The function of c-Fos in hepatocarcinogenesis

c-Fos, a member of the stress-activated Activator Protein 1 (AP-1) transcription factor family, is expressed in human hepatocellular cancer (HCC). Using genetically engineered mouse models (GEMMs) we show that hepatocyte-specific expression of c-Fos leads to a proliferative, de-differentiated phenotype, whereas hepatocyte-specific deletion of c-Fos protects against diethylnitrosamine (DEN)-induced liver cancer. Furthermore, c-Fos-expressing livers resemble human HCCs based on expression profiles. In the present RNA seq, we intend to analyze the transcriptomic profile of livers at 2 and 4 mo hepatocyte-specific c-Fos expression compared to the corresponding age-matched control mice. Moreover, we analyzed livers of mice with hepatocyte-specific deletion c-Fos at 48h after DEN treatment compared to identically treated control mice. Overall design: The general idea was to analyze the transcriptomic profile of hepatocyte-specific c-Fos over-expressing livers at 2 and 4 mo expression. Hereby, a hepatocyte-specific doxycycline (Dox)-switchable mouse model was (LAP-tTA; col1a1:Tet-O-fosFlag) was generated and c-Fos expression was induced at the age of 3 weeks by removal of doxycycline. Each sample LaptTA-fos-MUT represents an individual hepatocyte-specific c-fos expressing mouse at the indicated time-point and the corresponding identically treated control mouse LaptTA-fos-CO. Moreover, the transcriptomic profile of livers with hepatocyte-specific deletion of c-Fos at 48h after diethylnitrosamine (DEN)-induced liver cancer initiation was analyzed. For hepatocyte-specific knock-out of c-Fos, mice with conditional alleles of c-fos and the Alfp-Cre transgene were used. Control mice only carried the Alfp-Cre transgene. At the age of 8 weeks these mice were injected with 100mg/kg DEN. Each sample AlfpCre-fos-MUT_DEN represents an individual hepatocyte-specific c-fos knock-out mouse 48h after DEN and the identically treated control mouse AlfpCre-fos-CO-Cre+_DEN.

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Bakiri L, Hamacher R, Graña O, Guío-Carrión A, Campos-Olivas R, Martinez L, Dienes HP, Thomsen MK, Hasenfuss SC, Wagner EF