Aim: Deregulation of transforming growth factor (TGF)-beta function is a common feature of pancreatic cancer, rendering it unresponsive to radiotherapy. Krüppel-like factor 10 (KLF10) is an important transcription factor mediating TGF-beta 1 signaling. The aim of this study is to evaluate the mechanisms of Klf10 in regulating radio-sensitivity of pancreatic cancer. Methods: The expression of Klf10 and radio-sensitivity of genetically modulated and radiation selected pancreatic cancer cells were demonstrated by immunoblots and clonogenic assays. Chip-PCR and luciferase promoter assay were used to demonstrate down-stream targets interaction with Klf10. The level of autophagy, apoptosis and DNA damage after radiation was evaluated. Klf10 modulated tumor response to radiation was measured in orthotopic model. Klf10 expression was correlated with pathologic tumor regression in pancreatic cancer patients. Results: Decreasing Klf10 expression was found in Panc-1 cells with increasing radiation resistance. Over-expressing Klf10 suppressed surviving fraction of MiaPaCa cells after radiation. The observation was associated with increased apoptosis, DNA damage, and decreased autophagy. The expression of ultraviolet irradiation resistance-associated gene (UVRAG) was demonstrated to be transcriptionally suppressed by Klf10. In vitro studies demonstrated Klf10 regulated pancreatic cancer radiation sensitivity via UVRAG. In the orthotopic model, up-regulating Klf10 genetically or pharmacologically sensitized pancreatic tumors to radiation. Analysis from pancreatic cancer patients, receiving neoadjuvant chemo-radiotherapy before surgery, showed a significant correlation of high Klf10 expression with good pathologic tumor regression. Conclusions: Our results suggest Klf10 regulates radio-sensitivity of pancreatic cancer cells by transcriptionally suppressing UVRAG expression which modulates autophagy, apoptosis and DNA damage repair after radiation. Klf10 is a potential biomarker of tumor response to radiotherapy and a therapeutic target to pancreatic cancer.
