Belharazem Djeda, Grass Albert, Paul Cornelia, Vitacolonna Mario, Schalke Berthold, Rieker Ralf J, Körner Daniel, Jungebluth Philipp, Simon-Keller Katja, Hohenberger Peter, Roessner Eric M, Wiebe Karsten, Gräter Thomas, Kyriss Thomas, Ott German, Geserick Peter, Leverkus Martin, Ströbel Philipp, Marx Alexander
Institute of Pathology and Medical Research Center (ZMF), University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
Department of Thoracic Surgery, University Medical Centre Mannheim, University of Heidelberg, Mannheim, Germany.
Oncotarget. 2017 Feb 6;8(52):89580-89594. doi: 10.18632/oncotarget.15929. eCollection 2017 Oct 27.
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-L1 thymomas and TCs.
抗凋亡细胞FLICE样抑制蛋白cFLIP在正常组织稳态及多种肿瘤的发生发展中起关键作用，但其在正常胸腺（NT）、胸腺瘤和胸腺癌（TC）中的作用尚不清楚。通过qRT-PCR、蛋白质印迹法、shRNA技术以及针对存活、衰老和自噬的功能分析，对NT、胸腺瘤、胸腺鳞状细胞癌（TSCC）、源自TSCC的胸腺上皮细胞（TEC）活检组织以及TC细胞系1889c中cFLIP的表达、调控和功能进行了分析。与NT相比，超过90%的胸腺瘤和TSCC显示cFLIP表达增加。NT中cFLIP表达随年龄下降，但胸腺瘤中并非如此。在短期培养过程中，肿瘤性原代TEC中cFLIP表达水平下降明显慢于非肿瘤性原代TEC。通过shRNA下调cFLIP或抑制NF-κB可加速肿瘤性TEC的衰老，并诱导自噬和细胞死亡。结果表明cFLIP在正常胸腺退化以及胸腺瘤和TSCC的发生发展中起作用。由于cFLIP表达增加是一种已知的肿瘤逃逸机制，它可能在未来的临床试验中作为基于组织的生物标志物，包括在常见的PD-L1阳性胸腺瘤和TC中的免疫检查点抑制剂试验。
