Journal article
Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors
Cancer research (Chicago, Ill.), Vol.77(23), pp.6576-6588
12/01/2017
DOI: 10.1158/0008-5472.CAN-17-2281
PMCID: PMC5712258
PMID: 28993411
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
(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.
.
Details
- Title: Subtitle
- Sleeping Beauty Insertional Mutagenesis in Mice Identifies Drivers of Steatosis-Associated Hepatic Tumors
- Creators
- Barbara R Tschida - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaNuri A Temiz - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaTimothy P Kuka - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaLindsey A Lee - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaJesse D Riordan - Pacific Northwest Research Institute, Seattle, WashingtonCarlos A Tierrablanca - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaRobert Hullsiek - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaSandra Wagner - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaWendy A Hudson - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaMichael A Linden - Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MinnesotaKhalid Amin - Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MinnesotaPauline J Beckmann - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaRachel A Heuer - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaAaron L Sarver - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, MinnesotaJu Dong Yang - Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MinnesotaLewis R Roberts - Division of Gastroenterology and Hepatology, Mayo Clinic College of Medicine, Rochester, MinnesotaJoseph H Nadeau - Pacific Northwest Research Institute, Seattle, WashingtonAdam J Dupuy - Department of Anatomy and Cell Biology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IowaVincent W Keng - Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong KongDavid A Largaespada - Department of Pediatrics, Masonic Cancer Center and Center for Genome Engineering, University of Minnesota, Minneapolis, Minnesota. larga002@umn.edu vincent.keng@polyu.edu.hk
- Resource Type
- Journal article
- Publication Details
- Cancer research (Chicago, Ill.), Vol.77(23), pp.6576-6588
- Publisher
- United States
- DOI
- 10.1158/0008-5472.CAN-17-2281
- PMID
- 28993411
- PMCID
- PMC5712258
- ISSN
- 0008-5472
- eISSN
- 1538-7445
- Grant note
- F32 DK109651 / NIDDK NIH HHS T32 AI083196 / NIAID NIH HHS R50 CA211249 / NCI NIH HHS R01 CA132962 / NCI NIH HHS P30 CA086862 / NCI NIH HHS R01 CA113636 / NCI NIH HHS
- Language
- English
- Date published
- 12/01/2017
- Academic Unit
- Anatomy and Cell Biology; Pathology
- Record Identifier
- 9984025410802771
Metrics
18 Record Views