Topic Highlight
Copyright ©The Author(s) 2016.
World J Gastroenterol. Jan 7, 2016; 22(1): 300-325
Published online Jan 7, 2016. doi: 10.3748/wjg.v22.i1.300
Table 1 Hepatitis B virus-related transgenic mice
PreS/S/XEndogenousSurface proteinsUntil 6 mo: no obvious pathology[28]
PreS/S/X (two TGs)Endogenous and mouse metallothionein ISurface proteinsNot determined[29]
PreS/S/XMouse metallothionein I and AlbuminSurface proteinsGround glass[22,30-32,34]
7-9 mo: adenoma
12 mo: HCC
18 mo: HCC (100%)
Genome (2X)EndogenousSurface proteinsNot determined[241]
PreS/S (Knock-in)Mouse p21Surface proteins15-24 mo: HCC [53% (♂KI/+), 72% (♂KI/KI), 0% (♀KI/+ and KI/KI)][37]
PreS/SEndogenousSurface proteinsHCC[33,40]
XHuman α-1-antitrypsinHBx proteinFocal necrosis, hyperplasia nodule (Authors claimed that X is not tumorigenic)[42]
XEndogenousHBx protein4 mo: altered hepatocyte in multifocal area[43,44]
10 mo: tumor nodule
16 mo: tumor (80%)
24 mo: HCC (84%)
XEndogenousHBx protein6 mo: neoplastic nodules (66.6%)[41]
15-18 mo: small neoplastic nodule (100%) and HCC (75%)
X (Knock-in)Mouse p21HBx protein15-24 mo: HCC [60%-64% (♂KI/+ and KI/KI), 43%-46% (♀KI/+ and KI/KI)][37]
XMouse albuminHBx protein12 mo: dysplasia nodule (100%)[45-47]
16 mo: HCC (80%)
20 mo: HCC (90%-100%)
Precore/coreMouse metallothionein IPrecore proteinNot determined[56]
Precore/coreEndogenousCore protein12 mo: no hepatitis or HCC[13,57]
Precore/core (two TGs)EndogenousPrecore and core proteinsNot determined[58]
Genome (2X)EndogenousReplicative intermediates10 mo: no obvious pathology[60]
Genome (1.2X)EndogenousReplicative virus12 mo: no hepatitis or HCC[59,61]
24 mo: no obvious pathology
Genome (1.3X)EndogenousReplicative intermediatesUntil 12 mo: no obvious pathology[62]
Table 2 Mouse models of tumor suppressor genes in hepatocellular carcinoma
Official gene name (common name)Mouse genotypeMouse genetic backgroundPathologyTGS typeFunctionsHuman Chromosome locationExpression in human HCC tumorRef.
Autophagy regulator
Becn1 (Beclin1)Beclin1+/-Mixed (129Sv/J; C57BL/6J)16-18 mo: HCC (8%)Haplo-insufficiencyRegulation of autophagy17q21Down[85-87]
18-22 mo: HCC (26%)
Promote HBV-mediated HCC
Atg5Alb-Cre; Atg5flx/flxC57BL/62 mo: hepatic cell death, proliferation, inflammation, fibrosis and hepatomegalyRecessiveControl autophagosome formation6q21Down[90,91]
12 mo: hepatic adenoma (100%)
Atg7Alb-Cre; Atg7flx/flx;C57BL/64 mo: fatty liverRecessiveControl autophagosome formation3p25.3Up[92-94]
12 mo: hepatic adenoma (90.9%)
Cell cycle regulator
Klf6KLF6+/-C57BL/6Promote DEN-induced HCCHaplo-insufficiencyCell cycle regulation10p15Down[99,101]
Plk4Plk4+/-Mixed (129Sv;CD1)3 mo: mitotic failure in hepatocyte regenerationHaplo-insufficiencyControl of cell cycle progression4q28Down[104,105]
18-24 mo: HCC (30%)
Cdkn1a (p21)p21+/-Mixed (129Sv; C57BL/6)Promote γ-irradiation-induced HCCHaplo-insufficiencyInhibits the activity of CDK2 or CDK46p21.2Up[107,242]
p21-/-C57BL/6Promote HCC in Nemo liver-specific KORecessive[108]
Trp53 (p53)p53+/-C57BL/6Promote HBV-mediated and AFB1-induced HCCHaplo-insufficiencyDNA damage response transcription factor17p13.1Up[111,243]
Aflp-Cre; p53flx/flxC57BL/614-20 mo: HCC (90%)Recessive[112]
Protein ubiquination
Amfr (Gp78)Gp78-/-C57BL/612 mo: fatty liver, inflammation and HCC (24%)RecessiveE3 ubiquitin ligase16q21Down[117]
Park2 (Parkin)Parkin-/-Mixed (129/C57BL6SJL)11-12 mo: hepatocyte proliferation and hepatomegalyRecessiveE3 ubiquitin ligase6q25.2-q27Down[118,122]
16-17 mo: HCC (33%)
22-23 mo: HCC (45%)
Trim24Trim24-/-C57BL/62 mo: hepatic cell death and inflammationRecessiveE3 ubiquitin ligase7q32Up[119,125]
4-6 mo: fatty liver, fibrosis and liver nodule
9-21 mo: HCC (55%)
Genome stability maintenance
Anxa7 (Annexin 7)Anx7+/-C57BL/610 mo: HepatomegalyHaploinsufficiencyCa2+-dependent endocrine secretion10q22.2Up[131,132]
12 mo: HCC (3.6%)
Nbn (Nibrin)Nbn+/-Mixed (129Sv; C57BL/6)23 mo: HCC (8.6%)HaploinsufficiencyDNA repair8q21Up[134,244]
Pinx1PinX1+/-Mixed (129Sv; C57BL/6)9-18 mo: HCC (17.7%)HaploinsufficiencyTelomerase inhibitor8p23Down[136,137]
Sgol1 (Shugoshin 1)Sgo1+/-C57BL/64 mo: hepatocyte DNA damageHaploinsufficiencyProtector of chromosome cohesion and centrosome integrity3p24.3Up[139,140]
12 mo: HCC
Promote AOM-induced HCC
Metabolic function
Acox1 (Acyl-CoA oxidase 1)Aox-/-Mixed (129/Ola; C57BL/6)2-4 mo: fatty liver, inflammation and hepatocyte proliferationRecessivePeroxisomal β-oxidation17q25.1Not determined[144]
10-15 mo: HCC (100%)
BhmtBhmt-/-C57BL/61 mo: fatty liverRecessiveMethionine metabolism5q14.1Down[149,150]
12 mo: HCC (50%)
Nr1h4 (Farnesoid X receptor)Fxr-/-C57BL/6N3 mo: hepatic cell death and proliferationRecessiveTranscriptional regulation of synthesis and transport of bile acids12q23.1Down[155,157]
6-9 mo: fatty liver and inflammation
12 mo: fibrosis and HCC (16.1%)
Gnmt (Glycine N-methyltransferase)Gnmt-/-Mixed (129Sv; C57BL/6)3 mo: fatty liver and fibrosisRecessiveMethionine metabolism6p12Down[148,151]
8 mo: HCC (100%) at 8-mo
Abcb4 (Mdr2)Mdr2-/-129/OlaHsd3 mo: inflammation and fibrosisRecessivePhosphatidylcholine translocase7q21.1Down[156,158]
6-mo: HCC
Hippo signaling pathway
Stk4 (Mst1)Alb-Cre; Mst1/2flx/flxMixed (129Sv; C57BL/6;CD1)1 mo: hepatocyte proliferation and hepatomegalyRecessiveKinase (negative regulator)20q11.2Not determined[165,166]
6 mo: HCC (100%)
Stk3 (Mst2)Alb-Cre; Mst1/2flx/flxMixed (129Sv; C57BL/6;CD1)1 mo: hepatocyte proliferation and hepatomegalyRecessiveKinase (negative regulator)8q22.2Not determined[165,166]
6 mo: HCC (100%)
Nf2 (Neurofibromin 2)Alb-Cre; Nf2flx/flxMixed (FVB/N; C57BL/6)2 mo: oval cell over-proliferation and hepatomegalyRecessiveNegative regulator22q12.2Not determined[168]
7 mo: HCC (100%)
Jak/Stat signaling pathway
Socs1Socs1+/-C57BL/6Promote DEN-induced HCCHaploinsufficiencyNegative regulator16p13.13Down[174]
Socs3Socs3+/-Mixed (129Sv; C57BL/6)Promote DEN-induced HCCHaploinsufficiencyNegative regulator17q25.3Down[176]
Ptpn11 (Shp2)Alb-Cre; Shp2flx/flxC57BL/62-3 mo: inflammation and hepatic cell deathRecessiveProtein tyrosine phosphatase (negative regulator)12q24Down[179]
8-mo: hyperplasia nodule
12-18 mo: hepatic adenoma (68%)
Promote DEN-induced HCC
PtproPtpro-/-C57BL/6Promote DEN-induced HCCRecessiveReceptor-like protein tyrosine phosphatase (negative regulator)12p13.3Down[181,182]
NF-κB signaling pathway
Cyld (Cylindromatosis)Alfp-Cre; Cyldflx/flxC57BL/6 congenic1-2 mo: hepatic cell death, inflammation and fibrosisRecessiveDeubiquitinase (negative regulator)16q12.1Down[188,189]
12 mo: HCC
Lgals3 (Galectin-3)Gal3-/-CD16 mo: fatty liver and inflammationRecessiveRegulation of inflammatory responses14q22.3Up[192-194]
15 mo: fibrosis and liver nodule
25 mo: HCC (100%)
Ikbkg (Nemo)Alfp-Cre; Nemoflx/flxC57BL/62 mo: fatty liver, inflammation, hepatic cell death and proliferationRecessiveActivation of NF-κBXq28Down[195,196]
6 mo: dysplastic nodule
12 mo: HCC (100%)
Map3k7 (Tak1)Alfp-Cre; Tak1flx/flxMixed (129/Ola; C57BL/6)1-2 mo: hepatic cell death, proliferation and fibrosisRecessiveSerine/threonine protein kinase (Activation of the NF-κB)6q15Not determined[197]
4-8 mo: HCC (88%)
PI3K/Akt/mTOR signaling pathway
Stk11 (Lkb1)Lkb1+/-Mixed (129Sv; C57BL/6)10-12 mo: Hepatic hyperplasia, HCC (29%)RecessiveSerine/threonine kinase (activator of AMPK)19p13.3Down[201,202]
14 mo: HCC (75%)
PtenAlb-Cre; Ptenflx/flxC57BL/62-3 mo: fatty liver and hepatomegalyRecessivePhospholipid phosphatase (negative regulator)10q23.3Down[204,208]
9-10 mo: inflammation and fibrosis
17-18 mo: HCC (66%)
Raptor (Regulatory associated protein of mTOR, complex 1)Alb-Cre; Raptorflx/flxC57BL/62 mo: hepatic cell death, inflammation and fibrosisRecessiveActivation of mTOR activity17q25.3Up[209,210]
Promote DEN-induced HCC
TGF-β signaling pathway
Sptbn1 (β-spectrin)Elf+/-Mixed (129SvEv; Black Swiss)15 mo: Fatty liver, HCC (40%)HaploinsufficiencyPropagation of TGF-β signal2p21Down[214]
Tgfb1 (TGF-β1)Tgf-β1+/-C57BL/6NCrPromote DEN-induced HCCHaploinsufficiencyGrowth factor19q13.1Up[216,245]
Tgfbr2 (TGF-β type II receptor)TβR-II+/-Mixed (129Sv; C57BL/6)Promote DEN-induced HCCRecessiveTGF-β receptor3p22Down[217,218]
Wnt signaling pathway
ApcAdenovirus-Cre; Apcflx/flxC57BL/6N9 mo: HCC (67%)RecessiveAntagonist5q21Down[222,223]
Mir122Mir122a-/-C57BL/63 mo: fatty liver, inflammation and fibrosisRecessivePost-transcriptional regulation of gene expression18q21.31Down[227,228]
11 mo: HCC (75%)
Mir140Mir140-/-C57BL/6Promote DEN-induced HCCRecessivePost-transcriptional regulation of gene expression16q22.1Not determined[229]
Ncoa5 (Nuclear receptor coactivator 5)Ncoa5+/-Mixed (129Sv; C57BL/6)6 mo: fatty liverHaploinsufficiencyEstrogen receptor coactivator20q13.12Down[231]
10 mo: inflammation and fibrosis
10-18 mo: HCC (94%)
Prkar1aPrkar1a+/-Mixed (129Sv/J; C57BL/6)9-19 mo: HCC (29.4%)HaploinsufficiencyRegulation of the serine/ threonine kinase activity17q24.2Up[233,246]
Ncoa2 (Nuclear receptor coactivator 2)Ncoa2-/-Mixed (129Sv/J; C57BL/6)Promote DEN-induced HCCRecessiveTranscriptional coactivator8q13.3Down[235]
Nfe2l1 (Nuclear factor, erythroid 2-like 1)Alb-Cre; Nrf1flx/flxMixed (129Sv; C57BL/6)1-2 mo: fatty liver, necrosis and inflammationRecessiveTranscription factor17q21.3Not determined[238]
6 mo: fibrosis
12 mo: HCC (100%)