Elucidation of the mechanism of treatment resistance of lung cancer mediated by sphingolipids and MMP

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K18226
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 55040:Respiratory surgery-related
• Research Institution: Kanazawa Medical University
• Principal Investigator: MOTONO Nozomu 金沢医科大学, 医学部, 講師 (30634901)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: 肺癌 / 幹細胞 / スフィンゴリン脂質 / PRDX4 / TSHZ2

Outline of Final Research Achievements

In lung adenocarcinoma, the prognosis was poor in MIB-1 positive cases with decreased expression of the antioxidant enzyme PRDX4 and an index of cell proliferation, and decreased expression of PRDX4 was more common in the EGFR wild-type, which is the epidermal growth factor receptor. In addition, overexpression of PRDX4 suppressed the growth of lung adenocarcinoma, indicating that PRDX4 is a factor affecting prognosis in lung adenocarcinoma. Furthermore, it was confirmed that overexpression of TSHZ2, a nuclear protein, suppresses cell proliferation and induces apoptosis. In addition, SPHK1, which is a type of sphingosine lipid, showed a positive correlation between the staining concentration of SPHK1 and Ki-67, which is an index of proliferative ability, in fibroblast of the infiltrated part of lung adenocarcinoma.

Free Research Field

呼吸器外科

Academic Significance and Societal Importance of the Research Achievements

予後不良を引き起こす因子が癌幹細胞の活性化に関与するとの仮説を立てて、肺癌の多くを占める肺腺癌を標的とし、癌の浸潤・増殖および予後に影響を及ぼす因子を解析した。PRDX4やTSHZ2の発現低下による増殖能の活性化、SPHK1が肺癌の浸潤部のfibroblastで高発現することで増殖能が活性化することが確認された。また、SPHK1高発現例は予後不良となる傾向も認めた。今後、これらの因子が肺癌の癌幹細胞の活性化に寄与するかを検証・解明し創薬につなげることができれば、治療抵抗性の肺癌の治療成績を劇的に向上させる可能性がある。