Mechanisms of Cell proliferation and tumorigenesis in ATP1A1 gene mutated adrenal cells

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K16058
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 53020:Cardiology-related
• Research Institution: Hiroshima University
• Principal Investigator: Kobuke Kazuhiro 広島大学, 医系科学研究科(医), 寄附講座助教 (80805648)
• Project Period (FY): 2021-04-01 – 2023-03-31
• Keywords: 二次性高血圧症 / アルドステロン産生腫瘍 / 副腎皮質腫瘍 / 原発性アルドステロン症

Outline of Final Research Achievements

The purpose of this study was to elucidate the mechanisms of cell proliferation and tumorigenesis caused by mutations in the ATP-dependent Na/K pump gene (ATP1A1), which is one of the causes of aldosterone-producing adenomas. We found that physiological concentrations of strong glycosyltransferases activate the receptor signal of the Na/K pump, which is upregulated in APA, and elucidate the mechanism of tumor growth that leads to APA. We also showed that vitamin D receptor signaling activity is essential for APA tumor growth and that vitamin D receptor expression is regulated by DNA demethylation. In addition, administration of physiological concentrations of strong cardiac glycosides and administration or removal of vitamin D had no effect on aldosterone synthesis.

Free Research Field

二次性高血圧

Academic Significance and Societal Importance of the Research Achievements

今回明らかになった細胞増殖促進メカニズムは，必要なアルドステロン分泌を抑制することなく，細胞増殖によるアルドステロン過剰分泌，ならびに腫瘍形成を抑制することができると考えられ，正常の生体ホメオスタシスを障害しない新たな創薬につながる可能性がある．また、本研究過程においてATP1A1変異副腎皮質腫瘍モデル細胞株の樹立や，副腎腫瘍細胞の増殖を定量的に評価するメソッドなどの今後の本領域の研究における重要なツールの開発・確立も果たされた．このことは今後の本領域研究の進展に寄与する．