashita, K Arai, T Terashima, N Iida, K Fushimi, T Yamashita, Y Sakai, M Honda, K Harada, S Kaneko.
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Journal Title
Journal of Gastroenterology
Volume: -
Pages: 701-711
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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