Critical Role of the Sulfiredoxin-Peroxiredoxin IV Axis in Urethane-Induced Non-Small Cell Lung Cancer

Yanning Hao, Hong Jiang, Pratik Thapa, Na Ding, Aziza Alshahrani, Junichi Fujii, Michel B. Toledano, Qiou Wei

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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−/− and Srx−/−/Prx4−/− 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.

Original languageEnglish
Article number367
Issue number2
StatePublished - Feb 2023

Bibliographical note

Funding Information:
This research was supported by the National Institutes of Health [NCI R01CA222596, NIEHS T32ES07266], NCI Cancer Center Grant [P30 CA1777558], the Department of Defense [W81XWH-16-1-0203], the American Cancer Society [RSG-16-213-01-TBE], and the Kentucky Lung Cancer Research Program [KLCRP2016]. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health or other funding agencies.

Publisher Copyright:
© 2023 by the authors.


  • lung cancer
  • peroxiredoxin
  • sulfiredoxin
  • tumorigenesis

ASJC Scopus subject areas

  • Food Science
  • Physiology
  • Biochemistry
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology


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