The mechanisms of arsenic-induced carcinogenesis via fibroblast senescence

2020 Fiscal Year Final Research Report

• Project/Area Number: 18K17363
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 58020:Hygiene and public health-related: including laboratory approach
• Research Institution: National Institute for Environmental Studies
• Principal Investigator: Okamura Kazuyuki 国立研究開発法人国立環境研究所, 環境リスク・健康研究センター, 主任研究員 (50736064)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: ヒ素 / 細胞老化 / SASP / 線維芽細胞 / 肝臓 / 皮膚 / DNA損傷

Outline of Final Research Achievements

Although senescent cells themselves irreversibly stop proliferation, they secrete multiple factors called senescence-associated secretory phenotype (SASP) such as cytokines, chemokines, and matrix metalloproteinases. SASP is known to involve tumorigenesis. In this study, we revealed arsenite exposure induced premature senescence and following SASP induction in human derived hepatic stellate cell line (fibroblast-like) LX-2. Furthermore, high level of gene expression of SASP factors were remained even after removing arsenite from culture medium. Thus, it was shown that the effect of arsenite exposure persist even after exposure to arsenite has ceased. The gene expression changes of SASP factors were also observed in human derived skin fibroblast cell line HFb16d after arsenite exposure. Therefore, it is suggested that induction of SASP factors in fibroblasts by arsenite exposure is involved in carcinogenesis.

Free Research Field

環境毒性学

Academic Significance and Societal Importance of the Research Achievements

ヒ素曝露が引き起こす慢性中毒は世界的に深刻な環境問題のひとつであり、その中でも発癌は命に関わる問題であるが、機序は未解明である。これまでにヒ素曝露による細胞老化を介したSASPによる発癌メカニズムを検討した実験的研究は存在せず、本研究は肝臓、皮膚など慢性ヒ素中毒によって癌が生じる組織において発癌の共通機序としてSASP因子の亢進が関与する可能性を明らかにした。これによりヒ素曝露による発癌メカニズムを明らかにした。