title: Cyr61/CCN1 signaling is critical for epithelial-mesenchymal transition and stemness and promotes pancreatic carcinogenesis.
abstract: BACKGROUND
  Despite recent advances in outlining the mechanisms involved in pancreatic carcinogenesis, precise molecular pathways and cellular lineage specification remains incompletely understood.
  
  
  RESULTS
  We show here that Cyr61/CCN1 play a critical role in pancreatic carcinogenesis through the induction of EMT and stemness. Cyr61 mRNA and protein were detected in the early precursor lesions and their expression intensified with disease progression. Cyr61/CCN1 expression was also detected in different pancreatic cancer cell lines. The aggressive cell lines, in which the expressions of mesenchymal/stem cell molecular markers are predominant; exhibit more Cyr61/CCN1 expression. Cyr61 expression is exorbitantly higher in cancer stem/tumor initiating Panc-1-side-population (SP) cells. Upon Cyr61/CCN1 silencing, the aggressive behaviors are reduced by obliterating interlinking pathobiological events such as reversing the EMT, blocking the expression of stem-cell-like traits and inhibiting migration. In contrast, addition of Cyr61 protein in culture medium augments EMT and stemness features in relatively less aggressive BxPC3 pancreatic cancer cells. Using a xenograft model we demonstrated that cyr61/CCN1 silencing in Panc-1-SP cells reverses the stemness features and tumor initiating potency of these cells. Moreover, our results imply a miRNA-based mechanism for the regulation of aggressive behaviors of pancreatic cancer cells by Cyr61/CCN1.
  
  
  CONCLUSIONS
  In conclusion, the discovery of the involvement of Cyr61/CCN1 in pancreatic carcinogenesis may represent an important marker for PDAC and suggests Cyr61/CCN1 can be a potential cancer therapeutic target.
authors.affiliation: Cancer Research Unit, Veterans Affairs Medical Center, Kansas City, MO, USA.
authors.forename: Inamul
authors.initials: I
authors.lastname: Haque
authors.forename: Smita
authors.initials: S
authors.lastname: Mehta
authors.forename: Monami
authors.initials: M
authors.lastname: Majumder
authors.forename: Kakali
authors.initials: K
authors.lastname: Dhar
authors.forename: Archana
authors.initials: A
authors.lastname: De
authors.forename: Douglas
authors.initials: D
authors.lastname: McGregor
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Van Veldhuizen
authors.forename: Sushanta K
authors.initials: SK
authors.lastname: Banerjee
authors.forename: Snigdha
authors.initials: S
authors.lastname: Banerjee
mesh_terms: D000230:Adenocarcinoma / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D014408:Biomarkers, Tumor; D002465:Cell Movement; D055515:Cysteine-Rich Protein 61 / Q000096:biosynthesis* / Q000235:genetics; D058750:Epithelial-Mesenchymal Transition; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000473:pathology; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication; D034622:RNA Interference; D058985:Side-Population Cells; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D055515:Cysteine-Rich Protein 61; D035683:MicroRNAs