KLF4α Up-regulation Promotes Cell Cycle Progression and Reduces Survival Time of Patients With Pancreatic Cancer

Abstract

Krüppel-like factor 4 (KLF4) is a transcription factor associated with tumor suppression and oncogenesis. KLF4 suppresses pancreatic tumorigenesis by unknown mechanisms; we investigated alterations that might affect KLF4 function and lead to tumor formation. We identified different isoforms of KLF4 in pancreatic cancer cells by reverse-transcriptase polymerase chain reaction, cloning, and DNA sequence analyses. We constructed vectors to express the isoform KLF4α and characterize its function. Using real-time polymerase chain reaction, immunoprecipitation, and immunohistochemical analyses, we assessed expression of KLF4α in pancreatic cancer cell lines and tumor tissue samples; xenograft models were used to determine the effect of KLF4α on pancreatic tumorigenesis. We identified 4 KLF4 isoforms in human pancreatic cancer cells, designated KLF4α, KLF4β, KLF4γ, and KLF4δ. KLF4α localized primarily to the cytoplasm; its protein and messenger RNA were up-regulated in pancreatic cancer cell lines with high metastatic potential and human pancreatic tumors compared with normal pancreatic tissue. Transgenic expression of KLF4α reduced expression of p27(Kip1) and p21(Cip1), promoting cell cycle progression and in vivo tumor formation by pancreatic cancer cells. Increased expression of KLF4α in pancreatic tumor tissue was inversely correlated with overall time of survival in patients with stage II pancreatic ductal adenocarcinoma. We identified a splice variant of KLF4 (KLF4α) that is up-regulated in aggressive pancreatic cancer cells and human pancreatic tumor tissues. Increased expression promotes growth of pancreatic tumors in mice and is associated with reduced survival times of patients.