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Brunn, D.* ; Turkowski, K.* ; Günther, S.* ; Weigert, A.* ; Muley, T.* ; Kriegsmann, M.* ; Winter, H.* ; Dammann, R.H.* ; Stathopoulos, G.T. ; Thomas, M.* ; Guenther, A.* ; Grimminger, F.* ; Pullamsetti, S.S.* ; Seeger, W.* ; Savai, R.*

Interferon regulatory factor 9 promotes lung cancer progression via regulation of versican.

Cancers 13:208 (2021)
Publ. Version/Full Text Research data DOI PMC
Open Access Gold
Creative Commons Lizenzvertrag
Transcription factors can serve as links between tumor microenvironment signaling and oncogenesis. Interferon regulatory factor 9 (IRF9) is recruited and expressed upon interferon stimulation and is dependent on cofactors that exert in tumor-suppressing or oncogenic functions via the JAK-STAT pathway. IRF9 is frequently overexpressed in human lung cancer and is associated with decreased patient survival; however, the underlying mechanisms remain to be elucidated. Here, we used stably transduced lung adenocarcinoma cell lines (A549 and A427) to overexpress or knockdown IRF9. Overexpression led to increased oncogenic behavior in vitro, including enhanced proliferation and migration, whereas knockdown reduced these effects. These findings were confirmed in vivo using lung tumor xenografts in nude mice, and effects on both tumor growth and tumor mass were observed. Using RNA sequencing, we identified versican (VCAN) as a novel downstream target of IRF9. Indeed, IRF9 and VCAN expression levels were found to be correlated. We showed for the first time that IRF9 binds at a newly identified response element in the promoter region of VCAN to regulate its transcription. Using an siRNA approach, VCAN was found to enable the oncogenic properties (proliferation and migration) of IRF9 transduced cells, perhaps with CDKN1A involvement. The targeted inhibition of IRF9 in lung cancer could therefore be used as a new treatment option without multimodal interference in microenvironment JAK-STAT signaling.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Adenocarcinoma ; Interferon Regulatory Factor 9 (irf9) ; Lung Cancer ; Tumor Microenvironment (tme) ; Type I Interferons (ifns) ; Versican (vcan)
Language english
Publication Year 2021
HGF-reported in Year 2021
ISSN (print) / ISBN 2072-6694
Journal Cancers
Quellenangaben Volume: 13, Issue: 2, Pages: , Article Number: 208 Supplement: ,
Publisher MDPI
Publishing Place St Alban-anlage 66, Ch-4052 Basel, Switzerland
Reviewing status Peer reviewed
Institute(s) Institute of Lung Health and Immunity (LHI)
POF-Topic(s) 30202 - Environmental Health
Research field(s) Lung Research
PSP Element(s) G-501600-003
Grants European Research Council (ERC) Consolidator Grant
DFG, SFB CRC 1213
German Center for Lung Research (DZL)
Cardio-Pulmonary Institute (CPI)
Institute for Lung Health (ILH)
Rhön Klinikum AG grant
Von-Behring-Röntgen-Stiftung
Verein zur Förderung der Krebsforschung in Gieβen e.V
Max Planck Society
DOI 10.3390/cancers13020208
WOS ID WOS:000611109700001
Scopus ID 85099392841
PubMed ID 33430083
Erfassungsdatum 2021-03-26
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