Biomarkers of TGF-? signaling pathway and prognosis of pancreatic cancer.

ABSTRACT: Transforming growth factor (TGF)-? 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-? pathway has been under intensive investigation as a potential therapeutic target in the treatment of cancer. We hypothesized a correlation between TGF-?R2/SMAD4 expression in the tumor, plasma TGF-?1 ligand level, genetic variation in TGF-B pathway and prognosis of pancreatic cancer.We examined TGF-?R2 and SMAD4 protein expression in biopsy or surgical samples from 91 patients with pancreatic ductal adenocarcinoma (PDAC) using immunohistochemistry. Plasma level of TGF-?1 was measured in 644 patients with PDAC using ELISA. Twenty-eight single nucleotide polymorphisms (SNP) of the TGF-?1, TGF-?2, TGF-?3, TGF-?R1, TGF-?R2, and SMAD4 genes were determined in 1636 patients with PDAC using the Sequenom method. Correlation between protein expression in the tumor, plasma TGF-?1 level, and genotypes with overall survival (OS) was evaluated with Cox proportional regression models.The expression level of TGF-?R2 and SMAD4 as an independent marker was not associated with OS. However, patients with both low nuclear staining of TGF-?R2 and high nuclear staining of SMAD4 may have better survival (P = 0.06). The mean and median level of TGF-?1 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-?1 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-? pathway in pancreatic cancer, which can be utilized in targeted therapy clinical trials. High TGF-?1 plasma level, SMAD4 SNP or TGF-?R2/SMAD4 tumor protein expression may suggest a dependence on this pathway in patients with advanced pancreatic cancer.

SUBMITTER: Javle M 

PROVIDER: S-EPMC3896410 | biostudies-literature | 2014

REPOSITORIES: biostudies-literature