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

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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; Heinzelmann, Katharina; Günther, Andreas; Eickelberg, Oliver; Königshoff, Melanie.

I: American Journal of Respiratory Cell and Molecular Biology, Vol. 61, Nr. 6, 01.12.2019, s. 713-726.

Forskningsoutput: TidskriftsbidragArtikel i vetenskaplig tidskrift

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Ulke, Henrik M ; Mutze, Kathrin ; Lehmann, Mareike ; Wagner, Darcy E ; Heinzelmann, Katharina ; Günther, Andreas ; Eickelberg, Oliver ; Königshoff, Melanie. / The Oncogene ECT2 Contributes to a Hyperplastic, Proliferative Lung Epithelial Cell Phenotype in Idiopathic Pulmonary Fibrosis. I: American Journal of Respiratory Cell and Molecular Biology. 2019 ; Vol. 61, Nr. 6. s. 713-726.

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TY - JOUR

T1 - The Oncogene ECT2 Contributes to a Hyperplastic, Proliferative Lung Epithelial Cell Phenotype in Idiopathic Pulmonary Fibrosis

AU - Ulke, Henrik M

AU - Mutze, Kathrin

AU - Lehmann, Mareike

AU - Wagner, Darcy E

AU - Heinzelmann, Katharina

AU - Günther, Andreas

AU - Eickelberg, Oliver

AU - Königshoff, Melanie

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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.

KW - alveolar epithelial cells

KW - gene set enrichment analysis

KW - lung cancer

KW - lung fibrosis

KW - oncogenic pathways

U2 - 10.1165/rcmb.2019-0047OC

DO - 10.1165/rcmb.2019-0047OC

M3 - Article

VL - 61

SP - 713

EP - 726

JO - American Journal of Respiratory Cell and Molecular Biology

JF - American Journal of Respiratory Cell and Molecular Biology

SN - 1535-4989

IS - 6

ER -