The origin of autophagosome derived from the endoplasmic reticulum with a focus on pancreatic stellate cell activation genes

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09036
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 55020:Digestive surgery-related
• Research Institution: Kyushu University
• Principal Investigator: SAKAI Hiroshi 九州大学, 医学研究院, 共同研究員 (80611665)
• Co-Investigator(Kenkyū-buntansha): 江上 拓哉 九州大学, 医学研究院, 共同研究員 (40507787) ; 久保 真 九州大学, 医学研究院, 准教授 (60403961) ; 中山 宏道 九州大学, 医学研究院, 共同研究員 (80866773) ; 大内田 研宙 九州大学, 医学研究院, 准教授 (20452708)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 膵癌 / 膵星細胞 / オートファジー / 小胞体 / 隔離膜 / 新規治療薬 / ERAP2

Outline of Final Research Achievements

Pancreatic cancer is characterized by abundant stroma, of which pancreatic stellate cells (PSCs) are one component. Autophagy is involved in the activation of PSCs, which play an important role in the growth, metastasis, and invasion of pancreatic cancer cells. It has been reported that the isolation membrane, the origin of autophagy, originates from the endoplasmic reticulum (ER), and the relationship between autophagy and the ER has attracted attention. In this study, we showed that ERAP2, an endoplasmic reticulum-related gene among PSC activating genes, is involved in the autophagy pathway via the unfolded protein response signaling pathway in the endoplasmic reticulum, and that ERAP2 knockout PSCs suppress tumor growth effects and enhance the antitumor effect of gemcitabine. The results showed that ERAP2 knockout PSCs suppressed the tumor growth effect and enhanced the antitumor effect of gemcitabine.

Free Research Field

医歯薬学

Academic Significance and Societal Importance of the Research Achievements

膵癌は非常に予後不良な癌の１つであり、その浸潤、転移のメカニズムを解明することは新たな治療方法の開発に必須の課題である。本研究では小胞体関連遺伝子ERAP2がERストレス由来のオートファジーを介してPSCの活性化を制御していることを示し、ERAP2ノックアウトPSCの腫瘍抑制効果及びゲムシタビンとの併用効果を示した。
ERAP2がPSCの活性化を阻害する新たな治療ターゲットとなる可能性が示唆された。