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 – MGI References 28993411 – National Library of Medicine/PubMed

Models
Strain	Model Name	Treatment Agent(s)	Organ Affected	Frequency
[not specified]-Gt(ROSA)26Sor^{tm2(sb11)Njen} Speer6-ps1^{Tg(Alb-cre)21Mgn}/? TgTn(sb-T2/Onc)68Dla	Liver - Bile duct cholangiocarcinoma	ethanol choline-deficient	Liver - Bile duct	0
[not specified]-Gt(ROSA)26Sor^{tm2(sb11)Njen} Speer6-ps1^{Tg(Alb-cre)21Mgn}/? TgTn(sb-T2/Onc)68Dla	Liver hepatocellular adenoma	ethanol choline-deficient	Liver	observed
[not specified]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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)26Sor^{tm2(sb11)Njen} Speer6-ps1^{Tg(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)26Sor^{tm2(sb11)Njen} Speer6-ps1^{Tg(Alb-cre)21Mgn}/? TgTn(sb-T2/Onc)68Dla	Liver tumor	ethanol choline-deficient	Liver	65 - 81
[not specified]-Gt(ROSA)26Sor^{tm2(sb11)Njen} Speer6-ps1^{Tg(Alb-cre)21Mgn}/? TgTn(sb-T2/Onc)68Dla	Liver tumor	nitisinone (NTBC)	Liver	40 - 78
[not specified]-Gt(ROSA)26Sor^{tm2(sb11)Njen} TgTn(sb-T2/Onc)68Dla	Liver tumor	ethanol choline-deficient	Liver	22
[not specified]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(sb11)Njen}	Liver tumor	Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53) Sleeping Beauty transposon expressing Prkaca^L206R, Fah, firefly luciferase, and GFP (pT2/GD/Prkaca^L206R) nitisinone (NTBC)	Liver	17 - 43
[not specified]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(sb11)Njen}	Liver tumor	Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53) Sleeping Beauty transposon expressing Prkaca^L206R, Fah, firefly luciferase, and GFP (pT2/GD/Prkaca^L206R) nitisinone (NTBC)	Liver	31
[not specified]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(sb11)Njen}	Liver tumor	Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53) Sleeping Beauty transposon expressing Prkaca^L206R, Fah, firefly luciferase, and GFP (pT2/GD/Prkaca^L206R) ethanol choline-deficient	Liver	52 - 78
[not specified]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(sb11)Njen}	Liver tumor	Sleeping Beauty transposon expressing short hairpin against Trp53 and GFP (pT2/shp53) Sleeping Beauty transposon expressing Prkaca^L206R, Fah, firefly luciferase, and GFP (pT2/GD/Prkaca^L206R) ethanol choline-deficient	Liver	20
[not specified]-Fah^tm1Mgo Gt(ROSA)26Sor^{tm2(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

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