Dysregulated serum response factor triggers formation of hepatocellular carcinoma
View Publication
Export to EndNoteAbstract:
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.
Projects: C6: Organization and function of the sinusoidal system and the liver lob...
Hepatology
Hepatology 61(3) : 979
1st Mar 2015
Stefan Ohrnberger, Abhishek Thavamani, Albert Braeuning, Daniel B. Lipka, Milen Kirilov, Robert Geffers, Stella E. Authenrieth, Michael Römer, Andreas Zell, Michael Bonin, Michael Schwarz, Günther Schütz, Peter Schirmacher, Christoph Plass, Thomas Longerich, Alfred Nordheim
Authors
Attributions
None
- Created: 14th Dec 2015 at 15:12
- Last updated: 14th Dec 2015 at 15:15
Related items
