Activation of liver X receptor inhibits the development of pulmonary carcinomas induced by 3-methylcholanthrene and butylated hydroxytoluene in BALB/c mice.

Qixue Wang,Ying Liu,Qi Li,Yajun Duan,Xiaoxiao Yang,Lei Sun,Xingzhe Ma,Yuanli Chen,Di Zhang,Xiaoju Li,Yuquan Wei,Jihong Han,Rong Xiang

doi:10.1038/srep27295

Abstract

We previously reported that LXR ligand, T0901317, inhibited the growth of inoculated Lewis lung carcinoma in C57BL/6 mice by activating IFN-γ production. However, the effects of T0901317 on carcinogen-induced pulmonary carcinomas remain unknown. In this study, we initially conducted a statistical analysis on the data of human lung cancer samples extracted from the TCGA database, and determined that survival rate/time of lung cancer patients and grade of lung adenocarcinoma were positively and negatively related to lung IFN-γ levels, respectively. We then determined the inhibitory effects of T0901317 on mouse pulmonary carcinomas induced by 3-methylcholanthrene (MCA) and butylated hydroxytoluene (BHT) or urethane. We found that T0901317 reduced morbidity and mortality in MCA/BHT-injected BALB/c mice by inhibiting lung adenocarcinoma. T0901317 also protected C57BL/6 mice, but not IFN-γ deficient (IFN-γ−/−, C57BL/6 background) mice, against MCA/BHT-induced lung hyperplasia/inflammation. In addition, we determined that T0901317 inhibited urethane-induced lung tumors in BABL/c mice. Furthermore, we determined that T0901317 prevented metastasis of 4T1 breast cancer cells in BALB/c mice. Administration of T0901317 substantially increased serum IFN-γ levels and lung IFN-γ expression in BABL/c and C57BL/6 mice. Taken together, our study demonstrates that LXR inhibits MCA/BHT-induced pulmonary carcinomas in BABL/c mice and the inhibition is associated with induction of IFN-γ production.

Highlights

Liver X receptor (LXR), a ligand-activated transcription factor, plays an important role in cholesterol and lipid biosynthesis and metabolism
We determined that T0901317 administration inhibited growth of inoculated LLC1 tumors in C57BL/6 wild type mice but not mice lacking IFN-γexpression (IFN-γ−/−, C57BL/6 background) which indicates that the inhibition of tumor growth by T0901317 is dependent, at least in part, on the activation of IFN-γproduction
The results of histological evaluation on lung sections demonstrate that MCA/butylated hydroxytoluene (BHT) treatment resulted in crowded alveolar epithelial cells and alveolar septa surrounded by anisokaryosis and karyomegaly cells in Group 1 C57BL/6 wild type mice, which indicates the formation of atypical hyperplasia

Summary

Introduction

Liver X receptor (LXR), a ligand-activated transcription factor, plays an important role in cholesterol and lipid biosynthesis and metabolism. We used MCA/BHT-induced pulmonary tumors as a model to determine if LXR ligand can inhibit tumorigenesis, and the inhibition is related to activation of IFN-γproduction.

Results

Conclusion