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.
Highlights
Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon that is known to be carcinogenic
The heterozygous poly (ADP-ribose) glycohydrolase (PARG) knockout mice were used to characterize the role of PARG in protecting mice from BaP-induced lung cancer
Based on genomic DNA purified from mouse tails, PARG+/− mice were screened for our study as PARG−/− mice cannot survive to maturity
Summary
Benzo(a)pyrene (BaP) is a polycyclic aromatic hydrocarbon that is known to be carcinogenic. It is mainly produced by pyrolysis and incomplete combustion of carbonaceous materials and is widely distributed in both the working and living environment (Liu et al, 2008). A large number of experiments have shown that BaP can induce cancer in various animals (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2010; Kasala et al, 2016). On the basis of these studies, BaP was classified as a human class I carcinogen by the International Agency for Research on Cancer in 2006 (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2012). Recent evidence suggests that the incidence of lung cancer in China is the highest and the mortality is increasing at a rate of 4.5% per year (Chen et al, 2016)
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