Gene expression profiling of idiopathic interstitial pneumonias (IIPs): identification of potential diagnostic markers and therapeutic targets

Abstract

BackgroundChronic fibrosing idiopathic interstitial pneumonia (IIP) is characterized by alveolar epithelial damage, activation of fibroblast proliferation, and loss of normal pulmonary architecture and function. This study aims to investigate the genetic backgrounds of IIP through gene expression profiling and pathway analysis, and to identify potential biomarkers that can aid in diagnosis and serve as novel therapeutic targets.MethodsRNA extracted from lung specimens of 12 patients with chronic fibrosing IIP was profiled using Illumina Human WG-6 v3 BeadChips, and Ingenuity Pathway Analysis was performed to identify altered functional and canonical signaling pathways. For validating the results from gene expression analysis, immunohistochemical staining of 10 patients with chronic fibrosing IIP was performed.ResultsNinety-eight genes were upregulated in IIP patients relative to control subjects. Some of the upregulated genes, namely desmoglein 3 (DSG3), protocadherin gamma-A9 (PCDHGA9) and discoidin domain-containing receptor 1 (DDR1) are implicated in cell-cell interaction and/or adhesion; some, namely collagen type VII, alpha 1 (COL7A1), contactin-associated protein-like 3B (CNTNAP3B) and mucin-1 (MUC1) are encoding the extracellular matrix molecule or the molecules involved in cell-matrix interactions; and the others, namely CDC25C and growth factor independent protein 1B (GFI1B) are known to affect cell proliferation by affecting the progression of cell cycle or regulating transcription. According to pathway analysis, alternated pathways in IIP were related to cell death and survival and cellular growth and proliferation, which are more similar to cancer than to inflammatory response and immunological diseases. Using immunohistochemistry, we further validate that DSG3, the most highly upregulated gene, shows higher expression in chronic fibrosing IIP lung as compared to control lung.ConclusionWe identified several genes upregulated in chronic fibrosing IIP patients as compared to control, and found genes and pathways implicated in cancer, rather than in inflammatory or immunological disease to play important roles in the pathogenesis of IIPs. Moreover, DSG3 is a novel potential biomarker for chronic fibrosing IIP with its significantly high expression in IIP lung.

MUC1 intracellular bioactivation mediates lung fibrosis

“…MUC1 mRNA expression and KL6/MUC1 protein expression were shown previously to be elevated in human lung tissue from patients with various interstitial lung diseases compared with healthy controls 7 24. The distribution of KL6/MUC1 was found to be restricted to the ATII cell surface in healthy patients and patients with IPF 7.…”

Coexisting TIF1γ-positive Primary Pulmonary Lymphoepithelioma-like Carcinoma and Anti-TIF1γ Antibody-positive Dermatomyositis

“…3G). Immunohistochemical staining of TIF1γ was positive based on anti-TIF1γ antibody (sc-101179, 1:500, Santa Cruz Biotechnology, Santa Cruz, USA) as previously described (21). Epidermal growth factor receptor (EGFR) mutations and echi- (Fig.…”

“…3G ). Immunohistochemical staining of TIF1γ was positive based on anti-TIF1γ antibody (sc-101179, 1:500, Santa Cruz Biotechnology, Santa Cruz, USA) as previously described ( 21 ). Epidermal growth factor receptor (EGFR) mutations and echinoderm microtubule associated protein-like 4-anaplastic lymphoma kinase (EML 4-ALK) fusion were negative, whereas anti-programmed death Ligand-1 (PD-L1) was detected in 70% of the cells.…”

The Role of Telomerase and Telomeres in Interstitial Lung Diseases: From Molecules to Clinical Implications

“…Various factors may be involved in the pathogenesis of ILD, such as chromosomal damage [7], DNA repair deficiencies [8] and epithelial-mesenchymal transition due to endoplasmic reticulum stress [9,10]. These factors may result in distinctive gene expression changes [11], which may serve as diagnostic markers [12], and in DNA damage under interstitial lung disease, specifically under pulmonary fibrosis. As telomeres form protective structures at the ends of chromosomes, it is imperative to understand their role in development of ILDs and to evaluate them as potential targets in antifibrotic therapy.…”