Zott Tobias, Wolf Michael, Plessl-Walder Günter, Regele Heinz, Bergmann Michael, Meier-Menches Samuel M, Gerner Christopher, Silberhumer Gerd R, Bileck Andrea
Department of General Surgery, Medical University of Vienna, Vienna 1090, Austria.
Department of Analytical Chemistry, University of Vienna, Vienna 1090, Austria.
J Proteome Res. 2025 Aug 1;24(8):3990-4001. doi: 10.1021/acs.jproteome.5c00114. Epub 2025 Jun 26.
Chemoradiation prior to surgery in locally advanced rectal cancer is the current standard therapy but is not effective in all rectal cancer patients. Prognostic markers supporting patient stratification with respect to clinical response would therefore be desirable. The aim of this study was to investigate pathophysiological mechanisms underlying radioresistance and to identify potential prognostic markers by comparative proteome profiling. Therefore, formalin fixed paraffin-embedded tissue (FFPE) samples from rectal tumors ( = 50) and normal control tissue ( = 39) of nonresponders and responders to neoadjuvant chemoradiation were analyzed. As a result, 1685 robustly identified proteins were further evaluated. Comparing tumor with corresponding control samples revealed 221 differentially expressed proteins (FDR < 0.05) with FTL, PCOLCE, and RCN3 being most striking in tumor tissue. CEACAM 1, 5, and 6, as well as MCM protein complex components, were significantly up-regulated in tumor tissue of nonresponders. The autophagic activity-related and DNA damage repair proteins TOM1, CAPNS1, TP53BP1, HS1BP3, as well as COTL1 and DCPS, discriminated non- and nearly complete from complete responders. In the tumor-surrounding tissue of nonresponders, the innate immune response-suppressing protein CD55 was found specifically up-regulated. These proteins may serve as prognostic markers and potential therapeutic targets, requiring further validation in prospective studies.
在局部晚期直肠癌患者中，术前放化疗是当前的标准治疗方法，但并非对所有直肠癌患者都有效。因此，需要能够支持根据临床反应对患者进行分层的预后标志物。本研究的目的是探讨放射抗性背后的病理生理机制，并通过比较蛋白质组分析来确定潜在的预后标志物。因此，我们分析了新辅助放化疗无反应者和有反应者的直肠肿瘤福尔马林固定石蜡包埋组织（FFPE）样本（n = 50）和正常对照组织（n = 39）。结果，对1685种经可靠鉴定的蛋白质进行了进一步评估。将肿瘤样本与其相应的对照样本进行比较，发现了221种差异表达蛋白（FDR < 0.05），其中FTL、PCOLCE和RCN3在肿瘤组织中最为显著。癌胚抗原相关细胞黏附分子1、5和6以及微小染色体维持蛋白复合物成分在无反应者的肿瘤组织中显著上调。自噬活性相关蛋白和DNA损伤修复蛋白TOM1、CAPNS1、TP53BP1、HS1BP3以及COTL1和DCPS区分了无反应者和接近完全反应者与完全反应者。在无反应者的肿瘤周围组织中，发现先天免疫反应抑制蛋白CD55特异性上调。这些蛋白质可能作为预后标志物和潜在的治疗靶点，需要在前瞻性研究中进一步验证。
