KEGG   PATHWAY: pps05225
Entry
pps05225                    Pathway                                
Name
Hepatocellular carcinoma - Pan paniscus (bonobo)
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
pps05225  Hepatocellular carcinoma
pps05225

Organism
Pan paniscus (bonobo) [GN:pps]
Gene
100973153  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
100974885  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100968468  IGF2; insulin-like growth factor II isoform X2 [KO:K13769]
100981083  IGF1R; insulin-like growth factor 1 receptor isoform X1 [KO:K05087] [EC:2.7.10.1]
100995010  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
100984694  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 isoform X1 [KO:K05859] [EC:3.1.4.11]
100967981  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
100970296  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
100990245  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100991447  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
100993361  SHC1; SHC-transforming protein 1 isoform X3 [KO:K06279]
100974798  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
100972624  SHC3; SHC-transforming protein 3 isoform X2 [KO:K17448]
100991042  SHC4; SHC-transforming protein 4 [KO:K17449]
100993451  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100972953  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100980038  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100993386  HRAS; GTPase HRas isoform X1 [KO:K02833]
100990801  KRAS; GTPase KRas isoform X1 [KO:K07827]
100970465  NRAS; GTPase NRas isoform X2 [KO:K07828]
100990590  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
100971666  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
100972902  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100988422  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100977025  dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
100988437  dual specificity mitogen-activated protein kinase kinase 2-like [KO:K04369] [EC:2.7.12.2]
100979542  MAPK3; mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
100995567  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
100989732  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100990828  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100990108  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100994315  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
100986080  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X2 [KO:K02649]
100969981  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
100983152  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]
100995377  LOW QUALITY PROTEIN: phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN-like [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
100969444  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100991804  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100969217  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100980204  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
100986739  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X2 [KO:K04688] [EC:2.7.11.1]
100995177  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100988665  BAD; bcl2-associated agonist of cell death [KO:K02158]
100979809  BCL2L1; bcl-2-like protein 1 [KO:K04570]
103786410  MYC; myc proto-oncogene protein [KO:K04377]
100973837  RB1; retinoblastoma-associated protein [KO:K06618]
100983073  E2F1; transcription factor E2F1 [KO:K17454]
100984393  E2F2; transcription factor E2F2 isoform X1 [KO:K09389]
100986032  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
117978364  LOW QUALITY PROTEIN: telomerase reverse transcriptase-like [KO:K11126] [EC:2.7.7.49]
100993498  TERT; telomerase reverse transcriptase isoform X1 [KO:K11126] [EC:2.7.7.49]
100973941  TP53; cellular tumor antigen p53 [KO:K04451]
100977916  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
100990548  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
100992917  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
100982764  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
100991820  BAX; apoptosis regulator BAX isoform X3 [KO:K02159]
100983246  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
100992204  bcl-2 homologous antagonist/killer-like [KO:K14021]
100972583  DDB2; DNA damage-binding protein 2 isoform X3 [KO:K10140]
100989542  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
100975637  CDKN2A; cyclin-dependent kinase inhibitor 2A isoform X1 [KO:K06621]
100976294  CDK4; cyclin-dependent kinase 4 isoform X1 [KO:K02089] [EC:2.7.11.22]
100981258  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
100995605  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
100980947  TGFB1; transforming growth factor beta-1 proprotein isoform X2 [KO:K13375]
100985755  TGFB2; transforming growth factor beta-2 proprotein isoform X2 [KO:K13376]
100990987  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
100984463  TGFBR1; TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
100985497  TGFBR2; TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
100980706  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
100993322  SMAD3; mothers against decapentaplegic homolog 3 isoform X3 [KO:K23605]
100991127  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
100995465  WNT1; proto-oncogene Wnt-1 [KO:K03209]
100990322  WNT2; protein Wnt-2 [KO:K00182]
100983371  WNT2B; protein Wnt-2b isoform X1 [KO:K00182]
100992553  WNT3; proto-oncogene Wnt-3 [KO:K00312]
100977143  WNT3A; protein Wnt-3a isoform X1 [KO:K00312]
100992168  WNT4; protein Wnt-4 isoform X1 [KO:K00408]
100975676  WNT5B; protein Wnt-5b isoform X5 [KO:K00444]
100990957  WNT5A; protein Wnt-5a isoform X1 [KO:K00444]
100987794  WNT6; protein Wnt-6 [KO:K00445]
100995012  WNT7A; protein Wnt-7a isoform X1 [KO:K00572]
100977315  WNT7B; protein Wnt-7b [KO:K00572]
100993563  WNT8A; protein Wnt-8a isoform X1 [KO:K00714]
100969578  WNT8B; protein Wnt-8b [KO:K00714]
100993261  WNT9B; protein Wnt-9b isoform X1 [KO:K01064]
100986204  WNT9A; protein Wnt-9a isoform X1 [KO:K01064]
100995123  WNT10B; protein Wnt-10b [KO:K01357]
100988140  WNT10A; protein Wnt-10a [KO:K01357]
100989115  WNT11; protein Wnt-11 [KO:K01384]
100985948  WNT16; protein Wnt-16 isoform X1 [KO:K01558]
100983788  FZD7; frizzled-7 [KO:K02432]
103784670  FZD1; frizzled-1 [KO:K02432]
100994538  FZD2; frizzled-2 [KO:K02235]
100984879  FZD3; frizzled-3 isoform X1 [KO:K02329]
100984214  FZD4; frizzled-4 isoform X1 [KO:K02354]
100977034  FZD5; frizzled-5 [KO:K02375]
117974549  FZD8; frizzled-8 [KO:K02375]
100980889  FZD6; frizzled-6 [KO:K02376]
100977692  FZD10; frizzled-10 [KO:K02842]
100982738  FZD9; frizzled-9 [KO:K02842]
100992719  LRP6; low-density lipoprotein receptor-related protein 6 isoform X1 [KO:K03068]
100994237  LRP5; low-density lipoprotein receptor-related protein 5 isoform X3 [KO:K03068]
100977837  DVL3; segment polarity protein dishevelled homolog DVL-3 isoform X2 [KO:K02353]
100986952  DVL2; segment polarity protein dishevelled homolog DVL-2 isoform X1 [KO:K02353]
100991559  DVL1; segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353]
117974699  FRAT1; proto-oncogene FRAT1 [KO:K03069]
100980813  FRAT2; GSK-3-binding protein FRAT2 [KO:K03096]
100972306  GSK3B; glycogen synthase kinase-3 beta isoform X2 [KO:K03083] [EC:2.7.11.26]
100986279  AXIN1; axin-1 isoform X1 [KO:K02157]
100990800  AXIN2; axin-2 isoform X1 [KO:K04385]
100992823  APC; adenomatous polyposis coli protein isoform X10 [KO:K02085]
100982035  CTNNB1; catenin beta-1 isoform X1 [KO:K02105]
100978340  CSNK1A1; casein kinase I isoform X3 [KO:K08957] [EC:2.7.11.1]
100988309  CSNK1A1L; casein kinase I [KO:K08957] [EC:2.7.11.1]
100990723  casein kinase I-like [KO:K08957] [EC:2.7.11.1]
100980839  TCF7; LOW QUALITY PROTEIN: transcription factor 7 [KO:K02620]
100968002  TCF7L1; transcription factor 7-like 1 isoform X1 [KO:K04490]
100978424  TCF7L2; transcription factor 7-like 2 isoform X1 [KO:K04491]
100995847  LEF1; lymphoid enhancer-binding factor 1 isoform X2 [KO:K04492]
100978540  KEAP1; kelch-like ECH-associated protein 1 isoform X1 [KO:K10456]
100985885  NFE2L2; nuclear factor erythroid 2-related factor 2 isoform X2 [KO:K05638]
100977821  HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
100976664  NQO1; NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
100967236  GSTM4; glutathione S-transferase Mu 4 [KO:K00799] [EC:2.5.1.18]
100993315  GSTM5; glutathione S-transferase Mu 5 [KO:K00799] [EC:2.5.1.18]
100992371  GSTM3; glutathione S-transferase Mu 3 [KO:K00799] [EC:2.5.1.18]
100992034  GSTT2B; glutathione S-transferase theta-2B isoform X1 [KO:K00799] [EC:2.5.1.18]
100983759  MGST1; microsomal glutathione S-transferase 1 isoform X1 [KO:K00799] [EC:2.5.1.18]
100969075  glutathione S-transferase Mu 2-like [KO:K00799] [EC:2.5.1.18]
100982549  MGST2; microsomal glutathione S-transferase 2 isoform X1 [KO:K00799] [EC:2.5.1.18]
100969459  GSTO1; glutathione S-transferase omega-1 isoform X1 [KO:K00799] [EC:2.5.1.18]
100970018  GSTO2; glutathione S-transferase omega-2 isoform X1 [KO:K00799] [EC:2.5.1.18]
100975656  glutathione S-transferase A1 isoform X2 [KO:K00799] [EC:2.5.1.18]
100969133  GSTA4; glutathione S-transferase A4 [KO:K00799] [EC:2.5.1.18]
100975326  glutathione S-transferase A2 [KO:K00799] [EC:2.5.1.18]
100979335  glutathione S-transferase omega-1-like isoform X2 [KO:K00799] [EC:2.5.1.18]
100969609  glutathione S-transferase A3 isoform X2 [KO:K00799] [EC:2.5.1.18]
100991696  glutathione S-transferase theta-1 isoform X1 [KO:K00799] [EC:2.5.1.18]
100994222  uncharacterized protein LOC100994222 isoform X2 [KO:K00799] [EC:2.5.1.18]
100994084  MGST3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
100994581  glutathione S-transferase theta-4 isoform X1 [KO:K00799] [EC:2.5.1.18]
117977477  glutathione S-transferase theta-2B isoform X1 [KO:K00799] [EC:2.5.1.18]
117977478  glutathione S-transferase theta-1-like [KO:K00799] [EC:2.5.1.18]
103784121  glutathione S-transferase A3-like [KO:K00799] [EC:2.5.1.18]
100971150  glutathione S-transferase theta-4-like [KO:K00799] [EC:2.5.1.18]
117977467  glutathione S-transferase theta-4-like isoform X1 [KO:K00799] [EC:2.5.1.18]
100990234  GSTP1; glutathione S-transferase P [KO:K23790] [EC:2.5.1.18]
100977237  thioredoxin reductase 1, cytoplasmic isoform X3 [KO:K22182] [EC:1.8.1.9]
100982284  TXNRD2; thioredoxin reductase 2, mitochondrial isoform X1 [KO:K22182] [EC:1.8.1.9]
100972140  TXNRD3; thioredoxin reductase 3 [KO:K22182] [EC:1.8.1.9]
100983117  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
100991777  MET; hepatocyte growth factor receptor isoform X1 [KO:K05099] [EC:2.7.10.1]
100990740  GAB1; GRB2-associated-binding protein 1 isoform X2 [KO:K09593]
100970542  ACTG1; actin, cytoplasmic 2 [KO:K05692]
100990579  actin, cytoplasmic 1 [KO:K05692]
103784606  actin, alpha skeletal muscle-like [KO:K05692]
100987964  LOW QUALITY PROTEIN: actin-like [KO:K05692]
100968810  ACTL6A; actin-like protein 6A [KO:K11340]
100983170  ACTL6B; actin-like protein 6B [KO:K11652]
100968557  SMARCD2; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 isoform X1 [KO:K11650]
100980240  SMARCD1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 isoform X1 [KO:K11650]
100986542  SMARCD3; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 isoform X3 [KO:K11650]
100973441  PHF10; PHD finger protein 10 isoform X1 [KO:K22197]
100994189  DPF3; zinc finger protein DPF3 isoform X2 [KO:K22198]
100993329  DPF1; zinc finger protein neuro-d4 isoform X1 [KO:K22198]
100988406  ARID1A; AT-rich interactive domain-containing protein 1A isoform X1 [KO:K11653]
100973216  ARID1B; AT-rich interactive domain-containing protein 1B isoform X1 [KO:K11653]
100994253  SMARCE1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 isoform X1 [KO:K11651]
100996114  SMARCB1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 isoform X4 [KO:K11648]
100976295  SMARCC2; SWI/SNF complex subunit SMARCC2 isoform X6 [KO:K11649]
100987910  SMARCC1; SWI/SNF complex subunit SMARCC1 isoform X1 [KO:K11649]
100975588  SMARCA2; probable global transcription activator SNF2L2 isoform X1 [KO:K11647] [EC:5.6.2.-]
100975870  SMARCA4; transcription activator BRG1 isoform X1 [KO:K11647] [EC:5.6.2.-]
100973002  ARID2; AT-rich interactive domain-containing protein 2 [KO:K11765]
100980769  PBRM1; protein polybromo-1 isoform X6 [KO:K11757]
100984569  BRD7; bromodomain-containing protein 7 isoform X1 [KO:K11723]
100979007  LOW QUALITY PROTEIN: bromodomain-containing protein 7-like [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.
  Journal
Oncogene 29:4989-5005 (2010)
DOI:10.1038/onc.2010.236
Reference
PMID:26099527
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Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM
  Title
Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.
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Gastroenterology 149:1226-1239.e4 (2015)
DOI:10.1053/j.gastro.2015.05.061
Reference
PMID:17295177
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Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM.
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Genomics and signaling pathways in hepatocellular carcinoma.
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Semin Liver Dis 27:55-76 (2007)
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Reference
PMID:16799620
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Breuhahn K, Longerich T, Schirmacher P
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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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Dig Dis 29:289-302 (2011)
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PMID:23994386
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  Title
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J Hepatol 60:224-6 (2014)
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Reference
PMID:11935086
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Pathology and pathogenesis of hepatocellular carcinoma.
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Dig Dis 19:269-78 (2001)
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Reference
PMID:21303380
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Molecular pathogenesis of hepatocellular carcinoma.
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Alcohol Clin Exp Res 35:821-5 (2011)
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Reference
PMID:27895396
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Niu ZS, Niu XJ, Wang WH
  Title
Genetic alterations in hepatocellular carcinoma: An update.
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World J Gastroenterol 22:9069-9095 (2016)
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PMID:11956813
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Virchows Arch 440:345-52 (2002)
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Reference
PMID:23426905
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Int J Oncol 42:1133-8 (2013)
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PMID:23887712
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Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, Laurent A, Cherqui D, Balabaud C, Zucman-Rossi J
  Title
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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Reference
PMID:22561517
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Guichard C, Amaddeo G, Imbeaud S, Ladeiro Y, Pelletier L, Maad IB, Calderaro J, Bioulac-Sage P, Letexier M, Degos F, Clement B, Balabaud C, Chevet E, Laurent A, Couchy G, Letouze E, Calvo F, Zucman-Rossi J
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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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Reference
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Praslicka BJ, Kerins MJ, Ooi A
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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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Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL
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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
  Title
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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Reference
PMID:20019356
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Klaunig JE, Kamendulis LM, Hocevar BA
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Toxicol Pathol 38:96-109 (2010)
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Reference
PMID:11193292
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Krupp G, Bonatz G, Parwaresch R
  Title
Telomerase, immortality and cancer.
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Biotechnol Annu Rev 6:103-40 (2000)
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Cancer Discov 6:584-93 (2016)
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Related
pathway
pps04010  MAPK signaling pathway
pps04020  Calcium signaling pathway
pps04110  Cell cycle
pps04115  p53 signaling pathway
pps04151  PI3K-Akt signaling pathway
pps04310  Wnt signaling pathway
pps04350  TGF-beta signaling pathway
pps04932  Non-alcoholic fatty liver disease
pps04936  Alcoholic liver disease
pps05160  Hepatitis C
pps05161  Hepatitis B
KO pathway
ko05225   
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