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Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis.

ABSTRACT: Extracellular matrix (ECM) composition and stiffness are major driving forces for the development and persistence of fibrotic diseases. Lysyl oxidase (LOX) and LOX-like (LOXL) proteins play crucial roles in ECM remodeling due to their collagen crosslinking and intracellular functions. Here, we systematically investigated LOX/L expression in primary fibroblasts and epithelial cells under fibrotic conditions, Bleomycin (BLM) induced lung fibrosis and in human IPF tissue. Basal expression of all LOX/L family members was detected in epithelial cells and at higher levels in fibroblasts. Various pro-fibrotic stimuli broadly induced LOX/L expression in fibroblasts, whereas specific induction of LOXL2 and partially LOX was observed in epithelial cells. Immunohistochemical analysis of lung tissue from 14 IPF patients and healthy donors revealed strong induction of LOX and LOXL2 in bronchial and alveolar epithelium as well as fibroblastic foci. Using siRNA experiments we observed that LOXL2 and LOXL3 were crucial for fibroblast-to-myofibroblast transition (FMT). As FMT could only be reconstituted with an enzymatically active LOXL2 variant, we conclude that LOXL2 enzymatic function is crucial for fibroblast transdifferentiation. In summary, our study provides a comprehensive analysis of the LOX/L family in fibrotic lung disease and indicates prominent roles for LOXL2/3 in fibroblast activation and LOX/LOXL2 in IPF.

SUBMITTER: Aumiller V

PROVIDER: S-EPMC5428068 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis.

Aumiller Verena V Strobel Benjamin B Romeike Merrit M Schuler Michael M Stierstorfer Birgit E BE Kreuz Sebastian S

Scientific reports 20170310 1

Extracellular matrix (ECM) composition and stiffness are major driving forces for the development and persistence of fibrotic diseases. Lysyl oxidase (LOX) and LOX-like (LOXL) proteins play crucial roles in ECM remodeling due to their collagen crosslinking and intracellular functions. Here, we systematically investigated LOX/L expression in primary fibroblasts and epithelial cells under fibrotic conditions, Bleomycin (BLM) induced lung fibrosis and in human IPF tissue. Basal expression of all LO ...[more]

PMID: 28273952

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Project description:Background: Pancreatic adenocarcinoma (PDAC) is the most aggressive among all solid malignancies with delayed disease detection and limited effective treatment. However, due to the intricate heterogeneity and exclusive tumor microenvironment (TME), the development of effective therapy has been facing enormous challenges. The lysyl oxidases (LOXs) underpin the shaping of the TME to promote cancer growth, metastasis and modulate response to treatment. Materials and Methods: The mRNA expression, prognostic, and clinicopathological data for LOXs in PDAC from multiple open-access databases were summarized and analyzed. The protein expression was verified by immunohistochemistry (IHC). Co-expressed genes of LOXs were predicted and elaborated by LinkedOmics. Functional enrichment analysis of LOXs co-expressed genes was performed using Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). TIMER and TISIDB were applied to analyze the relationship between LOXs expression and immune infiltration. Results: The mRNA expression levels of LOX, LOXL1 and LOXL2 were significantly higher in PDAC, the expression levels of LOXL3 and LOXL4 were contrary in different databases. High mRNA levels of LOX and LOXL2 were associated with advanced PDAC stage, while elevated LOX and LOXL3 expression correlated with high tumor grade. The IHC staining showed higher expression levels of LOX, LOXL1 and LOXL2, lower expression level of LOXL3 in PDAC tissues, while the protein expression of LOXL4 made no difference. Functional enrichment analysis showed a close relationship with extracellular matrix (ECM) regulation, except that LOXL3 and its ligands were highly associated with immune-related functions. Further analysis suggested that LOX and LOXL3 strongly correlated with tumor-infiltrating lymphocytes (TILs), various immune signatures, and immune checkpoints. Finally, survival analysis revealed high LOX and LOXL2 expression predicted worse overall survival (OS), progression-free interval (PFI), and disease-specific survival (DSS). Conclusion: These findings indicated that the LOX family, especially LOX and LOXL2, might have a prospective value in PDAC oncogenesis, and they may become prognostic biomarkers, revealing a promising field in targeted therapy.

Dataset Information

Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis.

Publications

Comparative analysis of lysyl oxidase (like) family members in pulmonary fibrosis.

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