Increased cFLIP expression in thymic epithelial tumors blocks autophagy via NF-κB signalling
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Djeda Belharazem1, Albert Grass1, Cornelia Paul1, Mario Vitacolonna2, Berthold Schalke3, Ralf J. Rieker4,5, Daniel Körner6, Philipp Jungebluth6, Katja Simon-Keller1, Peter Hohenberger2, Eric M. Roessner2, Karsten Wiebe7, Thomas Gräter8, Thomas Kyriss9, German Ott10,11, Peter Geserick12, Martin Leverkus12,13,*, Philipp Ströbel14 and Alexander Marx1
1Institute of Pathology and Medical Research Center (ZMF), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
2Department of Thoracic Surgery, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany
3Department of Neurology, University of Regensburg, Regensburg, Germany
4Institute of Pathology, University Hospital Heidelberg, University of Heidelberg, Heidelberg, Germany
5Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
6Department of Thoracic Surgery, Thorax Clinic, University of Heidelberg, Heidelberg, Germany
7Department of Thoracic Surgery, University of Münster, Münster, Germany
8Department of Thoracic Surgery, Clinic Löwenstein, Löwenstein, Germany
9Department of Thoracic Surgery, Clinic Schillerhöhe, Robert-Bosch-Hospital, Gerlingen, Germany
10Department of Clinical Pathology, Robert-Bosch-Hospital, Stuttgart, Germany
11Dr. Margarete Fischer-Bosch Institute for Clinical Pharmacology, Stuttgart, Germany
12Department of Dermatology, Venereology, and Allergology, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany
13Department for Dermatology and Allergology, University Hospital Aachen, RWTH Aachen, Aachen, Germany
14Institute of Pathology, University Medical Center Göttingen, University of Göttingen, Göttingen, Germany
Djeda Belharazem, email: [email protected]
Keywords: thymic tumors, cFLIP, NF-κB, senescence, autophagy
Received: September 01, 2016 Accepted: December 26, 2016 Published: February 06, 2017
The anti-apoptotic cellular FLICE-like inhibitory protein cFLIP plays a pivotal role in normal tissues homoeostasis and the development of many tumors, but its role in normal thymus (NT), thymomas and thymic carcinomas (TC) is largely unknown.
Expression, regulation and function of cFLIP were analyzed in biopsies of NT, thymomas, thymic squamous cell carcinomas (TSCC), thymic epithelial cells (TECs) derived thereof and in the TC line 1889c by qRT-PCR, western blot, shRNA techniques, and functional assays addressing survival, senescence and autophagy. More than 90% of thymomas and TSCCs showed increased cFLIP expression compared to NT. cFLIP expression declined with age in NTs but not in thymomas. During short term culture cFLIP expression levels declined significantly slower in neoplastic than non-neoplastic primary TECs. Down-regulation of cFLIP by shRNA or NF-κB inhibition accelerated senescence and induced autophagy and cell death in neoplastic TECs.
The results suggest a role of cFLIP in the involution of normal thymus and the development of thymomas and TSCC. Since increased expression of cFLIP is a known tumor escape mechanism, it may serve as tissue-based biomarker in future clinical trials, including immune checkpoint inhibitor trials in the commonly PD-L1high thymomas and TCs.
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