TY - JOUR
T1 - Ablation of Liver X receptors α and β leads to spontaneous peripheral squamous cell lung cancer in mice
AU - Dai, Yu Bing
AU - Miao, Yi Fei
AU - Wu, Wan Fu
AU - Li, Yu
AU - D'Errico, Francesca
AU - Su, Wen
AU - Burns, Alan R.
AU - Huang, Bo
AU - Maneix, Laure
AU - Warner, Margaret
AU - Gustafsson, Jan Åke
N1 - Funding Information:
We thank our colleagues Dr. Kaberi Das and Christopher A. Brooks for assistance with mice handling, Dr. Bilqees Bhatti for Masson's Trichrome staining, and Margaret Gondo (College of Optometry, University of Houston) for processing samples of TEM. This study was supported by Emerging Technology Fund of Texas grants under Agreement 18 No. 300-9-1958, Cancer Prevention and Research Institute of Texas Grant RP110444-P1, the Robert A. Welch Fund Grant E-0044, the Swedish Science Council, the Center for Innovative Medicine, and National Eye Institute Grants P30EY007551-29 and EY018239 (to A.R.B.).
PY - 2016/7/5
Y1 - 2016/7/5
N2 - The etiology of peripheral squamous cell lung cancer (PSCCa) remains unknown. Here, we show that this condition spontaneously develops in mice in which the genes for two oxysterol receptors, Liver X Receptor (LXR) α (Nr1h3) and β (Nr1h2), are inactivated. By 1 y of age, most of these mice have to be euthanized because of severe dyspnea. Starting at 3 mo, the lungs of LXRα,βDko mice, but not of LXRα or LXRβ single knockout mice, progressively accumulate foam cells, so that by 1 y, the lungs are covered by a "golden coat." There is infiltration of inflammatory cells and progressive accumulation of lipid in the alveolar wall, type 2 pneumocytes, and macrophages. By 14 mo, there are three histological lesions: one resembling adenomatous hyperplasia, one squamous metaplasia, and one squamous cell carcinoma characterized by expression of transformation-related protein (p63), sex determining region Y-box 2 (Sox2), cytokeratin 14 (CK14), and cytokeratin 13 (CK13) and absence of thyroid transcription factor 1 (TTF1), and prosurfactant protein C (pro-SPC). RNA sequencing analysis at 12 mo confirmed a massive increase in markers of M1 macrophages and lymphocytes. The data suggest a previously unidentified etiology of PSCCa: cholesterol dysregulation and M1 macrophage-predominant lung inflammation combined with damage to, and aberrant repair of, lung tissue, particularly the peripheral parenchyma. The results raise the possibility that components of the LXR signaling may be useful targets in the treatment of PSCCa.
AB - The etiology of peripheral squamous cell lung cancer (PSCCa) remains unknown. Here, we show that this condition spontaneously develops in mice in which the genes for two oxysterol receptors, Liver X Receptor (LXR) α (Nr1h3) and β (Nr1h2), are inactivated. By 1 y of age, most of these mice have to be euthanized because of severe dyspnea. Starting at 3 mo, the lungs of LXRα,βDko mice, but not of LXRα or LXRβ single knockout mice, progressively accumulate foam cells, so that by 1 y, the lungs are covered by a "golden coat." There is infiltration of inflammatory cells and progressive accumulation of lipid in the alveolar wall, type 2 pneumocytes, and macrophages. By 14 mo, there are three histological lesions: one resembling adenomatous hyperplasia, one squamous metaplasia, and one squamous cell carcinoma characterized by expression of transformation-related protein (p63), sex determining region Y-box 2 (Sox2), cytokeratin 14 (CK14), and cytokeratin 13 (CK13) and absence of thyroid transcription factor 1 (TTF1), and prosurfactant protein C (pro-SPC). RNA sequencing analysis at 12 mo confirmed a massive increase in markers of M1 macrophages and lymphocytes. The data suggest a previously unidentified etiology of PSCCa: cholesterol dysregulation and M1 macrophage-predominant lung inflammation combined with damage to, and aberrant repair of, lung tissue, particularly the peripheral parenchyma. The results raise the possibility that components of the LXR signaling may be useful targets in the treatment of PSCCa.
KW - Inflammation
KW - Lipid metabolism
KW - Liver X receptor
KW - Macrophage
KW - Peripheral squamous cell lung carcinoma
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U2 - 10.1073/pnas.1607590113
DO - 10.1073/pnas.1607590113
M3 - Article
C2 - 27335465
AN - SCOPUS:84977279530
SN - 0027-8424
VL - 113
SP - 7614
EP - 7619
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 27
ER -