The axis of KEAP1/NRF2-PITX2-YAP contributes to the development of malignant mesothelioma

2018 Fiscal Year Final Research Report

• Project/Area Number: 17H07050
• Research Category: Grant-in-Aid for Research Activity Start-up
• Allocation Type: Single-year Grants
• Research Field: Respiratory surgery
• Research Institution: Iwate Medical University
• Principal Investigator: Shigeeda Wataru 岩手医科大学, 医学部, 助教 (00802828)
• Project Period (FY): 2017-08-25 – 2019-03-31
• Keywords: 悪性胸膜中皮腫 / NRF2 / PITX2 / KEAP1

Outline of Final Research Achievements

In pleural mesothelioma/lung cancer, we examined whether KEAP1/NRF2-PITX2-YAP axis abnormality is involved in the formation of drug resistance to ROS-producing anticancer drugs. We examined expression panels of related molecules and hypermethylation of the promoter region of PITX2 gene. In cell lines where hypermethylation had occurred in the promoter region of PITX2, activation of the KEAP1 / NRF2 system was observed. With PITX2-inducible clone, it was confirmed that the sensitivity to the anti-cancer drug is restored. It was speculated that these ROS removal mechanisms are responsible for the reduced sensitivity of anti-cancer drugs.

Free Research Field

胸部外科

Academic Significance and Societal Importance of the Research Achievements

本研究は，希少癌である胸悪性膜中皮腫の治療に際し，その抗がん薬感受性が左右非対称性の経路を決定づけるホメオボックス遺伝子PITX2のプロモーター領域の過メチル化に影響を受ける事を明らかにしたものである。難治性悪性胸膜中皮腫の開発にあたって，抗がん薬感受性低下の原因を明らかにした事は，新たな分子標的治療法の開発に有意義である。