Premium
Dysregulated serum response factor triggers formation of hepatocellular carcinoma
Author(s) -
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
Publication year - 2015
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1002/hep.27539
Subject(s) - hepatocellular carcinoma , medicine , cancer research , oncology
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‐VP16 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 SRF‐VP16 iHep 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‐VP16 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. (H epatology 2015;61:979–989)