Innovative mitochondrial-targeted gene therapy for hepatocellular carcinoma

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K15515
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Jikei University School of Medicine
• Principal Investigator: Onda Shinji 東京慈恵会医科大学, 医学部, 講師 (10459620)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: オートファジー / マイトファジー / ライソゾーム / 酸性βグルコシダーゼ

Outline of Final Research Achievements

We analyzed the function of acid β-glucosidase in hepatocellular carcinoma. In a human hepatocellular carcinoma cell line, PARK9 reduced the expression level of PARK9 protein and inhibited cell proliferation, invasion and migration ability. Mitochondrial accumulation was also confirmed by electron microscopy. We also confirmed a decrease in mitochondrial membrane potential and mitophagy activity, a mitochondrial-selective autophagy. Accumulation of iron, lipid peroxidation, and ROS in mitochondria was confirmed by flow cytometry and fluorescence microscopy.
In human hepatocellular carcinoma cell lines, inhibition of PARK9 activity induces mitochondrial dysfunction, resulting in abnormal iron metabolism, which in turn induces ferotosis.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

今後はさらにPARK9と薬剤耐性の関与に関して、肝細胞癌に対する分子標的治療薬であるレンバチニブの投与下で、薬剤のPARK9タンパク質発現量を評価する。最終的に、PARK9をノックダウンしたレンバチニブ耐性肝細胞癌細胞株において、レンバチニブの耐性を克服することを確認する。