title: Overexpression of far upstream element binding proteins: a mechanism regulating proliferation and migration in liver cancer cells.
abstract: Microtubule-dependent effects are partly regulated by factors that coordinate polymer dynamics such as the microtubule-destabilizing protein stathmin (oncoprotein 18). In cancer cells, increased microtubule turnover affects cell morphology and cellular processes that rely on microtubule dynamics such as mitosis and migration. However, the molecular mechanisms deregulating modifiers of microtubule activity in human hepatocarcinogenesis are poorly understood. Based on profiling data of human hepatocellular carcinoma (HCC), we identified far upstream element binding proteins (FBPs) as significantly coregulated with stathmin. Coordinated overexpression of two FBP family members (FBP-1 and FBP-2) in >70% of all analyzed human HCCs significantly correlated with poor patient survival. In vitro, FBP-1 predominantly induced tumor cell proliferation, while FBP-2 primarily supported migration in different HCC cell lines. Surprisingly, reduction of FBP-2 levels was associated with elevated FBP-1 expression, suggesting a regulatory interplay of FBP family members that functionally discriminate between cell division and mobility. Expression of FBP-1 correlated with stathmin expression in HCC tissues and inhibition of FBP-1 but not of FBP-2 drastically reduced stathmin at the transcript and protein levels. In contrast, further overexpression of FBP-1 did not affect stathmin bioavailability. Accordingly, analyzing nuclear and cytoplasmic areas of HCC cells revealed that reduced FBP-1 levels affected cell morphology and were associated with a less malignant phenotype.
  
  
  CONCLUSIONS
  The coordinated activation of FBP-1 and FBP-2 represents a novel and frequent pro-tumorigenic mechanism promoting proliferation (tumor growth) and motility (dissemination) of human liver cancer cells. FBPs promote tumor-relevant functions by at least partly employing the microtubule-destabilizing factor stathmin and represent a new potential target structure for HCC treatment.
authors: Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.
authors: Mona
authors: M
authors: Malz
authors: Achim
authors: A
authors: Weber
authors: Stephan
authors: S
authors: Singer
authors: Vera
authors: V
authors: Riehmer
authors: Michaela
authors: M
authors: Bissinger
authors: Marc-Oliver
authors: MO
authors: Riener
authors: Thomas
authors: T
authors: Longerich
authors: Christopher
authors: C
authors: Soll
authors: Arndt
authors: A
authors: Vogel
authors: Peter
authors: P
authors: Angel
authors: Peter
authors: P
authors: Schirmacher
authors: Kai
authors: K
authors: Breuhahn
mesh_terms: D017209:Apoptosis / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival / Q000502:physiology; D004265:DNA Helicases / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008870:Microtubules / Q000378:metabolism; D016601:RNA-Binding Proteins; D050777:Stathmin / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D016601:RNA-Binding Proteins; D050777:Stathmin; D004265:DNA Helicases