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Article

Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican

1
Max Planck Institute for Heart and Lung Research, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), 61231 Bad Nauheim, Germany
2
Institute of Biochemistry I, Faculty of Medicine, Goethe University Frankfurt, 60590 Frankfurt, Germany
3
Frankfurt Cancer Institute (FCI), Goethe University, 60596 Frankfurt am Main, Germany
4
Translational Research Unit, Member of the German Center for Lung Research (DZL), Thoraxklinik at Heidelberg University, 69126 Heidelberg, Germany
5
Translational Lung Research Center (TLRC) Heidelberg, Member of the German Center for Lung Research (DZL), 69126 Heidelberg, Germany
6
Institute of Pathology, University Hospital of Heidelberg, 69126 Heidelberg, Germany
7
Department of Surgery, Thoraxklinik, University Hospital Heidelberg, 69126 Heidelberg, Germany
8
Institute for Genetics, Member of the German Center for Lung Research (DZL), Justus Liebig University, 35392 Giessen, Germany
9
Comprehensive Pneumology Center (CPC) and Institute for Lung Biology and Disease (iLBD), Helmholtz Center Munich-German Research Center for Environmental Health (HMGU), Member of the German Center for Lung Research (DZL), 81377 Munich, Germany
10
Department of Oncology, Thoraxklinik, University Hospital Heidelberg, 69126 Heidelberg, Germany
11
Department of Internal Medicine, Member of the German Center for Lung Research (DZL), Member of the Cardio-Pulmonary Institute (CPI), Justus Liebig University, 35392 Giessen, Germany
12
Institute for Lung Health (ILH), Justus Liebig University, 35392 Giessen, Germany
*
Author to whom correspondence should be addressed.
Cancers 2021, 13(2), 208; https://doi.org/10.3390/cancers13020208
Received: 13 November 2020 / Revised: 30 December 2020 / Accepted: 2 January 2021 / Published: 8 January 2021
(This article belongs to the Special Issue Tumor Evolution: Progression, Metastasis and Therapeutic Response)
Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for more than 1.6 million deaths per year. The tumor microenvironment (TME) has been shown to play a crucial role in tumor progression and metastasis, and transcription factors link TME signaling to oncogenesis. Type I interferons (IFNs) are strong immune modulators that possess antiproliferative and proapoptotic properties. In this study, we investigated the role of the transcription factor interferon regulatory factor 9 (IRF9) in the IFN pathway in lung cancer. We performed in vitro and in vivo experiments to reveal the oncogenic properties of IRF9, which was highly upregulated in lung adenocarcinoma. For the first time, we showed that IRF9 binds to the promoter of the known oncogene versican, regulates its expression, and thereby promotes oncogenic activity.
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. View Full-Text
Keywords: lung cancer; adenocarcinoma; tumor microenvironment (TME); type I interferons (IFNs); interferon regulatory factor 9 (IRF9); versican (VCAN) lung cancer; adenocarcinoma; tumor microenvironment (TME); type I interferons (IFNs); interferon regulatory factor 9 (IRF9); versican (VCAN)
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MDPI and ACS Style

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 2021, 13, 208. https://doi.org/10.3390/cancers13020208

AMA Style

Brunn D, Turkowski K, Günther S, Weigert A, Muley T, Kriegsmann M, Winter H, Dammann RH, Stathopoulos GT, Thomas M, Guenther A, Grimminger F, Pullamsetti SS, Seeger W, Savai R. Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican. Cancers. 2021; 13(2):208. https://doi.org/10.3390/cancers13020208

Chicago/Turabian Style

Brunn, David, Kati Turkowski, Stefan Günther, Andreas Weigert, Thomas Muley, Mark Kriegsmann, Hauke Winter, Reinhard H. Dammann, Georgios T. Stathopoulos, Michael Thomas, Andreas Guenther, Friedrich Grimminger, Soni S. Pullamsetti, Werner Seeger, and Rajkumar Savai. 2021. "Interferon Regulatory Factor 9 Promotes Lung Cancer Progression via Regulation of Versican" Cancers 13, no. 2: 208. https://doi.org/10.3390/cancers13020208

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