Potential for targeted therapy of eIF2, a PKR-related molecule involved in carcinogenesis and progression of hepatocellular carcinoma.

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08008
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53010:Gastroenterology-related
• Research Institution: Ehime University
• Principal Investigator: Hiasa Yoichi 愛媛大学, 医学系研究科, 教授 (70314961)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: Protein kinase R / eIF2 / eIF2-alpha / eIF2-beta / eIF2-gamma / Hepatocellular carcinoma / Tumor proliferation / Apoptosis

Outline of Final Research Achievements

Protein kinase R (PKR) is known to be overexpressed and contribute to proliferation of hepatocellular carcinoma (HCC). In this study, I focused on eIF2, a translation initiation factor as a PKR-related molecule. In HCC patients with high expression of eIF2, had a poorer prognosis than those with low expression. In addition, the knockdown of eIF2 reduced the proliferative potential of HCC. The eIF2 is consisted by three subunits, and we revealed that the effect of each subunit on HCC was different. The eIF2α is well known to be associated with repression of RNA translation and apoptosis. However, the changes of eIF2β and eIF2γ, whose functions have not yet been clarified, had a greater impact on the progression of HCC compared to eIF2α. This study suggests that regulation of eIF2β and eIF2γ in the PKR-eIF2 pathway, would have some potentials as target therapies against HCC.

Free Research Field

消化器内科学

Academic Significance and Societal Importance of the Research Achievements

本研究ではPKR関連分子であるeIF2が肝細胞がんの予後に影響していることを明らかにした。
PKRをはじめとする上流シグナルによってeIF2αがリン酸化されることは知られているが、肝細胞がんにおいてPKR-eIF2α経路が発がんまたはがんの進展に及ぼす影響は明らかでない。本研究では、未だ作用について不明な点の多いeIF2βとeIF2γの発現抑制が腫瘍増殖能を抑制することを見出した。
翻訳開始因子であるeIF2の制御機序の解明は、肝細胞がんのみならず、様々な悪性腫瘍の分子標的治療に結び付く可能性がある。