Dysregulated serum response factor triggers formation of hepatocellular carcinoma. Issue 3 (30th January 2015)

• Record Type: Journal Article
• Authors: Ohrnberger, Stefan; Thavamani, Abhishek; Braeuning, Albert; Lipka, Daniel B.; Kirilov, Milen; Geffers, Robert; Authenrieth, Stella E.; Römer, Michael; Zell, Andreas; Bonin, Michael; Schwarz, Michael; Schütz, Günther; Schirmacher, Peter; Plass, Christoph; Longerich, Thomas; Nordheim, Alfred
• Is Part Of: Hepatology. Volume 61:Issue 3(2015:Mar.)
• Page Start: 979
• Page End: 989
• Publication Date: 2015-01-30
• Subjects: Heart -- Diseases -- Nursing -- Periodicals; Lungs -- Diseases -- Nursing -- Periodicals; Intensive care nursing -- Periodicals; Foie -- Maladies -- Périodiques; 616.362
• DOI: 10.1002/hep.27539
• Languages: English
• ISSNs: 0270-9139

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>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 <italic>SRF‐VP16^iHep</italic> mice, which conditionally express constitutively active SRF‐VP16 in hepatocytes, thereby controlling subsets of both Ras/MAPK‐ and Rho/actin‐stimulated target genes. All <italic>SRF‐VP16^iHep</italic> mice develop hyperproliferative liver nodules that progresses to lethal HCC. Some murine (m)HCCs acquire <italic>Ctnnb1</italic> 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 <italic>Igf2</italic>, correlating with CpG hypomethylation at the imprinted <italic>Igf2/H19</italic> locus. <italic>Conclusion: SRF‐VP16^iHep</italic> 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. (H<sc>epatology</sc> 2015;61:979–989)</p> </abstract>