Regulation of Wnt Singaling Pathway by Poly (ADP-Ribose) Glycohydrolase (PARG) Silencing Suppresses Lung Cancer in Mice Induced by Benzo(a)pyrene Inhalation Exposure

Abstract

Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon that specifically causes cancer and is widely distributed in the environment. Poly(ADP-ribosylation), as a key post-translational modification in BaP-induced carcinogenesis, is mainly catalyzed by poly (ADP-ribose) glycohydrolase (PARG) in eukaryotic organisms. Previously, it is found that PARG silencing can counteract BaP-induced carcinogenesis in vitro, but the mechanism remained unclear. In this study, we further examined this process in vivo by using heterozygous PARG knockout mice(PARG+/−). Wild-type and PARG+/− mice were individually treated with 0 or 10 μg/m3 BaP for 90 or 180 days by dynamic inhalation exposure. Pathological analysis of lung tissues showed that, with extended exposure time, carcinogenesis and injury in the lungs of WT mice was progressively worse; however, the injury was minimal and carcinogenesis was not detected in the lungs of PARG+/− mice. These results indicate that PARG gene silencing protects mice against lung cancer induced by BaP inhalation exposure. Furthermore, as the exposure time was extended, the protein phosphorylation level was down-regulated in WT mice, but up-regulated in PARG+/− mice. The relative expression of Wnt2b and Wnt5b mRNA in WT mice were significantly higher than those in the control group, but there was no significant difference in PARG+/− mice. Meanwhile, the relative expression of Wnt2b and Wnt5b proteins, as assessed by immunohistochemistry and Western blot analysis, was significantly up-regulated by BaP in WT mice; while in PARG+/− mice it was not statistically affected. Our work provides initial evidence that PARG silencing suppresses BaP induced lung cancer and stabilizes the expression of Wnt ligands, PARG gene and Wnt ligands may provide new options for the diagnosis and treatment of lung cancer.