Mechanism and clinical prediction of drug resistance associated with epithelial mesenchymal transition of lung cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K06793
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 47060:Clinical pharmacy-related
• Research Institution: Takasaki University of Health and Welfare
• Principal Investigator: Ogihara Takuo 高崎健康福祉大学, 薬学部, 教授 (80448886)
• Co-Investigator(Kenkyū-buntansha): 矢野 健太郎 高崎健康福祉大学, 薬学部, 講師 (40644290)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: P-糖タンパク / 上皮間葉転換 / 排出系トランスポーター / 転写調節因子 / ERMタンパク質 / mRNA / Snail / 免疫沈降法

Outline of Final Research Achievements

We analyzed the functional changes of efflux transporters such as P-glycoprotein(P-gp) and their scaffold proteins, ERM(Ezrin, Radixin, Moesin) during the induction of epithelial-mesenchymal transition (EMT) in cancer metastasis using the transcriptional regulator, Snail. The protein and mRNA expression levels of Moesin and Radixin were increased in human lung cancer-derived HCC827 and human liver cancer-derived HepG2 cells, respectively, indicating that P-gp function was enhanced. The mRNA level of P-gp was not increased, but only the membrane expression level was increased. The interaction between P-gp and Radixin, an ERM was investigated by immunoprecipitation, and Radixin was found to interact with P-gp. In HCC827, where the Snail gene was introduced, it was suggested that the expression and function of the efflux transporter MRP5 were enhanced.

Free Research Field

生物薬剤学

Academic Significance and Societal Importance of the Research Achievements

本研究の成果により、がん細胞において Snail 誘発性の EMT が生じる際に，ERMの発現増加に伴って排出系トランスポーター，特にP-gpの細胞膜発現が増加し，その機能が上昇することが確認された。またこのとき、発現が増加する ERM タンパク質は臓器毎に異なる可能性が示唆された。今回の検討により，がん多剤耐性は抗がん剤の曝露をきっかけとするだけでなく，がんの転移の際にも起こりえることが示唆され，さらにP-gpを細胞膜上に固定する足場タンパクは組織ごとに異なることから，組織特異的な抗がん薬の開発に繋がるものと期待される．