Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors

Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using (SB) transposon insertional mutagenesis in mice treated to induce...

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Published in:Cancer research (Chicago, Ill.) Ill.), 2017-12, Vol.77 (23), p.6576-6588
Main Authors: Tschida, Barbara R, Temiz, Nuri A, Kuka, Timothy P, Lee, Lindsey A, Riordan, Jesse D, Tierrablanca, Carlos A, Hullsiek, Robert, Wagner, Sandra, Hudson, Wendy A, Linden, Michael A, Amin, Khalid, Beckmann, Pauline J, Heuer, Rachel A, Sarver, Aaron L, Yang, Ju Dong, Roberts, Lewis R, Nadeau, Joseph H, Dupuy, Adam J, Keng, Vincent W, Largaespada, David A
Format: Article
Language:English
Subjects:
Acetyltransferase
Animals
Biological evolution
Carcinoma, Hepatocellular - genetics
Carcinoma, Hepatocellular - pathology
Cell Transformation, Neoplastic - genetics
Cyclic AMP
Cyclic AMP-Dependent Protein Kinases - genetics
Cyclic AMP-Dependent Protein Kinases - metabolism
DNA Transposable Elements - genetics
Epidemics
Evolution & development
Fatty liver
Fatty Liver - genetics
Fatty Liver - pathology
Female
Genetic screening
Health risks
Hepatocellular carcinoma
Humans
Inflammation
Insertional mutagenesis
Kinases
Liver
Liver - pathology
Liver cancer
Liver diseases
Liver Neoplasms - genetics
Liver Neoplasms - pathology
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Mutagenesis
Mutagenesis - genetics
Mutagenesis, Insertional - genetics
N-Acetyltransferase
N-Terminal Acetyltransferase E - biosynthesis
Obesity
Protein kinase A
Risk factors
Rodents
Signal transduction
Signal Transduction - genetics
Steatosis
Transposases - genetics
Tumorigenesis
Tumors
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Summary:Hepatic steatosis is a strong risk factor for the development of hepatocellular carcinoma (HCC), yet little is known about the molecular pathology associated with this factor. In this study, we performed a forward genetic screen using (SB) transposon insertional mutagenesis in mice treated to induce hepatic steatosis and compared the results to human HCC data. In humans, we determined that steatosis increased the proportion of female HCC patients, a pattern also reflected in mice. Our genetic screen identified 203 candidate steatosis-associated HCC genes, many of which are altered in human HCC and are members of established HCC-driving signaling pathways. The protein kinase A/cyclic AMP signaling pathway was altered frequently in mouse and human steatosis-associated HCC. We found that activated PKA expression drove steatosis-specific liver tumorigenesis in a mouse model. Another candidate HCC driver, the -acetyltransferase , which we found to be overexpressed in human steatosis-associated HCC and associated with decreased survival in human HCC, also drove liver tumorigenesis in a steatotic mouse model. This study identifies genes and pathways promoting HCC that may represent novel targets for prevention and treatment in the context of hepatic steatosis, an area of rapidly growing clinical significance. .
ISSN:0008-5472
1538-7445
DOI:10.1158/0008-5472.can-17-2281