TY - JOUR
T1 - Transcriptional regulation of alcohol induced liver fibrosis in a translational porcine hepatocellular carcinoma model
AU - Yasmin, Alvi
AU - Regan, Daniel P.
AU - Schook, Lawrence B.
AU - Gaba, Ron C.
AU - Schachtschneider, Kyle M.
N1 - Publisher Copyright:
© 2021 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM)
PY - 2021/3
Y1 - 2021/3
N2 - Hepatocellular carcinoma (HCC) is the 5th most common and 2nd deadliest cancer worldwide. HCC risk factors 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 disease, understanding the effects of the cirrhotic liver microenvironment on HCC tumor biology and therapeutic responses are critical. This study utilized the Oncopig Cancer Model—a transgenic pig model that recapitulates human HCC through induced expression of KRASG12D and TP53R167H driver mutations—to investigate the molecular mechanisms underlying alcohol induced liver disease. Oncopigs (n = 5) underwent fibrosis induction via infusion of ethanol and ethiodized oil (1:3 v/v dosed at 0.75 mL/kg) into the hepatic arterial circulation. Eight-weeks post induction, liver tissue samples from fibrotic and age-matched control (n = 5) Oncopigs were collected for histological evaluation and transcriptional profiling. Increased hepatic inflammation and fibrosis was observed in fibrotic Oncopigs via pathological assessment. Transcriptional profiling (RNA-seq) resulted in the identification of 4387 differentially expressed genes between Oncopig fibrotic and control livers. GO term enrichment analysis identified pathway alterations associated with cirrhosis progression in humans, including cell proliferation, angiogenesis, extracellular matrix deposition, and oxidation-reduction. Key alterations include activation of hepatic stellate cells, increased matrix metalloproteinase production, and altered expression of ABC and SLC transporter genes involved in transport of anticancer drugs.These results demonstrate Oncopig liver fibrosis recapitulates transcriptional hallmarks of human cirrhosis, making the Oncopig an ideal model for studying the effects of the cirrhotic liver microenvironment on HCC tumor biology and therapeutic response.
AB - Hepatocellular carcinoma (HCC) is the 5th most common and 2nd deadliest cancer worldwide. HCC risk factors 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 disease, understanding the effects of the cirrhotic liver microenvironment on HCC tumor biology and therapeutic responses are critical. This study utilized the Oncopig Cancer Model—a transgenic pig model that recapitulates human HCC through induced expression of KRASG12D and TP53R167H driver mutations—to investigate the molecular mechanisms underlying alcohol induced liver disease. Oncopigs (n = 5) underwent fibrosis induction via infusion of ethanol and ethiodized oil (1:3 v/v dosed at 0.75 mL/kg) into the hepatic arterial circulation. Eight-weeks post induction, liver tissue samples from fibrotic and age-matched control (n = 5) Oncopigs were collected for histological evaluation and transcriptional profiling. Increased hepatic inflammation and fibrosis was observed in fibrotic Oncopigs via pathological assessment. Transcriptional profiling (RNA-seq) resulted in the identification of 4387 differentially expressed genes between Oncopig fibrotic and control livers. GO term enrichment analysis identified pathway alterations associated with cirrhosis progression in humans, including cell proliferation, angiogenesis, extracellular matrix deposition, and oxidation-reduction. Key alterations include activation of hepatic stellate cells, increased matrix metalloproteinase production, and altered expression of ABC and SLC transporter genes involved in transport of anticancer drugs.These results demonstrate Oncopig liver fibrosis recapitulates transcriptional hallmarks of human cirrhosis, making the Oncopig an ideal model for studying the effects of the cirrhotic liver microenvironment on HCC tumor biology and therapeutic response.
KW - Alcoholic liver disease
KW - Fibrosis
KW - Matrix metalloproteinases
KW - Pig cancer model
KW - Translational research
UR - http://www.scopus.com/inward/record.url?scp=85099483630&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099483630&partnerID=8YFLogxK
U2 - 10.1016/j.biochi.2020.12.022
DO - 10.1016/j.biochi.2020.12.022
M3 - Article
C2 - 33444661
AN - SCOPUS:85099483630
SN - 0300-9084
VL - 182
SP - 73
EP - 84
JO - Biochimie
JF - Biochimie
ER -