title: A novel KLF4/LDHA signaling pathway regulates aerobic glycolysis in and progression of pancreatic cancer.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine Affiliated Ruijin Hospital, Shanghai, People's Republic of China. Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Min
authors.initials: M
authors.lastname: Shi
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas. Shanghai Key Laboratory of Pancreatic Diseases Research, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China. Department of Oncology, Shanghai Jiaotong University Affiliated First People's Hospital, Shanghai, People's Republic of China.
authors.forename: Jiujie
authors.initials: J
authors.lastname: Cui
authors.affiliation: Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China.
authors.forename: Jiawei
authors.initials: J
authors.lastname: Du
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Daoyan
authors.initials: D
authors.lastname: Wei
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Jia
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine Affiliated Ruijin Hospital, Shanghai, People's Republic of China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Shanghai Institute of Digestive Surgery, Shanghai Jiaotong University School of Medicine Affiliated Ruijin Hospital, Shanghai, People's Republic of China.
authors.forename: Zhenggang
authors.initials: Z
authors.lastname: Zhu
authors.affiliation: Department of Oncology and Tumor Institute, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People's Republic of China. kepxie@mdanderson.org gaoyon@hotmail.com.
authors.forename: Yong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Gastroenterology, Hepatology and Nutrition, The University of Texas MD Anderson Cancer Center, Houston, Texas. kepxie@mdanderson.org gaoyon@hotmail.com.
authors.forename: Keping
authors.initials: K
authors.lastname: Xie
mesh_terms: D000818:Animals; D015153:Blotting, Western; D047369:Chromatin Immunoprecipitation; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D005947:Glucose / Q000378:metabolism*; D006019:Glycolysis; D006801:Humans; D007124:Immunoenzyme Techniques; D007527:Isoenzymes / Q000235:genetics / Q000378:metabolism; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism*; D007770:L-Lactate Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D000080864:Lactate Dehydrogenase 5; D051379:Mice; D008819:Mice, Nude; D009367:Neoplasm Staging; D010179:Pancreas / Q000378:metabolism* / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: D007527:Isoenzymes; C000715467:KLF4 protein, human; C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D007770:L-Lactate Dehydrogenase; D000080864:Lactate Dehydrogenase 5; D005947:Glucose