Functional analysis of voltage-gated potassium channels in pancreatic cancer stem cells

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K08689
• 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: Kyoto Prefectural University of Medicine
• Principal Investigator: Harada Kyouichi 京都府立医科大学, 医学(系)研究科(研究院), 特任助教 (80804822)
• Co-Investigator(Kenkyū-buntansha): 大辻 英吾 京都府立医科大学, 医学(系)研究科(研究院), 教授 (20244600) ; 塩崎 敦 京都府立医科大学, 医学(系)研究科(研究院), 講師 (40568086)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 膵癌 / 癌幹細胞 / イオンチャネル

Outline of Final Research Achievements

Cells exhibiting strong ALDH1A1 activity were isolated from PK59 pancreatic cancer cells by cell sorting, and cancer stem cells (CSCs) were generated with the sphere formation assay. Microarray analysis revealed voltage-gated potassium channels were upregulated in CSCs, and its inhibitor 4-Aminopyridine effectively decreased the number of tumorspheres. An immunohistochemical analysis revealed a relationship between strong KCNB1 expression and a poor prognosis in esophageal cancer. In KYSE70 and TE5 cells, KCNB1 depletion with siRNA suppressed cell proliferation, cell cycle progression, and invasion/migration, and induced apoptosis. The results of the microarray analysis showed that the expressions of Ephrin receptor signaling related genes were changed in KCNB1-depleted cells. These results provide an insight into the role of KCNB1 as a biomarker, and that its specific inhibitor, 4-Aminopyridine, has potential as a targeted therapeutic agent against digestive cancer.

Free Research Field

消化器外科学

Academic Significance and Societal Importance of the Research Achievements

KCNB1、KCNC1、KCND1等のVGKCが膵癌幹細胞において高発現し、その阻害剤である4-アミノピリジンが癌幹細胞特異的に抑制効果を示すことを新たに見出した。4-アミノピリジンは多発性硬化症の治療薬として臨床で用いられている薬剤であり、その抗腫瘍効果を明らかにしたことの社会的意義は大きいと考えられる。また、KCNB1のEphrin receptor signalingを介する新たな腫瘍進展制御機構や、予後因子としての意義を明らかにし、バイオマーカーや治療標的としての可能性を示した。