The oncogene ECT2 contributes to a hyperplastic, proliferative lung epithelial cell phenotype in IPF

Research output: Contribution to journalArticle

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 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.

Details

Authors
  • Henrik M Ulke
  • Kathrin Mutze
  • Mareike Lehmann
  • Darcy E Wagner
  • Katharina Heinzelmann
  • Andreas Günther
  • Oliver Eickelberg
  • Melanie Königshoff
Organisations
External organisations
  • Comprehensive Pneumology Center
  • University of Colorado
  • Justus Liebig University Giessen
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Medical Genetics
  • Cardiac and Cardiovascular Systems
Original languageEnglish
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Publication statusE-pub ahead of print - 2019 May 30
Publication categoryResearch
Peer-reviewedYes