Abstract 417: SMAD3 upregulation is a novel biomarker of poor prognosis and epithelial-mesenchymal transition in pancreatic cancer.

Abstract

Abstract Pancreatic cancer has one of the worst survival rates among all cancers. Features like epithelial-mesenchymal transition (EMT) are often seen in pancreatic tumors and correlate with poor prognosis. The purpose of this study was to identify factors involved in EMT in pancreatic cancer that may serve as prognostic indicators. Gene-expression profiling identified overexpression of SMAD3 in pancreatic cancer with high-grade solitary cell infiltration, one of the EMT-like features. SMAD3 expression was then evaluated through immunohistochemical analysis using clinical specimens. SMAD3 was accumulated in the nuclei of tumor cells (positive rate ranging from 0% to 75%), but was not detected in most of the epithelial cells in the pancreatic duct. Upregulated SMAD3 (≥15% positive in nuclei of tumor cells) correlated with malignant characteristics, such as higher tumor grade (P = 0.001) and lymph node metastasis (P <0.001), as well as with EMT-like features, such as reduced E-cadherin (P = 0.013) and elevated vimentin (P = 0.032). SMAD3 knockdown in pancreatic cancer cells resulted in increased E-cadherin expression, decreased vimentin expression and decreased cell motility. The suppressed EMT-like features by SMAD3 knockdown were observed even in SMAD4-inactivated pancreatic cancer cells, suggesting that SMAD3 is involved in EMT induction, regardless of SMAD4 status. In clinical cases, SMAD3 upregulation and EMT-like features correlated with shorter survival time. Moreover, SMAD3 and E-cadherin were identified as independent prognostic factors by multivariate analysis, and the group of patients with both upregulated SMAD3 and reduced E-cadherin had the least favorable prognosis compared with other groups. Taken together, SMAD3 seems to play an important role in malignant progression of pancreatic cancer, and may provide a potential biomarker for poor prognosis of pancreatic cancer. Citation Format: Ken Yamazaki, Yohei Masugi, Kathryn Effendi, Michiie Sakamoto. SMAD3 upregulation is a novel biomarker of poor prognosis and epithelial-mesenchymal transition in pancreatic cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 417. doi:10.1158/1538-7445.AM2013-417