Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesis
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 expose...
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Elsevier
2025-02-01
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| Series: | Ecotoxicology and Environmental Safety |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0147651325001368 |
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| author | Lei Zhao Yi-Fang Wang Andrea Adamcakova-Dodd Peter S. Thorne Ranakul Islam Ke Jian Liu Fei Chen Jia Luo Ling-Zhi Liu |
| author_facet | Lei Zhao Yi-Fang Wang Andrea Adamcakova-Dodd Peter S. Thorne Ranakul Islam Ke Jian Liu Fei Chen Jia Luo Ling-Zhi Liu |
| author_sort | Lei Zhao |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-b178ebfa44a645feb706153627ba3e1f |
| institution | Kabale University |
| issn | 0147-6513 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Ecotoxicology and Environmental Safety |
| spelling | doaj-art-b178ebfa44a645feb706153627ba3e1f2025-02-09T04:59:36ZengElsevierEcotoxicology and Environmental Safety0147-65132025-02-01291117800Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesisLei Zhao0Yi-Fang Wang1Andrea Adamcakova-Dodd2Peter S. Thorne3Ranakul Islam4Ke Jian Liu5Fei Chen6Jia Luo7Ling-Zhi Liu8Department of Pathology, University of Iowa, Iowa, IA 52242, USA; Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Pathology, University of Iowa, Iowa, IA 52242, USA; Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Occupational and Environmental Health, University of Iowa, Iowa City, IA, 52242, USADepartment of Occupational and Environmental Health, University of Iowa, Iowa City, IA, 52242, USADepartment of Pathology, University of Iowa, Iowa, IA 52242, USA; Department of Medical Oncology, Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA 19107, USADepartment of Pathology, Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USADepartment of Pathology, Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USADepartment of Pathology, University of Iowa, Iowa, IA 52242, USADepartment of Pathology, University of Iowa, Iowa, IA 52242, USA; Department of Pathology, Stony Brook Cancer Center, Stony Brook University, Stony Brook, NY 11794, USA; Correspondence to: MART, Level 7, Room 0701, Lauterbur Drive, Stony Brook, NY 11794, USA.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.http://www.sciencedirect.com/science/article/pii/S0147651325001368Cr(VI)CarcinogenesisNrf2COX-2miR-379 |
| spellingShingle | Lei Zhao Yi-Fang Wang Andrea Adamcakova-Dodd Peter S. Thorne Ranakul Islam Ke Jian Liu Fei Chen Jia Luo Ling-Zhi Liu Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesis Ecotoxicology and Environmental Safety Cr(VI) Carcinogenesis Nrf2 COX-2 miR-379 |
| title | Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesis |
| title_full | Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesis |
| title_fullStr | Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesis |
| title_full_unstemmed | Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesis |
| title_short | Nrf2/cyclooxygenase 2 signaling in Cr(VI)-induced carcinogenesis |
| title_sort | nrf2 cyclooxygenase 2 signaling in cr vi induced carcinogenesis |
| topic | Cr(VI) Carcinogenesis Nrf2 COX-2 miR-379 |
| url | http://www.sciencedirect.com/science/article/pii/S0147651325001368 |
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