Javle Milind, Li Yanan, Tan Dongfeng, Dong Xiaoqun, Chang Ping, Kar Siddhartha, Li Donghui
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
PLoS One. 2014 Jan 20;9(1):e85942. doi: 10.1371/journal.pone.0085942. eCollection 2014.
Transforming growth factor (TGF)-β signaling pathway, may act both as a tumor suppressor and as a tumor promoter in pancreatic cancer, depending on tumor stage and cellular context. TGF-β pathway has been under intensive investigation as a potential therapeutic target in the treatment of cancer. We hypothesized a correlation between TGF-βR2/SMAD4 expression in the tumor, plasma TGF-β1 ligand level, genetic variation in TGF-B pathway and prognosis of pancreatic cancer.
We examined TGF-βR2 and SMAD4 protein expression in biopsy or surgical samples from 91 patients with pancreatic ductal adenocarcinoma (PDAC) using immunohistochemistry. Plasma level of TGF-β1 was measured in 644 patients with PDAC using ELISA. Twenty-eight single nucleotide polymorphisms (SNP) of the TGF-β1, TGF-β2, TGF-β3, TGF-βR1, TGF-βR2, and SMAD4 genes were determined in 1636 patients with PDAC using the Sequenom method. Correlation between protein expression in the tumor, plasma TGF-β1 level, and genotypes with overall survival (OS) was evaluated with Cox proportional regression models.
The expression level of TGF-βR2 and SMAD4 as an independent marker was not associated with OS. However, patients with both low nuclear staining of TGF-βR2 and high nuclear staining of SMAD4 may have better survival (P = 0.06). The mean and median level of TGF-β1 was 15.44 (SD: 10.99) and 12.61 (interquartile range: 8.31 to 19.04) ng/ml respectively. Patients with advanced disease and in the upper quartile range of TGF-β1 level had significantly reduced survival than those with low levels (P = 0.02). A significant association of SMAD4 SNP rs113545983 with overall survival was observed (P<0.0001).
Our data provides valuable baseline information regarding the TGF-β pathway in pancreatic cancer, which can be utilized in targeted therapy clinical trials. High TGF-β1 plasma level, SMAD4 SNP or TGF-βR2/SMAD4 tumor protein expression may suggest a dependence on this pathway in patients with advanced pancreatic cancer.
转化生长因子（TGF）-β信号通路在胰腺癌中可能既作为肿瘤抑制因子又作为肿瘤促进因子，这取决于肿瘤分期和细胞环境。TGF-β通路作为癌症治疗的潜在靶点一直受到深入研究。我们推测肿瘤中TGF-βR2/SMAD4表达、血浆TGF-β1配体水平、TGF-B通路的基因变异与胰腺癌预后之间存在关联。
我们使用免疫组织化学检测了91例胰腺导管腺癌（PDAC）患者活检或手术样本中TGF-βR2和SMAD4蛋白表达。使用酶联免疫吸附测定法（ELISA）检测了644例PDAC患者血浆中TGF-β1水平。使用Sequenom方法在1636例PDAC患者中测定了TGF-β1、TGF-β2、TGF-β3、TGF-βR1、TGF-βR2和SMAD4基因的28个单核苷酸多态性（SNP）。使用Cox比例回归模型评估肿瘤蛋白表达、血浆TGF-β1水平和基因型与总生存期（OS）之间的相关性。
TGF-βR2和SMAD4的表达水平作为独立标志物与总生存期无关。然而，TGF-βR2核染色低且SMAD4核染色高的患者可能有更好的生存期（P = 0.06）。TGF-β1的平均水平和中位数水平分别为15.44（标准差：10.99）和12.61（四分位间距：8.31至19.04）ng/ml。疾病晚期且TGF-β1水平处于上四分位数范围的患者生存期明显低于水平低的患者（P = 0.02）。观察到SMAD4 SNP rs113545983与总生存期存在显著关联（P<0.0001）。
我们的数据提供了关于胰腺癌中TGF-β通路的有价值的基线信息，可用于靶向治疗临床试验。高血浆TGF-β1水平、SMAD4 SNP或TGF-βR2/SMAD4肿瘤蛋白表达可能表明晚期胰腺癌患者对该通路存在依赖性。
