title: Ablation of Liver X receptors α and β leads to spontaneous peripheral squamous cell lung cancer in mice.
abstract: 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,β(Dko) 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.
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204;
authors.forename: Yu-Bing
authors.initials: YB
authors.lastname: Dai
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204;
authors.forename: Yi-Fei
authors.initials: YF
authors.lastname: Miao
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204;
authors.forename: Wan-Fu
authors.initials: WF
authors.lastname: Wu
authors.affiliation: Department of Pathology, Chongqing Medical University, Chongqing, China;
authors.forename: Yu
authors.initials: Y
authors.lastname: Li
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204;
authors.forename: Francesca
authors.initials: F
authors.lastname: D'Errico
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204;
authors.forename: Wen
authors.initials: W
authors.lastname: Su
authors.affiliation: College of Optometry, University of Houston, Houston, TX 77204;
authors.forename: Alan R
authors.initials: AR
authors.lastname: Burns
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204;
authors.forename: Bo
authors.initials: B
authors.lastname: Huang
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204;
authors.forename: Laure
authors.initials: L
authors.lastname: Maneix
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204;
authors.forename: Margaret
authors.initials: M
authors.lastname: Warner
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204; Center for Innovative Medicine, Department of Biosciences and Nutrition, Novum, 14186 Stockholm, Sweden jgustafsson@uh.edu.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
mesh_terms: D056809:Alveolar Epithelial Cells / Q000378:metabolism; D000818:Animals; D005347:Fibroblasts / Q000378:metabolism; D006706:Homeostasis; D050356:Lipid Metabolism; D000071518:Liver X Receptors / Q000502:physiology*; D008168:Lung / Q000378:metabolism* / Q000473:pathology; D008175:Lung Neoplasms / Q000209:etiology*; D008264:Macrophages / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018307:Neoplasms, Squamous Cell / Q000209:etiology*; D011014:Pneumonia / Q000209:etiology; D017423:Sequence Analysis, RNA
chemical_list: D000071518:Liver X Receptors
keywords: Liver X receptor; inflammation; lipid metabolism; macrophage; peripheral squamous cell lung carcinoma