Kruppel-Like Factor 10 Expression as a Prognostic Indicator for Pancreatic Adenocarcinoma

Deregulation of transforming growth factor (TGF)-beta function is a common feature of pancreatic cancer, rendering these cancers unresponsive to TGF-beta-stimulated growth inhibition. Recent findings have supported a primary role for Kruppel-like factor 10 (KLF10) as an important transcription factor involved in mediating TGF-beta 1 signaling. The aim of this study was to evaluate the correlation between KLF10 expression and the clinical and pathologic features of pancreatic cancer. Tissue specimens from patients with pancreatic adenocarcinoma were retrospectively collected for immunohistochemical analysis. To demonstrate that Klf10 expression was primarily regulated by methylation status, the Klf10 promoter was examined by methylation-specific PCR using a pancreatic cancer cell line (Panc-1). DNA methyltransferase (DNMT) inhibitor and small-interfering RNA depletion of DNMT genes were used to reverse KLF10 expression in the Panc-1 cells. In parallel, DNMT1 expression was evaluated in the pancreatic cancer tissue specimens. In 95 pancreatic cancer tissue specimens, KLF10 expression was inversely correlated with pancreatic cancer stage (P = 0.01). Multivariable analysis revealed that, in addition to the presence of distant metastasis at diagnosis (P = 0.001 and 0.001, respectively), KLF10 was another independent prognostic factor related to progression-free and overall survival (P = 0.018 and 0.037, respectively). The loss of KLF10 expression in advanced pancreatic cancer is correlated with altered methylation status, which seems to be regulated by DNMT1. Our results suggest that KLF10 is a potential clinical predictor for progression of pancreatic cancer. (Am J Pathol 2012, 181: 423-430; http://dx.doi.org/10.1016/j.ajpath.2012.04.025)