Rückert F, Hennig M, Petraki C D, Wehrum D, Distler M, Denz A, Schröder M, Dawelbait G, Kalthoff H, Saeger H-D, Diamandis E P, Pilarsky C, Grützmann R
Visceral, Thoracic and Vascular Surgery, University Hospital Carl Gustav Carus, Technical University of Dresden, Fetscherstrasse 74, Dresden 01307, Germany.
Br J Cancer. 2008 Nov 4;99(9):1484-92. doi: 10.1038/sj.bjc.6604717. Epub 2008 Oct 14.
Kallikreins play an important role in tumour microenvironment and as cancer biomarkers in different cancer entities. Previous studies suggested an upregulation of KLK10 and KLK6 in pancreatic ductal adenocarcinoma (PDAC). Therefore, we evaluated the clinicopathological role of these kallikreins and their value as biomarkers in PDAC.Differential expression was validated by DNA-microarrays and immunohistochemistry in normal and malignant pancreatic tissues. Sera concentrations of both kallikreins were evaluated using ELISA. In silico analysis of possible protein interactions and gene silencing of KLK10 in vitro using siRNAs gave further insights in the pathomechanisms.Gene expression analysis and immunohistochemistry demonstrated a strong expression for KLK10 and KLK6 in PDAC. Statistical analysis showed that co-expression of these kallikreins correlated with an R1-resection status (P=0.017) and worse outcome for overall survival (P=0.031). Multivariate analysis proofed that co-expression is an independent prognostic factor for survival (P=0.043). Importantly, KLK10 knockdown in AsPC-1 cells significantly reduced cell migration, whereas computational analysis suggested interaction of KLK6 with angiogenetic factors as an important mechanism.Co-expression of KLK10 and KLK6 plays an unfavourable role in PDAC. Our results suggest that this effect is likely mediated by an interaction with the factors of the extracellular matrix and enhancement of cancer cell motility.
激肽释放酶在肿瘤微环境中发挥重要作用，并作为不同癌症实体中的癌症生物标志物。先前的研究表明，激肽释放酶10（KLK10）和激肽释放酶6（KLK6）在胰腺导管腺癌（PDAC）中上调。因此，我们评估了这些激肽释放酶在PDAC中的临床病理作用及其作为生物标志物的价值。通过DNA微阵列和免疫组织化学在正常和恶性胰腺组织中验证差异表达。使用酶联免疫吸附测定（ELISA）评估两种激肽释放酶的血清浓度。对可能的蛋白质相互作用进行计算机分析，并使用小干扰RNA（siRNA）在体外对KLK10进行基因沉默，从而进一步深入了解发病机制。基因表达分析和免疫组织化学显示KLK10和KLK6在PDAC中强烈表达。统计分析表明，这些激肽释放酶的共表达与R1切除状态相关（P = 0.017），总体生存结果较差（P = 0.031）。多变量分析证明共表达是生存独立预后因素（P = 0.043）。重要的是，在AsPC-细胞中敲低KLK10可显著降低细胞迁移，而计算机分析表明KLK6与血管生成因子的相互作用是重要机制。KLK10和KLK6的共表达在PDAC中起不利作用。我们的结果表明，这种作用可能是由与细胞外基质因子的相互作用和癌细胞运动性增强介导的。
Zotero 插件
