title: Pancreatic cancer cell-derived IGFBP-3 contributes to muscle wasting.
abstract: BACKGROUND
  Progressive loss of skeletal muscle, termed muscle wasting, is a hallmark of cancer cachexia and contributes to weakness, reduced quality of life, as well as poor response to therapy. Previous studies have indicated that systemic host inflammatory response regarding tumor development results in muscle wasting. However, how tumor directly regulates muscle wasting via tumor-derived secreted proteins is still largely unknown.
  
  
  METHODS
  In this study, we performed bioinformatics analysis in two datasets of pancreatic ductal adenocarcinoma, which causes cancer cachexia and muscle wasting with the highest prevalence, and uncovered that IGFBP3, which encodes IGF-binding protein-3 (IGFBP-3), is dramatically up-regulated in pancreatic tumor samples. We also verified the wasting effect of IGFBP-3 on C2C12 muscle cells with biochemical and genetic assays.
  
  
  RESULTS
  IGFBP-3 potently leads to impaired myogenesis and enhanced muscle protein degradation, the major features of muscle wasting, via IGF signaling inhibition. Moreover, conditioned medium from Capan-1 pancreatic cancer cells, which contains abundant IGFBP-3, significantly induces muscle cell wasting. This wasting effect is potently alleviated by IGFBP3 knockdown in Capan-1 cells or IGFBP-3 antibody neutralization. Strikingly, compared to muscle cells, IGF signaling and proliferation rate of Capan-1 cells were rarely affected by IGFBP-3 treatment.
  
  
  CONCLUSIONS
  Our results demonstrated that pancreatic cancer cells induce muscle wasting via IGFBP-3 production.
authors.affiliation: Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, P.R. China. xyhuang1119@163.com.
authors.forename: Xiu-yan
authors.initials: XY
authors.lastname: Huang
authors.affiliation: Department of Radiology, Xuhui Central Hospital, Shanghai, 200031, PR China.
authors.forename: Zi-Li
authors.initials: ZL
authors.lastname: Huang
authors.affiliation: Collaborative Innovation Center of Tianjin for Medical Epigenetics, Key Laboratory of Hormone and Development (Ministry of Health), Metabolic Disease Hospital & Tianjin Institute of Endocrinology, Tianjin Medical University, Tianjin, 300070, China.
authors.forename: Ju-hong
authors.initials: JH
authors.lastname: Yang
authors.affiliation: Department of Radiology, Xuhui Central Hospital, Shanghai, 200031, PR China.
authors.forename: Yong-hua
authors.initials: YH
authors.lastname: Xu
authors.affiliation: Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA, 02215, USA.|Department of Medicine, Harvard Medical School, 25 Shattuck Street, Boston, MA, 02115, USA.
authors.forename: Jiu-Song
authors.initials: JS
authors.lastname: Sun
authors.affiliation: Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, P.R. China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Zheng
authors.affiliation: Howard Hughes Medical Institute; Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Chunyao
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Song
authors.affiliation: Department of General Surgery, Shanghai Jiaotong University Affiliated Sixth People's Hospital, Shanghai, 200233, P.R. China. zhouyuan201414@163.com.
authors.forename: Zhou
authors.initials: Z
authors.lastname: Yuan
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D024510:Muscle Development / Q000187:drug effects; D018908:Muscle Weakness / Q000453:epidemiology / Q000209:etiology* / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects; D010190:Pancreatic Neoplasms / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D017077:Culture Media, Conditioned; C515497:IGFBP3 protein, human; D018972:Insulin-Like Growth Factor Binding Protein 3