KEGG   PATHWAY: mcal05225
Entry
mcal05225                   Pathway                                
Name
Hepatocellular carcinoma - Mus caroli (Ryukyu mouse)
Description
Hepatocellular carcinoma (HCC) is a major type of primary liver cancer and one of the rare human neoplasms etiologically linked to viral factors. It has been shown that, after HBV/HCV infection and alcohol or aflatoxin B1 exposure, genetic and epigenetic changes occur. The recurrent mutated genes were found to be highly enriched in multiple key driver signaling processes, including telomere maintenance, TP53, cell cycle regulation, the Wnt/beta-catenin pathway (CTNNB1 and AXIN1), the phosphatidylinositol-3 kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway. Recent studies using whole-exome sequencing have revealed recurrent mutations in new driver genes involved in the chromatin remodelling (ARID1A and ARID2) and the oxidative stress (NFE2L2) pathways.
Class
Human Diseases; Cancer: specific types
Pathway map
mcal05225  Hepatocellular carcinoma
mcal05225

Organism
Mus caroli (Ryukyu mouse) [GN:mcal]
Gene
110295684  Tgfa; protransforming growth factor alpha [KO:K08774]
110304228  Egfr; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
110298427  Igf2; insulin-like growth factor II isoform X1 [KO:K13769]
110297825  Igf1r; insulin-like growth factor 1 receptor isoform X2 [KO:K05087] [EC:2.7.10.1]
110290454  Plcg1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
110300336  Plcg2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 isoform X1 [KO:K05859] [EC:3.1.4.11]
110304357  Prkca; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
110297826  Prkcb; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
110297763  Prkcg; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
110286681  Elk1; ETS domain-containing protein Elk-1 [KO:K04375]
110290710  Shc1; SHC-transforming protein 1 isoform X1 [KO:K06279]
110303444  Shc2; SHC-transforming protein 2 [KO:K17447]
110308134  Shc3; SHC-transforming protein 3 [KO:K17448]
110289726  Shc4; SHC-transforming protein 4 [KO:K17449]
110304772  Grb2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
110306968  Sos2; son of sevenless homolog 2 isoform X1 [KO:K03099]
110312423  Sos1; son of sevenless homolog 1 [KO:K03099]
110297313  Hras; GTPase HRas isoform X2 [KO:K02833]
110296194  Kras; GTPase KRas isoform X1 [KO:K07827]
110290873  Nras; GTPase NRas [KO:K07828]
110287540  Araf; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
110295945  Braf; serine/threonine-protein kinase B-raf isoform X5 [KO:K04365] [EC:2.7.11.1]
110296919  Raf1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
110301502  Map2k1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
110303196  Map2k2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
110297836  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
110311382  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
110290798  Pik3ca; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
110292183  Pik3cd; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
110301355  Pik3cb; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
110308009  Pik3r1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
110299855  Pik3r2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
110292624  phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
110285202  Pten; phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
110297609  Akt2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
110294471  Akt3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
110307022  Akt1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
110292680  Mtor; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
110285417  Rps6kb2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
110304919  Rps6kb1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
110285481  Bad; bcl2-associated agonist of cell death isoform X1 [KO:K02158]
110288823  Bcl2l1; bcl-2-like protein 1 [KO:K04570]
110310583  Myc; myc proto-oncogene protein [KO:K04377]
110309179  Rb1; retinoblastoma-associated protein [KO:K06618]
110289983  E2f1; transcription factor E2F1 [KO:K17454]
110293508  E2f2; transcription factor E2F2 isoform X1 [KO:K09389]
110308034  E2f3; transcription factor E2F3 isoform X1 [KO:K06620]
110307847  Tert; telomerase reverse transcriptase isoform X2 [KO:K11126] [EC:2.7.7.49]
110305297  Tp53; cellular tumor antigen p53 isoform X1 [KO:K04451]
110283679  Cdkn1a; cyclin-dependent kinase inhibitor 1 [KO:K06625]
110303739  Gadd45b; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
110296344  Gadd45a; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
110308191  Gadd45g; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
110297919  Bax; apoptosis regulator BAX isoform X1 [KO:K02159]
110283660  Bak1; bcl-2 homologous antagonist/killer [KO:K14021]
110290093  Ddb2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
110308520  Polk; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
110293174  cyclin-dependent kinase inhibitor 2A [KO:K06621]
110303132  Cdk4; cyclin-dependent kinase 4 isoform X1 [KO:K02089] [EC:2.7.11.22]
110294345  Cdk6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
110298189  Ccnd1; G1/S-specific cyclin-D1 isoform X1 [KO:K04503]
110298438  Tgfb1; transforming growth factor beta-1 proprotein [KO:K13375]
110292955  Tgfb2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
110306834  Tgfb3; transforming growth factor beta-3 proprotein [KO:K13377]
110292408  Tgfbr1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
110301725  Tgfbr2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
110284497  Smad2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
110301346  Smad3; mothers against decapentaplegic homolog 3 [KO:K23605]
110284933  Smad4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
110310964  Wnt1; proto-oncogene Wnt-1 [KO:K03209]
110296313  Wnt2; protein Wnt-2 [KO:K00182]
110291476  Wnt2b; protein Wnt-2b [KO:K00182]
110305853  Wnt3a; protein Wnt-3a [KO:K00312]
110304911  Wnt3; proto-oncogene Wnt-3 [KO:K00312]
110293218  Wnt4; protein Wnt-4 isoform X1 [KO:K00408]
110295760  Wnt5b; protein Wnt-5b [KO:K00444]
110309360  Wnt5a; protein Wnt-5a isoform X1 [KO:K00444]
110299810  Wnt6; protein Wnt-6 [KO:K00445]
110310689  Wnt7b; protein Wnt-7b isoform X1 [KO:K00572]
110296669  Wnt7a; protein Wnt-7a isoform X1 [KO:K00572]
110285759  Wnt8b; protein Wnt-8b [KO:K00714]
110285093  Wnt8a; protein Wnt-8a [KO:K00714]
110306039  Wnt9a; protein Wnt-9a [KO:K01064]
110305968  Wnt9b; protein Wnt-9b [KO:K01064]
110310912  Wnt10b; protein Wnt-10b isoform X1 [KO:K01357]
110300434  Wnt10a; protein Wnt-10a [KO:K01357]
110298907  Wnt11; protein Wnt-11 isoform X1 [KO:K01384]
110296883  Wnt16; protein Wnt-16 [KO:K01558]
110301431  Fzd7; frizzled-7 [KO:K02432]
110294363  Fzd1; frizzled-1 [KO:K02432]
110305336  Fzd2; frizzled-2 [KO:K02235]
110309352  Fzd3; frizzled-3 [KO:K02329]
110298417  Fzd4; frizzled-4 [KO:K02354]
110294401  Fzd5; frizzled-5 [KO:K02375]
110284745  Fzd8; frizzled-8 [KO:K02375]
110310580  Fzd6; frizzled-6 [KO:K02376]
110295350  Fzd9; frizzled-9 [KO:K02842]
110295197  Fzd10; frizzled-10 [KO:K02842]
110286073  Lrp5; low-density lipoprotein receptor-related protein 5 [KO:K03068]
110297114  Lrp6; low-density lipoprotein receptor-related protein 6 [KO:K03068]
110292264  Dvl1; segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353]
110304161  Dvl2; segment polarity protein dishevelled homolog DVL-2 [KO:K02353]
110311604  Dvl3; segment polarity protein dishevelled homolog DVL-3 [KO:K02353]
110299413  proto-oncogene FRAT1-like [KO:K03069]
110285589  Frat1; proto-oncogene FRAT1 [KO:K03069]
110285818  Frat2; GSK-3-binding protein FRAT2 [KO:K03096]
110311365  Gsk3b; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
110284040  Axin1; axin-1 isoform X1 [KO:K02157]
110304669  Axin2; axin-2 [KO:K04385]
110284455  Apc; adenomatous polyposis coli protein isoform X4 [KO:K02085]
110303367  Apc2; adenomatous polyposis coli protein 2 isoform X2 [KO:K02085]
110301052  Ctnnb1; catenin beta-1 [KO:K02105]
110284498  Csnk1a1; casein kinase I isoform X1 [KO:K08957] [EC:2.7.11.1]
110304948  Tcf7; transcription factor 7 isoform X2 [KO:K02620]
110296038  Tcf7l1; transcription factor 7-like 1 isoform X2 [KO:K04490]
110285273  Tcf7l2; transcription factor 7-like 2 isoform X5 [KO:K04491]
110290892  Lef1; lymphoid enhancer-binding factor 1 isoform X1 [KO:K04492]
110301406  Keap1; kelch-like ECH-associated protein 1 [KO:K10456]
110289412  Nfe2l2; nuclear factor erythroid 2-related factor 2 isoform X1 [KO:K05638]
110300233  Hmox1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
110300906  Nqo1; NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
110296158  Mgst1; microsomal glutathione S-transferase 1 isoform X1 [KO:K00799] [EC:2.5.1.18]
110285527  Gsto1; glutathione S-transferase omega-1 [KO:K00799] [EC:2.5.1.18]
110285529  glutathione S-transferase omega-2 [KO:K00799] [EC:2.5.1.18]
110290673  Gstm3; glutathione S-transferase Mu 3 [KO:K00799] [EC:2.5.1.18]
110291409  glutathione S-transferase Mu 2-like isoform X1 [KO:K00799] [EC:2.5.1.18]
110291410  glutathione S-transferase Mu 7 [KO:K00799] [EC:2.5.1.18]
110291412  glutathione S-transferase Mu 6 isoform X1 [KO:K00799] [EC:2.5.1.18]
110291414  LOW QUALITY PROTEIN: glutathione S-transferase Mu 3-like [KO:K00799] [EC:2.5.1.18]
110291415  glutathione S-transferase Mu 2 [KO:K00799] [EC:2.5.1.18]
110291416  glutathione S-transferase Mu 1 [KO:K00799] [EC:2.5.1.18]
110291417  glutathione S-transferase Mu 1 [KO:K00799] [EC:2.5.1.18]
110302042  glutathione S-transferase Mu 1-like isoform X1 [KO:K00799] [EC:2.5.1.18]
110284504  glutathione S-transferase-like [KO:K00799] [EC:2.5.1.18]
110302372  glutathione S-transferase A2-like [KO:K00799] [EC:2.5.1.18]
110291754  Mgst2; microsomal glutathione S-transferase 2 [KO:K00799] [EC:2.5.1.18]
110301652  glutathione S-transferase A4 [KO:K00799] [EC:2.5.1.18]
110301653  glutathione S-transferase A2 [KO:K00799] [EC:2.5.1.18]
110301654  glutathione S-transferase A1-like [KO:K00799] [EC:2.5.1.18]
110294358  Mgst3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
110303140  glutathione S-transferase theta-3 [KO:K00799] [EC:2.5.1.18]
110303152  glutathione S-transferase theta-2 [KO:K00799] [EC:2.5.1.18]
110303153  glutathione S-transferase theta-4 [KO:K00799] [EC:2.5.1.18]
110303154  glutathione S-transferase theta-1 isoform X1 [KO:K00799] [EC:2.5.1.18]
110288966  glutathione S-transferase A1 [KO:K00799] [EC:2.5.1.18]
110285868  glutathione S-transferase P 1 [KO:K23790] [EC:2.5.1.18]
110311240  Txnrd2; thioredoxin reductase 2, mitochondrial [KO:K22182] [EC:1.8.1.9]
110296407  Txnrd3; thioredoxin reductase 3 [KO:K22182] [EC:1.8.1.9]
110303865  Txnrd1; thioredoxin reductase 1, cytoplasmic isoform X3 [KO:K22182] [EC:1.8.1.9]
110294216  Hgf; hepatocyte growth factor isoform X1 [KO:K05460]
110295947  Met; hepatocyte growth factor receptor isoform X2 [KO:K05099] [EC:2.7.10.1]
110300068  Gab1; GRB2-associated-binding protein 1 isoform X4 [KO:K09593]
110304283  Actg1; actin, cytoplasmic 2 [KO:K05692]
110295381  Actb; actin, cytoplasmic 1 [KO:K05692]
110290799  Actl6a; actin-like protein 6A isoform X1 [KO:K11340]
110294721  Actl6b; actin-like protein 6B isoform X1 [KO:K11652]
110310627  Smarcd1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 [KO:K11650]
110305365  Smarcd2; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 [KO:K11650]
110295507  Smarcd3; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 isoform X1 [KO:K11650]
110312639  Phf10; PHD finger protein 10 isoform X1 [KO:K22197]
110299172  Dpf1; zinc finger protein neuro-d4 isoform X1 [KO:K22198]
110306735  Dpf3; zinc finger protein DPF3 isoform X1 [KO:K22198]
110292112  Arid1a; AT-rich interactive domain-containing protein 1A isoform X2 [KO:K11653]
110312433  Arid1b; AT-rich interactive domain-containing protein 1B isoform X2 [KO:K11653]
110304842  Smarce1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 [KO:K11651]
110303003  Smarcb1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 isoform X1 [KO:K11648]
110304000  Smarcc2; SWI/SNF complex subunit SMARCC2 isoform X1 [KO:K11649]
110301031  Smarcc1; SWI/SNF complex subunit SMARCC1 [KO:K11649]
110285425  Smarca2; probable global transcription activator SNF2L2 isoform X1 [KO:K11647] [EC:5.6.2.-]
110301564  Smarca4; transcription activator BRG1 isoform X4 [KO:K11647] [EC:5.6.2.-]
110310205  Arid2; AT-rich interactive domain-containing protein 2 isoform X1 [KO:K11765]
110309104  Pbrm1; protein polybromo-1 isoform X8 [KO:K11757]
110299772  Brd7; bromodomain-containing protein 7 isoform X1 [KO:K11723]
Compound
C00027  Hydrogen peroxide
C00039  DNA
C00076  Calcium cation
C00165  Diacylglycerol
C00533  Nitric oxide
C00704  Superoxide
C01245  D-myo-Inositol 1,4,5-trisphosphate
C01471  Acrolein
C05981  Phosphatidylinositol-3,4,5-trisphosphate
C06793  Vinyl chloride
C06800  Aflatoxin B1
C16844  Hydroxyl radical
C21641  Hydroperoxyl radical
C21642  4-Hydroxynonenal
Reference
PMID:20639898
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Whittaker S, Marais R, Zhu AX
  Title
The role of signaling pathways in the development and treatment of hepatocellular carcinoma.
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Oncogene 29:4989-5005 (2010)
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Reference
PMID:26099527
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Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM
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Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.
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Gastroenterology 149:1226-1239.e4 (2015)
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Reference
PMID:17295177
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Genomics and signaling pathways in hepatocellular carcinoma.
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Reference
PMID:16799620
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Dysregulation of growth factor signaling in human hepatocellular carcinoma.
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Oncogene 25:3787-800 (2006)
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PMID:19387255
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Curr Opin Gastroenterol 25:186-94 (2009)
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PMID:21829020
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J Hepatol 60:224-6 (2014)
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PMID:11935086
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PMID:27895396
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Niu ZS, Niu XJ, Wang WH
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Genetic alterations in hepatocellular carcinoma: An update.
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World J Gastroenterol 22:9069-9095 (2016)
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Virchows Arch 440:345-52 (2002)
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PMID:23426905
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Int J Oncol 42:1133-8 (2013)
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PMID:23887712
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High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.
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Nat Commun 4:2218 (2013)
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PMID:22561517
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Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.
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Nat Genet 44:694-8 (2012)
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The complex role of NRF2 in cancer: a genomic view
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Curr Opin Toxicol 1:37-45 (2016)
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PMID:24024136
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The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer.
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Redox Biol 1:45-9 (2013)
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Reference
PMID:21251164
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Taguchi K, Motohashi H, Yamamoto M
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Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution.
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Genes Cells 16:123-40 (2011)
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PMID:20019356
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Toxicol Pathol 38:96-109 (2010)
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PMID:11193292
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Telomerase, immortality and cancer.
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Biotechnol Annu Rev 6:103-40 (2000)
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Reference
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Genome Med 8:69 (2016)
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Reference
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  Title
c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma.
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J Hepatocell Carcinoma 2:29-38 (2015)
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Reference
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Vita M, Henriksson M
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The Myc oncoprotein as a therapeutic target for human cancer.
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Semin Cancer Biol 16:318-30 (2006)
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Reference
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Qu A, Jiang C, Cai Y, Kim JH, Tanaka N, Ward JM, Shah YM, Gonzalez FJ
  Title
Role of Myc in hepatocellular proliferation and hepatocarcinogenesis.
  Journal
J Hepatol 60:331-8 (2014)
DOI:10.1016/j.jhep.2013.09.024
Related
pathway
mcal04010  MAPK signaling pathway
mcal04020  Calcium signaling pathway
mcal04110  Cell cycle
mcal04115  p53 signaling pathway
mcal04151  PI3K-Akt signaling pathway
mcal04310  Wnt signaling pathway
mcal04350  TGF-beta signaling pathway
mcal04932  Non-alcoholic fatty liver disease
mcal04936  Alcoholic liver disease
mcal05160  Hepatitis C
mcal05161  Hepatitis B
KO pathway
ko05225   
LinkDB

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