Notch ligands Dll4 and Jag1 have antagonistic effects on hepatocellular carcinoma development

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K15826
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Tokyo Medical and Dental University (2020); The University of Tokyo (2019); Tokai University (2018)
• Principal Investigator: Nakano Yasuhiro 東京医科歯科大学, 難治疾患研究所, 助教 (80755439)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 肝細胞癌 / Notchリガンド / Notch受容体 / 肝線維化 / 肝星細胞

Outline of Final Research Achievements

In many types of cancer, the Notch signaling is one of the most common drivers of carcinogenesis. Hepatocellular carcinoma (HCC) is the third cancer killer in the world, but the type of Notch ligands and receptors influencing HCC development is unclear. Using diethylnitrosamine (DEN)-induced murine HCC model, we identified Notch ligands Dll4 and Jag1 as the genes whose expression was significantly correlated with that of the Notch target gene Hes1 in the cancer tissue. Using Dll4 or Jag1 conditional knockout mice, we investigated how different Notch ligands modulate DEN-induced hepatic carcinogenesis. Hepatocyte lineage-specific Dll4 knockout suppressed HCC progression via loss of Notch1 signaling. On the other hand, Jag1 deletion induced ectopic Dll4 expression in hepatocytes by loss of Notch2 signaling, which led to HCC progression. These results suggest that different ligands and receptors have different effects on Notch signaling in HCC development.

Free Research Field

肝臓学

Academic Significance and Societal Importance of the Research Achievements

肝癌は世界的に死者数の多い癌であり、その治療法開発が待たれる。肝線維化・肝硬変を背景として肝癌は発生・進展するが、線維化が進行した肝臓においては正常肝と比較し、肝再生能が低下する。このため、肝癌を切除した場合には、残存肝の再生能が乏しいために術後肝不全を引き起こすリスクを伴う。本研究課題は「肝癌の抑止」と「線維肝再生」の両方を可能とする治療法の開発基盤を構築することを目的とした。本研究の成果として、線維肝の再生を促進するNotchリガンドJag1からのNotch2シグナルが肝癌の進展を抑止することを明らかにした。