The inhibitor of protein kinase R (PKR) suppresses tumor proliferation and angiogenesis in hepatocellular carcinoma in vitro and in vivo models

2019 Fiscal Year Final Research Report

• Project/Area Number: 18K15818
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Ehime University
• Principal Investigator: Watanabe Takao 愛媛大学, 医学系研究科, 講師 (90650458)
• Project Period (FY): 2018-04-01 – 2020-03-31
• Keywords: 肝細胞癌 / PKR / 細胞増殖 / 血管新生 / 阻害剤 / 増殖因子

Outline of Final Research Achievements

We tested the effect of protein kinase R (PKR) inhibitor C16 on proliferation of HCC Huh7 cells in vitro and tumor progression and angiogenesis of tumor bearing mouse of Huh7 in vivo.
C16 suppressed proliferation of Huh7 cells in a dose-dependent manner in vitro evaluated with the MTT assay. Mouse models with xenograft transplantation showed that the inhibitor suppressed the growth of HCC cells in vivo. Moreover, C16 decreased angiogenesis in HCC tissue in the xenograft model. Consistent with these results in mice, transcript levels of vascular endothelial growth factor-A and factor-B, platelet-derived growth factor-A and factor-B, fibroblast growth factor-2, epidermal growth factor, and hepatocyte growth factor, which are angiogenesis-related growth factors, were significantly decreased by C16 in vitro.
In conclusion, the PKR inhibitor C16 blocked tumor cell growth and angiogenesis via a decrease in mRNA levels of several growth factors. C16 may be useful in the treatment of HCC.

Free Research Field

消化器内科

Academic Significance and Societal Importance of the Research Achievements

現在、肝細胞癌に対する治療は、手術、内科的な局所治療としてRFA、TACEなどが用いられている。しかし肝細胞癌患者の高齢化、その高い再発率から患者への負担の少ない薬物治療の開発が必要である。治療効果のエビデンスのある薬物もごく限られているのが現状である。本研究では細胞株とマウスを用いた検討を行い、PKR阻害剤により肝細胞癌の増殖、血管新生が抑制されることを示した。PKRをターゲットとした治療は肝細胞癌における新規治療となり得ると考えられた。