Ohrnberger, Stefan and Thavamani, Abhishek and Braeuning, Albert and Lipka, Daniel B and Kirilov, Milen and Geffers, Robert and Authenrieth, Stella E and Römer, Michael and Zell, Andreas and Bonin, Michael and Schwarz, Michael and Schütz, Günther and Schirmacher, Peter and Plass, Christoph and Longerich, Thomas and Nordheim, Alfred

Dysregulated serum response factor triggers formation of hepatocellular carcinoma

Hepatology (2015)

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.

Conclusion: 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.

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BibTeX

@article{Ohrnberger2014,
  author = {Ohrnberger, Stefan and Thavamani, Abhishek and Braeuning, Albert
	and Lipka, Daniel B and Kirilov, Milen and Geffers, Robert and Authenrieth,
	Stella E and R\"omer, Michael and Zell, Andreas and Bonin, Michael
	and Schwarz, Michael and Sch\"{u}tz, G\"{u}nther and Schirmacher,
	Peter and Plass, Christoph and Longerich, Thomas and Nordheim, Alfred},
  title = {{Dysregulated serum response factor triggers formation of hepatocellular carcinoma}},
  journal = {Hepatology},
  year = {2015},
  month = mar,
  doi = {10.1002/hep.27539},
  issn = {1527-3350},
  pmid = {25266280},
  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 \emph{SRF-VP16\textsuperscript{iHep}} mice,
    which conditionally express constitutively active SRF-VP16 in hepatocytes,
    thereby controlling subsets of both Ras/MAPK- and Rho/actin-stimulated
    target genes. All \emph{SRF-VP16\textsuperscript{iHep}} mice develop hyperproliferative liver nodules
    that progresses to lethal HCC. Some murine (m)HCCs acquire \emph{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 \emph{Igf2}, correlating with CpG hypomethylation at the
    imprinted \emph{Igf2/H19} locus.

    \emph{Conclusion:}
    \emph{SRF-VP16\textsuperscript{iHep}} 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.},
  url = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365683/},
  pdf = {http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4365683/pdf/hep0061-0979.pdf},
}