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The Oncogene ECT2 Contributes to a Hyperplastic, Proliferative Lung Epithelial Cell Phenotype in Idiopathic Pulmonary Fibrosis

Ulke, Henrik M ; Mutze, Kathrin ; Lehmann, Mareike ; Wagner, Darcy E LU orcid ; Heinzelmann, Katharina ; Günther, Andreas ; Eickelberg, Oliver and Königshoff, Melanie (2019) In American Journal of Respiratory Cell and Molecular Biology 61(6). p.713-726
Abstract

Idiopathic pulmonary fibrosis (IPF) and lung cancer represent progressive lung diseases with a poor prognosis. IPF represents a risk factor for the development of lung cancer, and the incidence of lung cancer is increased in patients with IPF. Disease pathogenesis of IPF and lung cancer involves common genetic alterations, dysregulated pathways, and the emergence of hyperplastic and metaplastic epithelial cells. Here, we aimed to identify novel, common mediators that might contribute to epithelial cell reprogramming in IPF. Gene set enrichment analysis (GSEA) of publicly available non-small cell lung cancer (NSCLC) and IPF datasets revealed a common pattern of misregulated genes, linked to cell proliferation and transformation. The... (More)

Idiopathic pulmonary fibrosis (IPF) and lung cancer represent progressive lung diseases with a poor prognosis. IPF represents a risk factor for the development of lung cancer, and the incidence of lung cancer is increased in patients with IPF. Disease pathogenesis of IPF and lung cancer involves common genetic alterations, dysregulated pathways, and the emergence of hyperplastic and metaplastic epithelial cells. Here, we aimed to identify novel, common mediators that might contribute to epithelial cell reprogramming in IPF. Gene set enrichment analysis (GSEA) of publicly available non-small cell lung cancer (NSCLC) and IPF datasets revealed a common pattern of misregulated genes, linked to cell proliferation and transformation. The oncogene epithelial cell transforming sequence 2 (ECT2), a guanine nucleotide exchange factor (GEF) for Rho GTPases, was highly enriched in both, IPF and NSCLC, compared to non-diseased controls. Increased expression of ECT2 was verified by qPCR and Western blotting in bleomycin-induced lung fibrosis and human IPF tissue. Immunohistochemistry demonstrated strong expression of ECT2 staining in hyperplastic type II alveolar epithelial (ATII) cells in IPF, as well as its colocalization with PCNA, a well-known proliferation marker. Increased ECT2 expression coincided with enhanced proliferation of primary mouse ATII cells as analyzed by flow cytometric analysis. ECT2 knockdown in ATII cells resulted in decreased proliferation and collagen I expression in vitro. These data suggest that the oncogene ECT2 contributes to epithelial cell reprogramming in IPF and further underline the hyperplastic, proliferative ATII cell as a potential target in patients with IPF and lung cancer.

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author
; ; ; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
alveolar epithelial cells, gene set enrichment analysis, lung cancer, lung fibrosis, oncogenic pathways
in
American Journal of Respiratory Cell and Molecular Biology
volume
61
issue
6
pages
14 pages
publisher
American Thoracic Society
external identifiers
  • pmid:31145635
  • scopus:85075524068
  • pmid:31145635
ISSN
1535-4989
DOI
10.1165/rcmb.2019-0047OC
language
English
LU publication?
yes
id
b8392796-0b61-4b6e-a654-059ba6d36de6
date added to LUP
2019-06-02 09:17:30
date last changed
2024-04-16 09:20:55
@article{b8392796-0b61-4b6e-a654-059ba6d36de6,
  abstract     = {{<p>Idiopathic pulmonary fibrosis (IPF) and lung cancer represent progressive lung diseases with a poor prognosis. IPF represents a risk factor for the development of lung cancer, and the incidence of lung cancer is increased in patients with IPF. Disease pathogenesis of IPF and lung cancer involves common genetic alterations, dysregulated pathways, and the emergence of hyperplastic and metaplastic epithelial cells. Here, we aimed to identify novel, common mediators that might contribute to epithelial cell reprogramming in IPF. Gene set enrichment analysis (GSEA) of publicly available non-small cell lung cancer (NSCLC) and IPF datasets revealed a common pattern of misregulated genes, linked to cell proliferation and transformation. The oncogene epithelial cell transforming sequence 2 (ECT2), a guanine nucleotide exchange factor (GEF) for Rho GTPases, was highly enriched in both, IPF and NSCLC, compared to non-diseased controls. Increased expression of ECT2 was verified by qPCR and Western blotting in bleomycin-induced lung fibrosis and human IPF tissue. Immunohistochemistry demonstrated strong expression of ECT2 staining in hyperplastic type II alveolar epithelial (ATII) cells in IPF, as well as its colocalization with PCNA, a well-known proliferation marker. Increased ECT2 expression coincided with enhanced proliferation of primary mouse ATII cells as analyzed by flow cytometric analysis. ECT2 knockdown in ATII cells resulted in decreased proliferation and collagen I expression in vitro. These data suggest that the oncogene ECT2 contributes to epithelial cell reprogramming in IPF and further underline the hyperplastic, proliferative ATII cell as a potential target in patients with IPF and lung cancer.</p>}},
  author       = {{Ulke, Henrik M and Mutze, Kathrin and Lehmann, Mareike and Wagner, Darcy E and Heinzelmann, Katharina and Günther, Andreas and Eickelberg, Oliver and Königshoff, Melanie}},
  issn         = {{1535-4989}},
  keywords     = {{alveolar epithelial cells; gene set enrichment analysis; lung cancer; lung fibrosis; oncogenic pathways}},
  language     = {{eng}},
  month        = {{12}},
  number       = {{6}},
  pages        = {{713--726}},
  publisher    = {{American Thoracic Society}},
  series       = {{American Journal of Respiratory Cell and Molecular Biology}},
  title        = {{The Oncogene ECT2 Contributes to a Hyperplastic, Proliferative Lung Epithelial Cell Phenotype in Idiopathic Pulmonary Fibrosis}},
  url          = {{http://dx.doi.org/10.1165/rcmb.2019-0047OC}},
  doi          = {{10.1165/rcmb.2019-0047OC}},
  volume       = {{61}},
  year         = {{2019}},
}