The role of HIF1 alfa in sorafenib resistant hepatocellular carcinoma

• Project/Area Number: 17K09433
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Sapporo Medical University
• Principal Investigator: Akutsu Noriyuki 札幌医科大学, 医学部, 助教 (50531191)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 肝細胞癌 / 薬剤耐性 / 癌

Outline of Final Research Achievements

We hypothesized that the resistance of sorafenib treatment in hepatocellular carcinoma occurs by increasing PD-L1 expression that is directly enhanced by HIF1α. We cultured hepatocellular carcinoma cell lines using cobalt addition or a hypoxic chamber, and compared with control cell lines cultured under normoxia. HIF1α was upregulated in the culture with cobalt and hypoxia chamber. However, PD-L1 expression was not enhanced by either RT-PCR or Western blotting. PD-L1 expression was enhanced by adding IFNγ to hepatocellular carcinoma cell lines and was further enhanced by the addition of cobalt.

Academic Significance and Societal Importance of the Research Achievements

IFNγを添加することでPD-L1の発現が亢進され、さらに低酸素状態でPD-L1発現が増強する結果から、低酸素が何らかの間接的な影響でIFNγを産生し、肝細胞癌株に対してPD-L1の発現を亢進し、腫瘍免疫回避に働いている可能性が考えられた。今後、間接的な作用についてさらなる研究を進めていきたいと考えている。