Hartl Leonie, Duitman JanWillem, Aberson Hella L, Chen Kan, Dijk Frederike, Roelofs Joris J T H, Dings Mark P G, Hooijer Gerrit K J, Hernanda Pratika Y, Pan Qiunwei, Busch Olivier R, Besselink Marc G H, Boerman Ton, Peppelenbosch Maikel P, Bijlsma Maarten F, Spek C Arnold
Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, 1182 DB Amsterdam, The Netherlands.
Cancers (Basel). 2020 Sep 7;12(9):2546. doi: 10.3390/cancers12092546.
CCAAT/enhancer-binding protein δ (C/EBPδ) is a transcription factor involved in growth arrest and differentiation, which has consequently been suggested to harbor tumor suppressive activities. However, C/EBPδ over-expression correlates with poor prognosis in glioblastoma and promotes genomic instability in cervical cancer, hinting at an oncogenic role of C/EBPδ in these contexts. Here, we explore the role of C/EBPδ in pancreatic cancer. We determined C/EBPδ expression in biopsies from pancreatic cancer patients using public gene-expression datasets and in-house tissue microarrays. We found that C/EBPδ is highly expressed in healthy pancreatic ductal cells but lost in pancreatic ductal adenocarcinoma. Furthermore, loss of C/EBPδ correlated with increased lymph node involvement and shorter overall survival in pancreatic ductal adenocarcinoma patients. In accordance with this, in vitro experiments showed reduced clonogenic capacity and proliferation of pancreatic ductal adenocarcinoma cells following C/EBPδ re-expression, concurrent with decreased sphere formation capacity in soft agar assays. We thus report a previously unrecognized but important tumor suppressor role of C/EBPδ in pancreatic ductal adenocarcinoma. This is of particular interest since only few tumor suppressors have been identified in the context of pancreatic cancer. Moreover, our findings suggest that restoration of C/EBPδ activity could hold therapeutic value in pancreatic ductal adenocarcinoma, although the latter claim needs to be substantiated in future studies.
CCAAT/增强子结合蛋白δ（C/EBPδ）是一种参与生长停滞和分化的转录因子，因此有人认为它具有肿瘤抑制活性。然而，C/EBPδ的过表达与胶质母细胞瘤的不良预后相关，并促进宫颈癌的基因组不稳定，这表明在这些情况下C/EBPδ具有致癌作用。在这里，我们探讨C/EBPδ在胰腺癌中的作用。我们使用公共基因表达数据集和内部组织微阵列确定了胰腺癌患者活检组织中C/EBPδ的表达。我们发现C/EBPδ在健康的胰腺导管细胞中高表达，但在胰腺导管腺癌中缺失。此外，C/EBPδ的缺失与胰腺导管腺癌患者淋巴结受累增加和总生存期缩短相关。与此一致的是，体外实验表明，C/EBPδ重新表达后，胰腺导管腺癌细胞的克隆形成能力和增殖能力降低，同时软琼脂试验中的球体形成能力也降低。因此，我们报告了C/EBPδ在胰腺导管腺癌中一个以前未被认识但重要的肿瘤抑制作用。这一点特别有趣，因为在胰腺癌背景下仅发现了少数肿瘤抑制因子。此外，我们的研究结果表明，恢复C/EBPδ的活性可能对胰腺导管腺癌具有治疗价值，尽管这一说法需要在未来的研究中得到证实。
