title: Dysregulated serum response factor triggers formation of hepatocellular carcinoma.
abstract: The ubiquitously expressed transcriptional regulator serum response factor (SRF) is controlled by both Ras/MAPK (mitogen-activated protein kinase) and Rho/actin signaling pathways, which are frequently activated in hepatocellular carcinoma (HCC). We generated SRF-VP16iHep mice, which conditionally express constitutively active SRF-VP16 in hepatocytes, thereby controlling subsets of both Ras/MAPK- and Rho/actin-stimulated target genes. All SRF-VP16iHep mice develop hyperproliferative liver nodules that progresses to lethal HCC. Some murine (m)HCCs acquire Ctnnb1 mutations equivalent to those in human (h)HCC. The resulting transcript signatures mirror those of a distinct subgroup of hHCCs, with shared activation of oncofetal genes including Igf2, correlating with CpG hypomethylation at the imprinted Igf2/H19 locus.
  
  
  CONCLUSIONS
  SRF-VP16iHep mHCC reveal convergent Ras/MAPK and Rho/actin signaling as a highly oncogenic driver mechanism for hepatocarcinogenesis. This suggests simultaneous inhibition of Ras/MAPK and Rho/actin signaling as a treatment strategy in hHCC therapy.
authors.affiliation: Department for Molecular Biology, Interfaculty Institute of Cell Biology, Tuebingen University, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Ohrnberger
authors.forename: Abhishek
authors.initials: A
authors.lastname: Thavamani
authors.forename: Albert
authors.initials: A
authors.lastname: Braeuning
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Lipka
authors.forename: Milen
authors.initials: M
authors.lastname: Kirilov
authors.forename: Robert
authors.initials: R
authors.lastname: Geffers
authors.forename: Stella E
authors.initials: SE
authors.lastname: Autenrieth
authors.forename: Stella E
authors.initials: SE
authors.lastname: Authenrieth
authors.forename: Michael
authors.initials: M
authors.lastname: Römer
authors.forename: Andreas
authors.initials: A
authors.lastname: Zell
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.forename: Michael
authors.initials: M
authors.lastname: Schwarz
authors.forename: Günther
authors.initials: G
authors.lastname: Schütz
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.forename: Christoph
authors.initials: C
authors.lastname: Plass
authors.forename: Thomas
authors.initials: T
authors.lastname: Longerich
authors.forename: Alfred
authors.initials: A
authors.lastname: Nordheim
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D018899:CpG Islands; D019175:DNA Methylation; D020869:Gene Expression Profiling; D022781:Hepatocytes / Q000473:pathology; D017405:Herpes Simplex Virus Protein Vmw65 / Q000235:genetics; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics; D008114:Liver Neoplasms, Experimental / Q000209:etiology*; D008214:Lymphocytes / Q000473:pathology; D051379:Mice; D009154:Mutation; D026362:Serum Response Factor / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics
chemical_list: C495267:CTNNB1 protein, mouse; D017405:Herpes Simplex Virus Protein Vmw65; D026362:Serum Response Factor; D051176:beta Catenin; D007335:Insulin-Like Growth Factor II