PO.CL12.02 · 临床研究
肿瘤微环境中的Galectin-2表达：胰腺导管腺癌进展的一条沉默通路
Galectin-2 expression in the tumor microenvironment: A silent pathway of pancreatic ductal adenocarcinoma progression
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
背景：胰腺导管腺癌（PDAC）是一种侵袭性癌症，具有复杂的微环境，其中galectin类蛋白发挥关键作用。本研究评估了galectin类蛋白的表达，以探究其作为预后生物标志物的潜力。
方法：对938例原发性PDAC患者队列进行了计算机模拟（in silico）转录组分析。使用激光显微切割、免疫组织化学和RT-qPCR评估PDAC活检组织肿瘤区和基质区的表达谱。通过ELISA测量血清GAL-2水平。还使用KIC小鼠模型评估了肿瘤进展不同阶段的GAL2表达。
结果：为分析人PDAC中galectin的转录组表达谱，在938例诊断为原发性PDAC肿瘤的个体队列中评估了LGALS基因的转录本。LGALS2成为一个关键转录本，在PDAC样本中的表达水平比中位数低两倍。LGALS转录本的相关性分析揭示LGALS2、LGALS3、LGALS4和LGALS9之间存在正相关簇，而LGALS1与LGALS2之间存在负相关。与对照组和正常胰腺组织相比，LGALS2表达在原发性肿瘤（p = 8.76E-22）和转移部位（p = 2.75E-30）中下调。在KIC小鼠模型中，观察到LGALS2表达在整个肿瘤进展过程中逐步降低，从早期病变到已建立的原发性和转移性肿瘤。高LGALS2表达与经典型和高分化上皮型PDAC亚型相关，而低表达则是基底样型、鳞状型和间充质型肿瘤的特征。重要的是，LGALS2表达增加与更好的无病生存期和总生存期相关。此外，较高的LGALS2表达与接受FOLFIRINOX方案治疗的患者总生存期改善显著相关（p = 4.08E-02）。另外，在诊断为PDAC的患者活检中观察到低GAL-2蛋白表达。PDAC患者的血清GAL-2水平显著较低，尤其是与健康捐献者相比有转移的患者。启动子低甲基化（CpG岛cpg25247183）被确定为其下调背后的一种潜在调控机制。
结论：LGALS2表达在PDAC进展不同阶段的下调凸显了其在肿瘤发病机制中的重要性，并提示其作为预后和治疗生物标志物的潜力。
查看英文原文 English abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with a complex microenvironment in which galectins play key roles. This study evaluated galectins expression to investigate its potential as a prognostic biomarker.
Methods: Transcriptomic analyses were performed in silico on a cohort of 938 individuals with primary PDAC. Laser microdissection, immunohistochemistry, and RT-qPCR were used to assess the expression profile in the tumor and stromal regions of PDAC biopsies. Serum GAL-2 levels were measured by ELISA. GAL2 expression was also evaluated during distinct stages of tumor progression using the KIC murine model.
Results: To analyze the galectin transcriptomic expression profile in human PDAC, transcripts of LGALS genes were evaluated in a cohort of 938 individuals diagnosed with primary PDAC tumors. LGALS2 emerged as a key transcript, exhibiting expression levels two-fold below the median in PDAC samples. Correlation analysis of LGALS transcripts revealed a positive cluster among LGALS2 , LGALS3 , LGALS4 , and LGALS9 , and a negative association between LGALS1 and LGALS2 . LGALS2 expression was downregulated in primary tumors (p = 8.76E-22) and metastatic sites (p = 2.75E-30) compared to both the control group and normal pancreatic tissue. In the KIC mouse model, a progressive reduction in LGALS2 expression was observed throughout tumor progression, from early lesions to established primary and metastatic tumors. High LGALS2 expression was associated with classical and well-differentiated epithelial PDAC subtypes, whereas low expression characterized basal-like, squamous, and mesenchymal tumors. Importantly, increased LGALS2 expression correlated with better disease-free and overall survival. Furthermore, higher LGALS2 expression was significantly associated with improved overall survival in patients treated with the FOLFIRINOX regimen (p = 4.08E-02). Additionally, low GAL-2 protein expression was observed in biopsies from patients diagnosed with PDAC. Serum GAL-2 levels were significantly lower in PDAC patients, especially those with metastasis when compared to health donors. Promoter hypomethylation (CpG island cpg25247183) was identified as a potential regulatory mechanism underlying its downregulation.
Conclusions: The downregulation of LGALS2 expression across different stages of PDAC progression underscores its importance in tumor pathogenesis and suggests its potential as a prognostic and therapeutic biomarker.
利益披露 Disclosure
M. J. Rêgo, None..
M. P. D. Sampaio, None..
A. P. B. Albuquerque, None..
C. Montenegro, None..
M. Rosa, None.