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Supplementary Figures S2-4 from Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors

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posted on 2023-03-31, 00:48 authored by Barbara R. Tschida, Nuri A. Temiz, Timothy P. Kuka, Lindsey A. Lee, Jesse D. Riordan, Carlos A. Tierrablanca, Robert Hullsiek, Sandra Wagner, Wendy A. Hudson, Michael A. Linden, Khalid Amin, Pauline J. Beckmann, Rachel A. Heuer, Aaron L. Sarver, Ju Dong Yang, Lewis R. Roberts, Joseph H. Nadeau, Adam J. Dupuy, Vincent W. Keng, David A. Largaespada

Transposon insertion profiles from animals with tumors sharing 0-2(S2), 3(S3), or >3(S4) insertions

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NIH

American Cancer Society

Hong Kong Polytechnic University

The Shenzhen Science and Technology

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ARTICLE ABSTRACT

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 Sleeping Beauty (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 N-acetyltransferase NAT10, 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. Cancer Res; 77(23); 6576–88. ©2017 AACR.

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    Cancer Research

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    Keywords

    Gastrointestinal CancersLiver cancerPreclinical Models

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