Reference SummaryTschida BR, Cancer Res 2017 Dec 1;77(23):6576-6588

Title

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

Authors

Tschida BR; Temiz NA; Kuka TP; Lee LA; Riordan JD; Tierrablanca CA; Hullsiek R; Wagner S; Hudson WA; Linden MA; Amin K; Beckmann PJ; Heuer RA; Sarver AL; Yang JD; Roberts LR; Nadeau JH; Dupuy AJ; Keng VW; Largaespada DA

Journal

Cancer Res

Volume

77

Issue

23

Year

2017

Pages

6576-6588

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. (c)2017 AACR.

Links

J:252310 – Mouse Genome Informatics
28993411 – National Library of Medicine/PubMed

Models

Strain Model Name Treatment Agent(s) Organ Affected Frequency Model Details
[not specified]-Gt(ROSA)26Sortm2(sb11)Njen Speer6-ps1Tg(Alb-cre)21Mgn/? TgTn(sb-T2/Onc)68Dla Liver - Bile duct cholangiocarcinoma
  • ethanol
  • choline-deficient
Liver - Bile duct

0

[not specified]-Gt(ROSA)26Sortm2(sb11)Njen Speer6-ps1Tg(Alb-cre)21Mgn/? TgTn(sb-T2/Onc)68Dla Liver hepatocellular adenoma
  • ethanol
  • choline-deficient
Liver

observed

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver hepatocellular adenoma
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • nitisinone (NTBC)
  • Sleeping Beauty transposon expressing Fah, firefly luciferase, and GFP (pkT2/GD-GFP)
Liver

7 - 14

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver hepatocellular adenoma
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • ethanol
  • choline-deficient
  • Sleeping Beauty transposon expressing Fah, firefly luciferase, and GFP (pkT2/GD-GFP)
Liver

30

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver hepatocellular adenoma
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • ethanol
  • choline-deficient
  • Sleeping Beauty transposon expressing Fah, firefly luciferase, and GFP (pkT2/GD-GFP)
Liver

12.5

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver hepatocellular adenoma
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • ethanol
  • choline-deficient
  • Sleeping Beauty transposon expressing Fah, firefly luciferase, and GFP (pkT2/GD-GFP)
Liver

22

[not specified]-Gt(ROSA)26Sortm2(sb11)Njen Speer6-ps1Tg(Alb-cre)21Mgn/? TgTn(sb-T2/Onc)68Dla Liver hepatocellular carcinoma
  • ethanol
  • choline-deficient
Liver

observed

C57BL/6J Liver hepatocellular carcinoma
  • high saturated fat, high sucrose
Liver

observed

[not specified]-Gt(ROSA)26Sortm2(sb11)Njen Speer6-ps1Tg(Alb-cre)21Mgn/? TgTn(sb-T2/Onc)68Dla Liver tumor
  • ethanol
  • choline-deficient
Liver

65 - 81

[not specified]-Gt(ROSA)26Sortm2(sb11)Njen Speer6-ps1Tg(Alb-cre)21Mgn/? TgTn(sb-T2/Onc)68Dla Liver tumor
  • nitisinone (NTBC)
Liver

40 - 78

[not specified]-Gt(ROSA)26Sortm2(sb11)Njen TgTn(sb-T2/Onc)68Dla Liver tumor
  • ethanol
  • choline-deficient
Liver

22

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • Sleeping Beauty transposon expressing Nat10, Fah, firefly luciferase, and GFP (pT2/GD-Nat10)
  • nitisinone (NTBC)
Liver

50 - 91

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • Sleeping Beauty transposon expressing Nat10, Fah, firefly luciferase, and GFP (pT2/GD-Nat10)
  • nitisinone (NTBC)
Liver

68

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • Sleeping Beauty transposon expressing Nat10, Fah, firefly luciferase, and GFP (pT2/GD-Nat10)
  • ethanol
  • choline-deficient
Liver

92

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • Sleeping Beauty transposon expressing Nat10, Fah, firefly luciferase, and GFP (pT2/GD-Nat10)
  • ethanol
  • choline-deficient
Liver

50

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • Sleeping Beauty transposon expressing Nat10, Fah, firefly luciferase, and GFP (pT2/GD-Nat10)
  • ethanol
  • choline-deficient
Liver

71

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • Sleeping Beauty transposon expressing PrkacaL206R, Fah, firefly luciferase, and GFP (pT2/GD/PrkacaL206R)
  • nitisinone (NTBC)
Liver

17 - 43

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • Sleeping Beauty transposon expressing PrkacaL206R, Fah, firefly luciferase, and GFP (pT2/GD/PrkacaL206R)
  • nitisinone (NTBC)
Liver

31

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • Sleeping Beauty transposon expressing PrkacaL206R, Fah, firefly luciferase, and GFP (pT2/GD/PrkacaL206R)
  • ethanol
  • choline-deficient
Liver

52 - 78

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • Sleeping Beauty transposon expressing PrkacaL206R, Fah, firefly luciferase, and GFP (pT2/GD/PrkacaL206R)
  • ethanol
  • choline-deficient
Liver

20

[not specified]-Fahtm1Mgo Gt(ROSA)26Sortm2(sb11)Njen Liver tumor
  • Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53)
  • nitisinone (NTBC)
  • Sleeping Beauty transposon expressing Fah, firefly luciferase, and GFP (pkT2/GD-GFP)
Liver

0