p63 - Key molecule in the early phase of epithelial abnormality in idiopathic pulmonary fibrosis |
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Authors: | Murata Kengo Ota Satoshi Niki Toshiro Goto Akiteru Li Chih-Ping Ruriko Urbiztondo Maria Rhea Ishikawa Shumpei Aburatani Hiroyuki Kuriyama Takayuki Fukayama Masashi |
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Institution: | Department of Human Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1, Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan. |
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Abstract: | Idiopathic pulmonary fibrosis (IPF) is the most common lung disease predisposing lung cancer. To clarify the early phase of epithelial abnormalities in IPF, we used an in vitro squamous metaplasia model, transforming growth factor beta1 (TGF beta1)-treated airway epithelial cells (BEAS-2B). The model repeated the expression of squamous epithelial character, such as involucrin, and keratin 6 and 14. DNA microarray analysis disclosed a unique expression signature in TGF beta1-treated airway epithelial cells, 20 specifically up-regulated genes including p63, jagged 1 (jag1) and the genes of structure proteins. Western blotting and RT-PCR analysis revealed that DeltaNp63alpha was the dominant isoform of p63 in our experimental model. Immunohistochemical analysis demonstrated the expression of p63 and jag1 in lung tissues of IPF. Inhibition of p63 with siRNA caused the down-regulation of jag1 expression, but not of involucrin, or keratin 6 and 14. Interestingly, the up-regulation of p63 was totally suppressed by N-acetyl-l-cysteine (NAC), but not by dexamethasone or pirfenidone. Thus, the p63-jag1 pathway may be up-regulated at an early phase of epithelial abnormalities in IPF, which can be overcome by NAC even in the TGF beta1-rich milieu. |
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Keywords: | Dexamethasone Idiopathic pulmonary fibrosis jagged 1 Lung carcinoma l-cysteine" target="_blank">N-Acetyl-l-cysteine p63 Pirfenidone Squamous metaplasia Transforming growth factor β |
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