Mechanistic insights into the patho-etiology of lung cancer, especially focusing on the protective effects of promising antioxidant enzyme, PRDX4

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07454
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49030:Experimental pathology-related
• Research Institution: Kanazawa Medical University
• Principal Investigator: YAMADA Sohsuke 金沢医科大学, 医学部, 教授 (90525453)
• Co-Investigator(Kenkyū-buntansha): 郭 シン 金沢医科大学, 医学部, 助教 (40816328) ; 浦本 秀隆 金沢医科大学, 医学部, 教授 (90389445)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 抗酸化ストレス因子 / ペルオキシレドキシン(PRDX) / PRDX4 / 肺癌 / 動物モデル

Outline of Final Research Achievements

Peroxiredoxin 4 (PRDX4), initially reported as an antioxidant, is overexpressed in lung cancer and participates in its progression. However, its role in the urethane-induced lung tumor model is undetermined. Human PRDX4 overexpression transgenic (Tg) mice and non-Tg mice were intraperitoneally injected with urethane to induce lung tumor. After 6 months, both the average number of tumors (more than 0.5 mm) and tumor diameter per mouse in the Tg group were significantly larger than in non-Tg controls. Tumor cell proliferation was enhanced, while tumor cell apoptosis was suppressed in Tg mice. Systemic oxidative stress and oxidative stress in lung tumors were inhibited by PRDX4 overexpression. In lung tumor tissue, the expressions of cytokines, including interleukin-1 beta (IL-1β) and matrix metallopeptidase 9 (MMP9), were elevated in Tg. In conclusion, PRDX4 overexpression modulated tumor microenvironment and promoted tumor development in the mouse urethane-induced lung cancer model.

Free Research Field

実験病理

Academic Significance and Societal Importance of the Research Achievements

PRDX4の過剰発現は、腫瘍の微小環境をcriticalに調節し、ウレタンによる肺癌誘発マウスモデルにおける腫瘍発生を促進し得ることを、世界で初めて突き止め先駆けて公表し得た。今後は、肺癌治療における抗酸化酵素の臨床応用が大きく期待されるため、さらに詳細な分子メカニズムの解明、一方で生体応用へ向けた新たなモデルの構築（in vivoだけでなくin vitro系も含めた）を模索している。
当研究成果の学術的意義はtranslational researchとしての意義が非常に深い。さらに、肺癌治療における抗酸化酵素PRDX4の応用が将来的に期待されるという、社会的意義にも富んでいる。