C/EBP-Family Redundancy Determines Patient Survival and Lymph Node Involvement in PDAC.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a dismal disease with a poor clinical prognosis and unsatisfactory treatment options. We previously found that the transcription factor CCAAT/Enhancer-Binding Protein Delta (C/EBPδ) is lowly expressed in PDAC compared to healthy pancreas duct cells, and that patient survival and lymph node involvement in PDAC is correlated with the expression of C/EBPδ in primary tumor cells. C/EBPδ shares a homologous DNA-binding sequence with other C/EBP-proteins, leading to the presumption that other C/EBP-family members might act redundantly and compensate for the loss of C/EBPδ. This implies that patient stratification could be improved when expression levels of multiple C/EBP-family members are considered simultaneously. In this study, we assessed whether the quantification of C/EBPβ or C/EBPγ in addition to that of C/EBPδ might improve the prediction of patient survival and lymph node involvement using a cohort of 68 resectable PDAC patients. Using Kaplan-Meier analyses of patient groups with different C/EBP-expression levels, we found that both C/EBPβ and C/EBPγ can partially compensate for low C/EBPδ and improve patient survival. Further, we uncovered C/EBPβ as a novel predictor of a decreased likelihood of lymph node involvement in PDAC, and found that C/EBPβ and C/EBPδ can compensate for the lack of each other in order to reduce the risk of lymph node involvement. C/EBPγ, on the other hand, appears to promote lymph node involvement in the absence of C/EBPδ. Altogether, our results show that the redundancy of C/EBP-family members might have a profound influence on clinical prognoses and that the expression of both C/EPBβ and C/EBPγ should be taken into account when dichotomizing patients according to C/EBPδ expression.

• Authors: Leonie Hartl, Joris J T H Roelofs, Frederike Dijk, Maarten F Bijlsma, JanWillem Duitman, C Arnold Spek
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 24 Issue 2 (Jan 12 2023) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 36675048 (Publication Type: Journal Article)

Chemical References

• CCAAT-Enhancer-Binding Protein-beta
• CCAAT-Enhancer-Binding Protein-delta
• CCAAT-Enhancer-Binding Proteins
• CEBPD protein, human
• CCAAT-enhancer-binding protein-gamma
• CEBPB protein, human

Topics

• Humans
• CCAAT-Enhancer-Binding Protein-beta (genetics, metabolism)
• CCAAT-Enhancer-Binding Protein-delta (genetics, metabolism)
• CCAAT-Enhancer-Binding Proteins (genetics, metabolism)
• Gene Expression Regulation (genetics, physiology)
• Lymph Nodes (metabolism, pathology)
• Pancreatic Neoplasms (genetics, metabolism, pathology)
• Carcinoma, Pancreatic Ductal (genetics, metabolism, pathology)
• Lymphatic Metastasis (genetics, pathology, physiopathology)
• Prognosis