Document Type
Article
Publication Date
2-1-2025
Abstract
Long-term exposure to hexavalent chromium [Cr(VI)] has been linked to lung cancer, and cyclooxygenase-2 (COX-2) is a well-known inflammatory factor. However, the role and mechanism of COX-2 in Cr(VI)-induced carcinogenesis are not clear yet. To address this question, we employed a mouse model exposed to Cr(VI) through intranasal instillation of particulate zinc chromate (ZnCrO4) for 12 weeks. Metabolomics and RNA-seq assays revealed enhanced activity of the arachidonic acid (AA)/eicosanoid metabolism pathway in lung tissues from mice exposed to Cr(VI). COX-2, the key enzyme of the AA/eicosanoid pathway, was significantly upre- gulated in Cr(VI)-exposed lung tissues, as well as in the Cr(VI)-induced transformed (Cr-T) cells compared to parental BEAS-2B (B2B) cells. We then employed multidisciplinary in vitro and in vivo functional assays to characterize the role of COX-2 in Cr(VI)-induced lung cancer. The results indicated that COX-2 functioned as an oncogene to promote the malignant transformation of B2B cells and enhance the proliferation, migration, tumor growth, and angiogenesis of Cr-T cells. Nuclear factor E2-related factor-2 (Nrf2) was identified as a transcription factor for COX-2. Nrf2 was upregulated in response to Cr(VI) exposure and contributed to Cr(VI)-induced lung cancers, in part by upregulating COX-2 expression. Moreover, microRNA-379 (miR-379) was found to target COX-2 to inhibit its expression posttranscriptionally. MiR-379 was downregulated in Cr(VI)-exposed lung tissues and Cr-T cells, and ectopic miR-379 expression reduced Cr-T cell viability and migration, with partial reversal upon COX-2 restoration. In summary, our study revealed the oncogenic role of COX-2 and identified two novel regulatory mechanisms for COX-2 overexpression in Cr(VI)-induced carcinogenesis.
Recommended Citation
Zhao, Lei; Wang, Yi-Fang; Adamcakova-Dodd, Andrea; Thorne, Peter; Islam, Ranakul; Liu, Ke Jian; Chen, Fei; Luo, Jia; and Liu, Ling-Zhi, "Nrf2/cyclooxygenase 2 Signaling in Cr(VI)-Induced Carcinogenesis" (2025). Kimmel Cancer Center Faculty Papers. Paper 146.
https://jdc.jefferson.edu/kimmelccfp/146
Creative Commons License
This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.
PubMed ID
39923569
Language
English
Included in
Disorders of Environmental Origin Commons, Enzymes and Coenzymes Commons, Genetic Phenomena Commons, Pathological Conditions, Signs and Symptoms Commons
Comments
This article is the author's final published version in Ecotoxicology and environmental safety, Volume 291, February 2025, Article number 117800.
The published version is available at https://doi.org/10.1016/j.ecoenv.2025.117800.
Copyright © 2025 Published by Elsevier Inc