title: Small proline rich protein 2a in benign and malignant liver disease.
abstract: STAT3-driven expression of small proline rich protein 2a (SPRR2a), which acts as an src homology 3 (SH3) domain ligand, induces biliary epithelial cell (BEC) epithelial-mesenchymal transition (EMT), which, in turn, promotes wound healing. SPRR2a also quenches free radicals and protects against oxidative stress and DNA damage in nonneoplastic BEC. Sprr2a-induced EMT also increases local invasiveness of cholangiocarcinomas (CC), but prevents metastases. Understanding SPRR2a regulation of EMT has potential for therapeutic targeting in both benign and malignant liver disease. Molecular mechanisms responsible for SPRR2a-induced EMT were characterized, in vitro, and then evidence for utilization of these pathways was sought in human intrahepatic CC, in vivo, using multiplex labeling and software-assisted morphometric analysis. SPRR2a complexes with ZEB1 and CtBP on the microRNA (miR)-200c/141 promoter resulting in synergic suppression of miR-200c/141 transcription, which is required for maintenance of the BEC epithelial phenotype. SPRR2a induction promotes dephosphorylation and nuclear translocation of the SH3-domain containing protein GRB2 and an SH3-domain ligand in ZEB1 is required for SPRR2a-induced synergic suppression of miR-200c/141. Multiplex protein labeling of CC and morphometric analyses showed: 1) up-regulation of ZEB-1, and 2) down-regulation of CK19 in intrahepatic CC compared to nonneoplastic BEC, consistent with previous CC proteomic studies showing EMT during cholangiocarcinogenesis.
  
  
  CONCLUSIONS
  SPRR2a modulates ZEB-1 signaling by way of miR-200c/141-associated EMT through SH3-domain networks and contributes to benign and malignant BEC wound-healing responses.
authors.affiliation: Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA; Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Mizuguchi
authors.forename: Kumiko
authors.initials: K
authors.lastname: Isse
authors.forename: Susan
authors.initials: S
authors.lastname: Specht
authors.forename: John G
authors.initials: JG
authors.lastname: Lunz
authors.forename: Natasha
authors.initials: N
authors.lastname: Corbitt
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Takizawa
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Demetris
mesh_terms: D000429:Alcohol Oxidoreductases / Q000235:genetics / Q000378:metabolism; D001650:Bile Duct Neoplasms / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism / Q000503:physiopathology*; D045744:Cell Line, Tumor; D018281:Cholangiocarcinoma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D055233:Cornified Envelope Proline-Rich Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008107:Liver Diseases / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000502:physiology; D000071799:Zinc Finger E-box-Binding Homeobox 1; D018909:src Homology Domains / Q000502:physiology
chemical_list: D055233:Cornified Envelope Proline-Rich Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C533895:MIRN141 microRNA, human; C533896:MIRN200 microRNA, human; D035683:MicroRNAs; C101744:SPRR2A protein, human; D014157:Transcription Factors; C486307:ZEB1 protein, human; D000071799:Zinc Finger E-box-Binding Homeobox 1; D000429:Alcohol Oxidoreductases; C096794:C-terminal binding protein