Altered transcriptional regulation underlying alcohol induced liver cirrhosis in a porcine hepatocellular carcinoma model

A. Yasmin, D.P. Regan, L.B. Schook, R.C. Gaba, K.M. Schachtschneider
Plant and Animal Genome Conference XXVII, January 12-16 2019, San Diego, CA

Hepatocellular carcinoma (HCC) is the 5th most common cancer globally and 2nd deadliest cancer worldwide. Risk factors for HCC include alcohol induced liver cirrhosis, which prompts hepatic inflammation, cell necrosis, and fibrosis deposition. As 25% of HCC cases are associated with alcohol induced liver cirrhosis worldwide, understanding the effects of the cirrhotic liver microenvironment on HCC tumor biology and therapeutic responses are critical. This study utilized the Oncopig Cancer Model (OCM)—a transgenic pig model that recapitulates human HCC through induced expression of KRASG12D and TP53R167H transgenes—to investigate the molecular mechanisms underlying alcohol induced liver cirrhosis. Oncopigs (n=5) underwent cirrhosis induction via infusion of absolute ethanol and ethiodized oil (1:3 v/v dosed at 0.75 mL/kg) into the hepatic arterial circulation. Eight-weeks post cirrhosis induction, animals were sacrificed and increased hepatic inflammation and fibrosis compared to age-matched control samples (n=5) was observed via pathological assessment. Transcriptional profiling was performed via RNA-seq resulting in the identification of 4,387 differentially expressed genes (DEGs) between OCM cirrhotic and control livers. GO term enrichment analysis identified 239 GO terms significantly enriched for DEGs, including cell proliferation, angiogenesis, extracellular matrix deposition, and oxidation-reduction. OCM cirrhosis recapitulated transcriptional hallmarks of human cirrhosis, including activation of hepatic stellate cells, Ras/MAPK signaling, hypoxia-induced angiogenesis, and inflammation. These results demonstrate the ability of OCM liver cirrhosis to mimic human liver cirrhosis at the transcriptional level, indicating the OCM represents an ideal translational model for investigating the effects of the cirrhotic liver microenvironment on HCC tumor biology and therapeutic response.