Laboratory for Experimental Oncology and Radiobiology, Center for Experimental and Molecular Medicine, Amsterdam UMC Location University of Amsterdam, 1105 AZ Amsterdam, The Netherlands.
Cancer Center Amsterdam, Cancer Biology and Immunology, 1081 HV Amsterdam, The Netherlands.
Int J Mol Sci. 2023 Jan 12;24(2):1537. doi: 10.3390/ijms24021537.
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.
胰腺导管腺癌 (PDAC) 是一种预后较差且治疗选择不理想的疾病。我们之前发现，与健康胰腺导管细胞相比，转录因子 CCAAT/增强子结合蛋白 Delta (C/EBPδ) 在 PDAC 中表达水平较低，并且 PDAC 患者的生存和淋巴结受累情况与肿瘤细胞中 C/EBPδ 的表达相关。C/EBPδ 与其他 C/EBP 蛋白共享同源的 DNA 结合序列，因此推测其他 C/EBP 家族成员可能存在冗余作用，从而弥补 C/EBPδ 的缺失。这意味着当同时考虑多个 C/EBP 家族成员的表达水平时，患者分层可能会得到改善。在这项研究中，我们评估了在 68 例可切除的 PDAC 患者队列中，除了 C/EBPδ 之外，C/EBPβ 或 C/EBPγ 的定量分析是否可以改善对患者生存和淋巴结受累的预测。通过对具有不同 C/EBP 表达水平的患者组进行 Kaplan-Meier 分析，我们发现 C/EBPβ 和 C/EBPγ 都可以部分弥补 C/EBPδ 的低表达并改善患者的生存。此外，我们发现 C/EBPβ 是 PDAC 淋巴结受累可能性降低的一个新的预测因子，并发现 C/EBPβ 和 C/EBPδ 可以相互补偿以降低淋巴结受累的风险。另一方面，C/EBPγ 在缺乏 C/EBPδ 的情况下似乎会促进淋巴结受累。总的来说，我们的结果表明 C/EBP 家族成员的冗余性可能对临床预后有深远的影响，并且在根据 C/EBPδ 表达将患者分为两类时，应该考虑到 C/EPBβ 和 C/EBPγ 的表达。
