CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells

Leonie Hartl; JanWillem Duitman; Hella L Aberson; Kan Chen; Frederike Dijk; Joris J T H Roelofs; Mark P G Dings; Gerrit K J Hooijer; Pratika Y Hernanda; Qiunwei Pan; Olivier R Busch; Marc G H Besselink; Ton Boerman; Maikel P Peppelenbosch; Maarten F Bijlsma; C Arnold Spek

doi:10.3390/cancers12092546

CCAAT/Enhancer-Binding Protein Delta (C/EBPδ): A Previously Unrecognized Tumor Suppressor that Limits the Oncogenic Potential of Pancreatic Ductal Adenocarcinoma Cells

Cancers (Basel). 2020 Sep 7;12(9):2546. doi: 10.3390/cancers12092546.

Authors

Leonie Hartl^{1

2}, JanWillem Duitman^{1

2}, Hella L Aberson¹, Kan Chen³, Frederike Dijk^{2

4}, Joris J T H Roelofs⁴, Mark P G Dings^{1

2}, Gerrit K J Hooijer⁴, Pratika Y Hernanda⁵, Qiunwei Pan³, Olivier R Busch⁶, Marc G H Besselink⁷, Ton Boerman⁴, Maikel P Peppelenbosch³, Maarten F Bijlsma^{1

2

8}, C Arnold Spek^{1

2}

Affiliations

¹ Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
² Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, 1182 DB Amsterdam, The Netherlands.
³ Department of Gastroenterology and Hepatology, Erasmus Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands.
⁴ Department of Pathology, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
⁵ Laboratory of Medical Genetics, University of Wijaya Kusuma Surabaya, Jawa Timur 60225, Indonesia.
⁶ Department of Surgery, Cancer Center Amsterdam, Amsterdam University Medical Center, University of Amsterdam, 1182 DB Amsterdam, The Netherlands.
⁷ Hepato-Pancreato-Biliary Surgery, Amsterdam University Medical Center, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
⁸ Oncode Institute, 3521 AL Utrecht Amsterdam, The Netherlands.

Abstract

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.

Keywords: CCAAT/enhancer-binding protein delta; CEBPD; PDAC; ampullary carcinoma; intrapancreatic cholangiocarcinoma; pancreatic ductal adenocarcinoma; tumor suppressor.

Abstract

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