The Sulfiredoxin‐Peroxiredoxin axis promotes urethane‐induced lung adenocarcinoma through the regulation of the tumor microenvironment

Abstract

Lung adenocarcinoma is the most common type of lung cancer and has a strong association with tobacco smoking. Smoking leads to the accumulation of reactive oxygen species (ROS) and oxidative stress damages to macromolecules, leading to abnormal cell growth & proliferation, transformation, changes in cell metabolism and a variety of other physiological functions. Accumulation of ROS only leads to increased expression of cellular antioxidants that contribute to tumorigenesis and cancer progression. Sulfiredoxin (Srx) is the only enzyme that reduces over‐oxidized forms of typical 2‐Cys Peroxiredoxins (Prxs). Compared to other Prx family members, Srx preferentially interacts with and has a higher binding affinity to Prx4. Our previously work demonstrated that the Srx‐Prx4 axis enhances the RAS/RAF‐MEK‐ERK signaling cascade to promote lung cancer cell proliferation and metastasis. However, the role of the Srx‐Prx axis in de novo lung tumorigenesis has not been explored.In this study, Prx4‐/‐ mice and Srx‐/‐Prx4‐/‐ mice were generated and mouse lung carcinogenesis was induced by a well‐established urethane protocol. Briefly, wildtype and knockout mice at 8‐week of age were injected intraperitoneally with 1g/kg of urethane once per week for three successive weeks. Ten weeks after the administration of urethane, all mice were euthanized and examined for tumors. Our results indicate that both knockout mice have significantly reduced rates on tumor incidence, multiplicity, and size. Compared with tumors from wildtype mice, the rate of cell proliferation in tumors from either knockout mice is significantly decreased.Macrophages are the most abundant immune cells identified in the tumor microenvironment of solid tumors and their presence correlates with reduced survival in most cancers. In addition to all other markers, we also compared the presence of two distinct states of polarized macrophages including the classically activated macrophage (M1) and the alternatively activated macrophage subsets (M2) in urethane‐induced tumors using specific surface marker staining. We found that there are significantly increased numbers of M1 cells in tumors of either Prx4‐/‐ or Srx‐/‐Prx4‐/‐ mice compared with those of wildtype mice. In contrast, there are significantly few numbers of M2 cells in tumors from either knockout mice.It has been shown that M1 macrophages have immune‐stimulatory properties through the expression of a series of pro‐inflammatory cytokines, chemokines, and effector molecules, whereas M2 cells express a wide array of anti‐inflammatory molecules. Therefore, the difference in tumor‐associated macrophages caused by the loss of Prx4 or Srx and Prx4 may contribute to the reduced lung tumorigenesis observed in the mouse model. In addition, bioinformatic analysis shows that Prx4 is overexpressed in the majority of cancers, and the increased expression of Srx and Prx4 both show a strong correlation with poor prognosis in lung adenocarcinoma patients.