Journal article
Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesis
Ecotoxicology and environmental safety, Vol.291, 117800
02/2025
DOI: 10.1016/j.ecoenv.2025.117800
PMCID: PMC12439351
PMID: 39923569
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 upregulated 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.
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•Arachidonic acid/eicosanoid pathway and COX-2 are upregulated after Cr(VI) exposure.•COX-2 promotes Cr(VI)-induced malignant transformation.•COX-2 is an oncogene in Cr(VI)-induced transformed (Cr-T) cells.•Nrf2 plays an oncogenic role by directly inducing COX-2 transcriptional activation.•MiR-379 directly targets COX-2, acting as a tumor suppressor in Cr-T cells.
Details
- Title: Subtitle
- Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesis
- Creators
- Lei Zhao - Thomas Jefferson UniversityYi-Fang Wang - Thomas Jefferson UniversityAndrea Adamcakova-Dodd - University of IowaPeter S. Thorne - University of IowaRanakul Islam - Thomas Jefferson UniversityKe Jian Liu - Stony Brook UniversityFei Chen - Stony Brook UniversityJia Luo - University of Iowa
- Resource Type
- Journal article
- Publication Details
- Ecotoxicology and environmental safety, Vol.291, 117800
- DOI
- 10.1016/j.ecoenv.2025.117800
- PMID
- 39923569
- PMCID
- PMC12439351
- NLM abbreviation
- Ecotoxicol Environ Saf
- ISSN
- 0147-6513
- eISSN
- 1090-2414
- Publisher
- Elsevier Inc
- Grant note
- American Cancer Society Research Scholar Award: NEC-129306 NIH/NIEHS: K02ES029119 Environmental Health Sciences Research Center: NIH P30ES005605
This work was in part supported by the American Cancer Society Research Scholar Award (NEC-129306 to L.Z. Liu) and NIH/NIEHS K02 grant (K02ES029119 to L.Z. Liu), and the animal studies were supported by the Environmental Health Sciences Research Center (NIH P30ES005605 to P.S. Thorne).
- Language
- English
- Date published
- 02/2025
- Academic Unit
- Civil and Environmental Engineering; Occupational and Environmental Health; Pathology
- Record Identifier
- 9984791076802771
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