Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung Cancer
Non-small cell lung cancer (NSCLC), the most common type of lung cancer, etiologically associates with tobacco smoking which mechanistically contributes to oxidative stress to facilitate the occurrence of mutations, oncogenic transformation and aberrantly activated signaling pathways. Our previous r...
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MDPI AG
2023-02-01
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| Series: | Antioxidants |
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| author | Yanning Hao Hong Jiang Pratik Thapa Na Ding Aziza Alshahrani Junichi Fujii Michel B. Toledano Qiou Wei |
| author_facet | Yanning Hao Hong Jiang Pratik Thapa Na Ding Aziza Alshahrani Junichi Fujii Michel B. Toledano Qiou Wei |
| author_sort | Yanning Hao |
| collection | DOAJ |
| description | Non-small cell lung cancer (NSCLC), the most common type of lung cancer, etiologically associates with tobacco smoking which mechanistically contributes to oxidative stress to facilitate the occurrence of mutations, oncogenic transformation and aberrantly activated signaling pathways. Our previous reports suggested an essential role of Sulfiredoxin (Srx) in promoting the development of lung cancer in humans, and was causally related to Peroxiredoxin IV (Prx4), the major downstream substrate and mediator of Srx-enhanced signaling. To further explore the role of the Srx-Prx4 axis in de novo lung tumorigenesis, we established Prx4<sup>−/−</sup> and Srx<sup>−/−</sup>/Prx4<sup>−/−</sup> mice in pure FVB/N background. Together with wild-type litter mates, these mice were exposed to carcinogenic urethane and the development of lung tumorigenesis was evaluated. We found that disruption of the Srx-Prx4 axis, either through knockout of Srx/Prx4 alone or together, led to a reduced number and size of lung tumors in mice. Immunohistological studies found that loss of Srx/Prx4 led to reduced rate of cell proliferation and less intratumoral macrophage infiltration. Mechanistically, we found that exposure to urethane increased the levels of reactive oxygen species, activated the expression of and Prx4 in normal lung epithelial cells, while knockout of Prx4 inhibited urethane-induced cell transformation. Moreover, bioinformatics analysis found that the Srx-Prx4 axis is activated in many human cancers, and their increased expression is tightly correlated with poor prognosis in NSCLC patients. |
| first_indexed | 2024-03-11T09:13:47Z |
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| id | doaj.art-274442d49f9e4745984fc025b82906bc |
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| issn | 2076-3921 |
| language | English |
| last_indexed | 2024-03-11T09:13:47Z |
| publishDate | 2023-02-01 |
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| series | Antioxidants |
| spelling | doaj.art-274442d49f9e4745984fc025b82906bc2023-11-16T18:47:11ZengMDPI AGAntioxidants2076-39212023-02-0112236710.3390/antiox12020367Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung CancerYanning Hao0Hong Jiang1Pratik Thapa2Na Ding3Aziza Alshahrani4Junichi Fujii5Michel B. Toledano6Qiou Wei7Department of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USADepartment of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USADepartment of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USADepartment of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USADepartment of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USADepartment of Biochemistry and Molecular Biology, Graduate School of Medical Science, Yamagata University, Yamagata 990-8560, JapanInstitute for Integrative Biology of the Cell (I2BC), CEA, CNRS, Université Paris-Saclay, 91198 Gif-sur-Yvette, FranceDepartment of Toxicology and Cancer Biology, University of Kentucky, Lexington, KY 40506, USANon-small cell lung cancer (NSCLC), the most common type of lung cancer, etiologically associates with tobacco smoking which mechanistically contributes to oxidative stress to facilitate the occurrence of mutations, oncogenic transformation and aberrantly activated signaling pathways. Our previous reports suggested an essential role of Sulfiredoxin (Srx) in promoting the development of lung cancer in humans, and was causally related to Peroxiredoxin IV (Prx4), the major downstream substrate and mediator of Srx-enhanced signaling. To further explore the role of the Srx-Prx4 axis in de novo lung tumorigenesis, we established Prx4<sup>−/−</sup> and Srx<sup>−/−</sup>/Prx4<sup>−/−</sup> mice in pure FVB/N background. Together with wild-type litter mates, these mice were exposed to carcinogenic urethane and the development of lung tumorigenesis was evaluated. We found that disruption of the Srx-Prx4 axis, either through knockout of Srx/Prx4 alone or together, led to a reduced number and size of lung tumors in mice. Immunohistological studies found that loss of Srx/Prx4 led to reduced rate of cell proliferation and less intratumoral macrophage infiltration. Mechanistically, we found that exposure to urethane increased the levels of reactive oxygen species, activated the expression of and Prx4 in normal lung epithelial cells, while knockout of Prx4 inhibited urethane-induced cell transformation. Moreover, bioinformatics analysis found that the Srx-Prx4 axis is activated in many human cancers, and their increased expression is tightly correlated with poor prognosis in NSCLC patients.https://www.mdpi.com/2076-3921/12/2/367sulfiredoxinperoxiredoxinlung cancertumorigenesis |
| spellingShingle | Yanning Hao Hong Jiang Pratik Thapa Na Ding Aziza Alshahrani Junichi Fujii Michel B. Toledano Qiou Wei Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung Cancer Antioxidants sulfiredoxin peroxiredoxin lung cancer tumorigenesis |
| title | Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung Cancer |
| title_full | Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung Cancer |
| title_fullStr | Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung Cancer |
| title_full_unstemmed | Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung Cancer |
| title_short | Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung Cancer |
| title_sort | critical role of the sulfiredoxin peroxiredoxin iv axis in urethane induced non small cell lung cancer |
| topic | sulfiredoxin peroxiredoxin lung cancer tumorigenesis |
| url | https://www.mdpi.com/2076-3921/12/2/367 |
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