scholarly journals Non-Tumor CCAAT/Enhancer-Binding Protein Delta Potentiates Tumor Cell Extravasation and Pancreatic Cancer Metastasis Formation

Biomolecules ◽  
2021 ◽  
Vol 11 (8) ◽  
pp. 1079
Author(s):  
JanWillem Duitman ◽  
Leonie Hartl ◽  
Joris J. T. H. Roelofs ◽  
Maarten F. Bijlsma ◽  
C. Arnold Spek
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Cell ◽  
Cancer Metastasis ◽  
Binding Protein ◽  
Ductal Adenocarcinoma ◽  
Strong Impact ◽  
Metastasis Formation ◽  
Genetic Ablation ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

CCAAT/enhancer-binding protein delta (C/EBPδ) is a transcription factor involved in apoptosis and proliferation, which is downregulated in pancreatic ductal adenocarcinoma (PDAC) cells. Loss of nuclear C/EBPδ in PDAC cells is associated with decreased patient survival and pro-tumorigenic properties in vitro. Interestingly however, next to C/EBPδ expression in tumor cells, C/EBPδ is also expressed by cells constituting the tumor microenvironment and by cells comprising the organs and parenchyma. However, the functional relevance of systemic C/EBPδ in carcinogenesis remains elusive. Here, we consequently assessed the potential importance of C/EBPδ in somatic tissues by utilizing an orthotopic pancreatic cancer model. In doing so, we show that genetic ablation of C/EBPδ does not significantly affect primary tumor growth but has a strong impact on metastases; wildtype mice developed metastases at multiple sites, whilst this was not the case in C/EBPδ-/- mice. In line with reduced metastasis formation in C/EBPδ-/- mice, C/EBPδ-deficiency also limited tumor cell dissemination in a specific extravasation model. Tumor cell extravasation was dependent on the platelet-activating factor receptor (PAFR) as a PAFR antagonist inhibited tumor cell extravasation in wildtype mice but not in C/EBPδ-/- mice. Overall, we show that systemic C/EBPδ facilitates pancreatic cancer metastasis, and we suggest this is due to C/EBPδ-PAFR-dependent tumor cell extravasation.

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

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2546
Author(s):  
Leonie Hartl ◽  
JanWillem Duitman ◽  
Hella L. Aberson ◽  
Kan Chen ◽  
Frederike Dijk ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Tumor Suppressor ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Binding Protein ◽  
Ductal Adenocarcinoma ◽  
Ductal Cells ◽  
Enhancer Binding Protein ◽  
Adenocarcinoma Cells ◽  
Ccaat Enhancer Binding Protein

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.

scholarly journals Genetic Ablation of CCAAT/Enhancer Binding Protein α in Epidermis Reveals Its Role in Suppression of Epithelial Tumorigenesis

2007 ◽  
Vol 67 (14) ◽  
pp. 6768-6776 ◽  
Author(s):  
Kari D. Loomis ◽  
Songyun Zhu ◽  
Kyungsil Yoon ◽  
Peter F. Johnson ◽  
Robert C. Smart
Keyword(s):  
Binding Protein ◽  
Genetic Ablation ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein

scholarly journals Dysregulation of CCAAT/enhancer binding protein-alpha (CEBPA) expression in the bone marrow of acute myeloid leukemia patients

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Naglaa M. Hassan ◽  
Fadwa Said ◽  
Roxan E. Shafik ◽  
Mona S. Abdellateif
Keyword(s):  
Bone Marrow ◽  
Acute Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Binding Protein ◽  
Response To Treatment ◽  
Pathological Features ◽  
Poor Prognostic Factor ◽  
Enhancer Binding Protein ◽  
Ccaat Enhancer Binding Protein ◽  
Acute Myeloid

Abstract Background Acute myeloid leukemia (AML) is a heterogeneous malignant disease characterized by accumulation of different types of mutations commonly the CCAAT/enhancer binding protein-alpha (CEBPA). However, the dysregulations of CEBPA expression in AML is still a debatable issue. The aim of the current study was to assess CEBPA gene expression in bone marrow (BM) aspiration specimens of 91 AML patients, compared to 20 control donors of bone marrow transplantation (BMT), using RT-PCR. Data were correlated with patients’ clinico-pathological features, response to treatment, progression-free survival (PFS), and overall survival (OS) rates. Results There was overexpression of CEBPA gene in AML patients compared to normal control [1.7 (0.04–25.6) versus 0.17 (0–4.78), respectively, P < 0.001]. Upregulation of CEBPA expression associated significantly with increased BM hypercellularity, total leucocyte counts, peripheral blood blast cell count, and poor PFS (P < 0.001, 0.002, 0.001, and 0.013, respectively). There was no significant association between CEBPA expression and any other relevant clinico-pathological features or OS rates (P = 0.610) of the patients. ROC analysis for biological relevance of CEBPA expression with AML showed that sensitivity and specificity of CEBPA expression at a cut-off value of 0.28 are 92.3% and 78.6%, respectively (P < 0.001). All patients who had CEBPA overexpression and mutant FLT3 showed BM hypercellularity, adverse cytogenetic risk, increased TLC, and PB blast cells count (P = 0.007, P < 0.001, 0.016, and 0.002, respectively). Conclusion CEBPA overexpression could be used as a genetic biological marker for AML diagnosis, as well as a poor prognostic factor for disease progression. It has no impact on OS rates of the patients.

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