title: Nuclear expression of the ubiquitin ligase seven in absentia homolog (SIAH)-1 induces proliferation and migration of liver cancer cells.
abstract: OBJECTIVE
  Differential expression of tumor-relevant proteins based on aberrant proteasomal degradation may contribute to human (hepato)carcinogenesis. Recently, we identified the E3 ubiquitin ligase seven in absentia homolog (SIAH)-1 as frequently dysregulated in human hepatocellular carcinoma (HCC). We therefore systematically analyzed the expression, functional relevance, as well as possible downstream effectors of SIAH-1 in human liver carcinogenesis.
  
  
  METHODS
  SIAH-1 expression was analyzed at the transcript and protein levels in human hepatocarcinogenesis and in HCC cells. Proliferation, apoptosis, and migration of different HCC cell lines were examined after siRNA-mediated inhibition of SIAH-1. In order to identify downstream effectors that mediate SIAH-1 effects, correlative analyses of protein expression profiles were performed.
  
  
  RESULTS
  In HCC tissues both reduction of cytoplasmic SIAH-1 and especially its nuclear accumulation positively correlated with HCC progression. RNA interference revealed that nuclear expression of SIAH-1 predominantly supported HCC cell proliferation and migration while only moderately affecting anti-apoptosis. In de-differentiated human HCCs, nuclear SIAH-1 accumulation significantly correlated with the expression of the transcription factor far-upstream element (FUSE)-binding protein (FBP)-3. In vitro, SIAH-1 positively and indirectly regulated FBP-3 which itself primarily supported HCC cell proliferation. Indeed, high level expression of FBP-3 in human HCCs significantly correlated with reduced overall survival of patients.
  
  
  CONCLUSIONS
  Nuclear accumulation of the E3 ubiquitin ligase SIAH-1 supports different pro-tumorigenic cellular processes associated with tumor growth and tumor cell dissemination in human hepatocarcinogenesis. It promotes HCC cell proliferation by at least partly employing the transcription factor FBP-3. Therefore, interference with SIAH-1 activity represents a promising approach to suppress HCC growth.
authors.affiliation: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors.forename: Antje
authors.initials: A
authors.lastname: Brauckhoff
authors.forename: Mona
authors.initials: M
authors.lastname: Malz
authors.forename: Darjus
authors.initials: D
authors.lastname: Tschaharganeh
authors.forename: Nisar
authors.initials: N
authors.lastname: Malek
authors.forename: Achim
authors.initials: A
authors.lastname: Weber
authors.forename: Marc-Oliver
authors.initials: MO
authors.lastname: Riener
authors.forename: Christopher
authors.initials: C
authors.lastname: Soll
authors.forename: Jana
authors.initials: J
authors.lastname: Samarin
authors.forename: Michaela
authors.initials: M
authors.lastname: Bissinger
authors.forename: Jan
authors.initials: J
authors.lastname: Schmidt
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Volker
authors.initials: V
authors.lastname: Ehemann
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Kai
authors.initials: K
authors.lastname: Breuhahn
mesh_terms: D017209:Apoptosis; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D003593:Cytoplasm / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism*; D000098563:Seven in Absentia Proteins
chemical_list: D004268:DNA-Binding Proteins; C492259:FUBP3 protein, human; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D014157:Transcription Factors; D044767:Ubiquitin-Protein Ligases; D000098563:Seven in Absentia Proteins