title: FBW7 (F-box and WD Repeat Domain-Containing 7) Negatively Regulates Glucose Metabolism by Targeting the c-Myc/TXNIP (Thioredoxin-Binding Protein) Axis in Pancreatic Cancer.
abstract: FBW7 functions as a tumor suppressor by targeting oncoproteins for destruction. We previously reported that the oncogenic mutation of KRAS inhibits the tumor suppressor FBW7 via the Ras-Raf-MEK-ERK pathway, which facilitates the proliferation and survival of pancreatic cancer cells. However, the underlying mechanism by which FBW7 suppresses pancreatic cancer remains unexplored. Here, we sought to elucidate the function of FBW7 in pancreatic cancer glucose metabolism and malignancy.
  
  
  
  Combining maximum standardized uptake value (SUVmax), which was obtained preoperatively via a PET/CT scan, with immunohistochemistry staining, we analyzed the correlation between SUVmax and FBW7 expression in pancreatic cancer tissues. The impact of FBW7 on glucose metabolism was further validated in vitro and in vivo Finally, gene expression profiling was performed to identify core signaling pathways.
  
  
  
  The expression level of FBW7 was negatively associated with SUVmax in pancreatic cancer patients. FBW7 significantly suppressed glucose metabolism in pancreatic cancer cells in vitro Using a xenograft model, MicroPET/CT imaging results indicated that FBW7 substantially decreased 18F-fluorodeoxyglucose ((18)F-FDG) uptake in xenograft tumors. Gene expression profiling data revealed that TXNIP, a negative regulator of metabolic transformation, was a downstream target of FBW7. Mechanistically, we demonstrated that TXNIP was a c-Myc target gene and that FBW7 regulated TXNIP expression in a c-Myc-dependent manner.
  
  
  
  Our results thus reveal that FBW7 serves as a negative regulator of glucose metabolism through regulation of the c-Myc/TXNIP axis in pancreatic cancer. Clin Cancer Res; 22(15); 3950-60. ©2016 AACR.
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Shunrong
authors.initials: S
authors.lastname: Ji
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Yi
authors.initials: Y
authors.lastname: Qin
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liang
authors.affiliation: Department of Breast Surgery, Shanghai Jiao Tong University affiliated Shanghai Sixth Hospital, Shanghai, China.
authors.forename: Run
authors.initials: R
authors.lastname: Huang
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Si
authors.initials: S
authors.lastname: Shi
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Jiang
authors.initials: J
authors.lastname: Liu
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Kaizhou
authors.initials: K
authors.lastname: Jin
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Dingkong
authors.initials: D
authors.lastname: Liang
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Xu
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhang
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Xu
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China.
authors.forename: Quanxing
authors.initials: Q
authors.lastname: Ni
authors.affiliation: Department of Molecular and Cellular Oncology, the University of Texas M.D. Anderson Cancer Center, Houston, Texas.
authors.forename: Paul J
authors.initials: PJ
authors.lastname: Chiao
authors.affiliation: Department of Surgery, The University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.
authors.forename: Min
authors.initials: M
authors.lastname: Li
authors.affiliation: Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China. Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China. Pancreatic Cancer Institute, Fudan University, Shanghai, China. yuxianjun@fudanpciorg.
authors.forename: Xianjun
authors.initials: X
authors.lastname: Yu
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D000073979:F-Box-WD Repeat-Containing Protein 7 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D019788:Fluorodeoxyglucose F18; D015870:Gene Expression; D005947:Glucose / Q000378:metabolism*; D064593:Heterografts; D006801:Humans; D051379:Mice; D010190:Pancreatic Neoplasms / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism*; D000072078:Positron Emission Tomography Computed Tomography; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*
chemical_list: D002352:Carrier Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; C486715:TXNIP protein, human; D019788:Fluorodeoxyglucose F18; D005947:Glucose