TY - JOUR
T1 - Krüpple-like factor 10 regulates radio-sensitivity of pancreatic cancer via UV radiation resistance-associated gene
AU - Chang, Vincent Hung Shu
AU - Tsai, Yi Chih
AU - Tsai, Ya Li
AU - Peng, Shu Ling
AU - Chen, Su Liang
AU - Chang, Tsung Ming
AU - Yu, Winston Chun Yuan
AU - Ch'ang, Hui Ju
N1 - Funding Information:
The study is supported by grants from National Health Research Institutes (NHRI, CA-104-PP-11), Taiwan and Ministry of Science and Technology (MOST 104-2314-B-400-017-MY3), Taiwan.
Publisher Copyright:
© 2017
PY - 2017/3/1
Y1 - 2017/3/1
N2 - Background and purpose Krüpple-like factor 10 (Klf10), an early response gene of TGFβ, was reported to be a prognostic biomarker for pancreatic cancer survival. The role of Klf10 in predicting tumor response to cancer treatment is unknown. Materials and methods Genetically manipulated MiaPaCa and Panc-1 cells were established to evaluate clonogenic survival, autophagy, apoptosis and DNA repair after radiation. The interaction between Klf10 and UV radiation resistance-associated gene (UVRAG) was demonstrated by ChiP-PCR and luciferase reporter assay. Orthotopic murine tumor model and clinical specimens were used to evaluate radio-sensitivity of pancreatic cancer. Results We found Klf10 silencing correlates with enhanced pancreatic cancer clonogenic survival and murine tumor growth after radiation. UVRAG was an essential down-stream mediator transcriptionally suppressed by Klf10. Silencing UVRAG mRNA in Klf10 depleted Panc-1 cells reversed the radio-resistant phenotypes including decreased apoptosis and enhanced DNA repair as well as autophagy. Metformin, an anti-diabetic agent, was found to increase Klf10 and suppress UVRAG expression to improve radiation cytotoxicity in pancreatic cancer. The predictive value of Klf10 in radiation response and the inverse correlation with UVRAG were confirmed in cohorts of pancreatic cancer patients. Conclusions Klf10 is a potential biomarker in predicting and sensitizing radiation effect in pancreatic cancer.
AB - Background and purpose Krüpple-like factor 10 (Klf10), an early response gene of TGFβ, was reported to be a prognostic biomarker for pancreatic cancer survival. The role of Klf10 in predicting tumor response to cancer treatment is unknown. Materials and methods Genetically manipulated MiaPaCa and Panc-1 cells were established to evaluate clonogenic survival, autophagy, apoptosis and DNA repair after radiation. The interaction between Klf10 and UV radiation resistance-associated gene (UVRAG) was demonstrated by ChiP-PCR and luciferase reporter assay. Orthotopic murine tumor model and clinical specimens were used to evaluate radio-sensitivity of pancreatic cancer. Results We found Klf10 silencing correlates with enhanced pancreatic cancer clonogenic survival and murine tumor growth after radiation. UVRAG was an essential down-stream mediator transcriptionally suppressed by Klf10. Silencing UVRAG mRNA in Klf10 depleted Panc-1 cells reversed the radio-resistant phenotypes including decreased apoptosis and enhanced DNA repair as well as autophagy. Metformin, an anti-diabetic agent, was found to increase Klf10 and suppress UVRAG expression to improve radiation cytotoxicity in pancreatic cancer. The predictive value of Klf10 in radiation response and the inverse correlation with UVRAG were confirmed in cohorts of pancreatic cancer patients. Conclusions Klf10 is a potential biomarker in predicting and sensitizing radiation effect in pancreatic cancer.
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U2 - 10.1016/j.radonc.2017.01.001
DO - 10.1016/j.radonc.2017.01.001
M3 - Article
C2 - 28104298
AN - SCOPUS:85009469664
VL - 122
SP - 476
EP - 484
JO - Radiotherapy and Oncology
JF - Radiotherapy and Oncology
SN - 0167-8140
IS - 3
ER -
