Table S1. Clinicopathologic characteristics of the patients Represented by the pancreatic TMA specimens; Table S2. The alterations of glycolysis-related genes in GSE21768 Table S3. The alterations of glycolysis-related genes in GSE3113 Table S4. LDHA expression and clinicopathologic characteristics of the pancreatic cancer patients Table S5. LDHB expression and clinicopathologic characteristics of the pancreatic cancer patients Table S6. KLF4 expression and clinicopathologic characteristics of the pancreatic cancer patients
ARTICLE ABSTRACTPurpose: Krüppel-like factor 4 (KLF4) is a transcription factor and putative tumor suppressor. However, little is known about its effect on aerobic glycolysis in pancreatic tumors. Therefore, we investigated the clinical significance, biologic effects, and mechanisms of dysregulated KLF4 signaling in aerobic glycolysis in pancreatic cancer cells.Experimental Design: Expression of KLF4 and lactate dehydrogenase A (LDHA) in 70 primary pancreatic tumors and 10 normal pancreatic tissue specimens was measured. Also, the underlying mechanisms of altered KLF4 expression and its impact on aerobic glycolysis in pancreatic cancer cells were investigated.Results: We found a negative correlation between KLF4 and LDHA expression in pancreatic cancer cells and tissues and that their expression was associated with clinicopathologic features of pancreatic cancer. KLF4 underexpression and LDHA overexpression were correlated with disease stage and tumor differentiation. Experimentally, KLF4 overexpression significantly attenuated the aerobic glycolysis in and growth of pancreatic cancer cells both in vitro and in orthotopic mouse models, whereas knockdown of KLF4 expression had the opposite effect. Enforced KLF4 expression decreased LDHA expression, whereas small interfering RNA–mediated knockdown of KLF4 expression had the opposite effect. Mechanistically, KLF4 bound directly to the promoter regions of the LDHA gene and negatively regulated its transcription activity.Conclusions: Dysregulated signaling in this novel KLF4/LDHA pathway significantly impacts aerobic glycolysis in and development and progression of pancreatic cancer. Clin Cancer Res; 20(16); 4370–80. ©2014 AACR.