KEGG   PATHWAY: zca05225
Entry
zca05225                    Pathway                                
Name
Hepatocellular carcinoma - Zalophus californianus (California sea lion)
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
zca05225  Hepatocellular carcinoma
zca05225

Disease
H00048  Hepatocellular carcinoma
Organism
Zalophus californianus (California sea lion) [GN:zca]
Gene
113907956  WNT9B; protein Wnt-9b [KO:K01064]
113908035  AXIN2; axin-2 isoform X1 [KO:K04385]
113908099  SMARCD2; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 isoform X2 [KO:K11650]
113908204  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
113908652  FZD6; frizzled-6 isoform X1 [KO:K02376]
113908779  DPF3; zinc finger protein DPF3 isoform X1 [KO:K22198]
113908972  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
113908979  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
113909118  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
113909166  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
113909494  SHC4; SHC-transforming protein 4 isoform X1 [KO:K17449]
113909653  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha isoform X1 [KO:K04402]
113910017  AKT1; RAC-alpha serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113910186  TGFB3; transforming growth factor beta-3 proprotein isoform X1 [KO:K13377]
113911009  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
113911010  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
113911106  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
113911220  SMARCD3; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 isoform X1 [KO:K11650]
113911366  MET; hepatocyte growth factor receptor isoform X1 [KO:K05099] [EC:2.7.10.1]
113911568  MYC; myc proto-oncogene protein isoform X1 [KO:K04377]
113911578  WNT2; protein Wnt-2 [KO:K00182]
113911646  FZD1; frizzled-1 [KO:K02432]
113911688  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
113911759  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
113911953  WNT16; protein Wnt-16 [KO:K01558]
113912307  TXNRD2; thioredoxin reductase 2, mitochondrial isoform X1 [KO:K22182] [EC:1.8.1.9]
113912320  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
113912376  E2F2; transcription factor E2F2 [KO:K09389]
113912422  SMAD4; mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
113913064  [KO:K00799] [EC:2.5.1.18]
113913122  FZD10; frizzled-10 [KO:K02842]
113913179  SMARCB1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 isoform X1 [KO:K11648]
113913183  [KO:K00799] [EC:2.5.1.18]
113913184  [KO:K00799] [EC:2.5.1.18]
113913185  [KO:K00799] [EC:2.5.1.18]
113913186  [KO:K00799] [EC:2.5.1.18]
113913242  SMAD2; mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
113913785  FRAT2; GSK-3-binding protein FRAT2 [KO:K03096]
113913839  GSTM3; glutathione S-transferase Mu 3 [KO:K00799] [EC:2.5.1.18]
113913864  DDB2; DNA damage-binding protein 2 isoform X1 [KO:K10140]
113913921  FZD4; frizzled-4 isoform X1 [KO:K02354]
113913994  [KO:K23790]
113914083  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
113914159  GSTP1; LOW QUALITY PROTEIN: glutathione S-transferase P [KO:K23790]
113914236  FRAT1; proto-oncogene FRAT1 [KO:K03069]
113914285  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
113914398  [KO:K23790]
113914497  WNT11; protein Wnt-11 [KO:K01384]
113914539  BAD; bcl2-associated agonist of cell death [KO:K02158]
113914579  IGF2; insulin-like growth factor II isoform X1 [KO:K13769]
113914701  LRP5; low-density lipoprotein receptor-related protein 5 isoform X1 [KO:K03068]
113914876  HRAS; GTPase HRas isoform X1 [KO:K02833]
113915830  KEAP1; kelch-like ECH-associated protein 1 [KO:K10456]
113916148  APC2; adenomatous polyposis coli protein 2 isoform X1 [KO:K02085]
113916244  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
113916310  PBRM1; protein polybromo-1 isoform X1 [KO:K11757]
113916383  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
113916407  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
113916433  WNT4; protein Wnt-4 isoform X1 [KO:K00408]
113916464  SMARCA4; transcription activator BRG1 isoform X1 [KO:K11647] [EC:5.6.2.-]
113917006  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
113917022  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
113917098  SMARCC1; SWI/SNF complex subunit SMARCC1 isoform X1 [KO:K11649]
113917179  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
113917509  WNT7A; protein Wnt-7a [KO:K00572]
113917714  CTNNB1; catenin beta-1 [KO:K02105]
113917867  SHC2; SHC-transforming protein 2 isoform X1 [KO:K17447]
113918049  DVL3; segment polarity protein dishevelled homolog DVL-3 [KO:K02353]
113918078  TXNRD3; thioredoxin reductase 3 isoform X3 [KO:K22182] [EC:1.8.1.9]
113918151  ACTL6A; actin-like protein 6A isoform X1 [KO:K11340]
113918500  WNT5A; protein Wnt-5a isoform X1 [KO:K00444]
113918509  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
113918785  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]
113918898  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
113919207  FZD5; frizzled-5 [KO:K02375]
113919460  NFE2L2; nuclear factor erythroid 2-related factor 2 isoform X1 [KO:K05638]
113919651  RB1; retinoblastoma-associated protein isoform X1 [KO:K06618]
113920227  WNT10A; protein Wnt-10a [KO:K01357]
113920419  [KO:K23790]
113920600  FZD7; frizzled-7 [KO:K02432]
113920632  WNT6; protein Wnt-6 [KO:K00445]
113921420  [KO:K22182] [EC:1.8.1.9]
113921680  SMARCD1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 isoform X1 [KO:K11650]
113921779  LRP6; low-density lipoprotein receptor-related protein 6 isoform X1 [KO:K03068]
113921783  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
113921792  KRAS; GTPase KRas isoform X1 [KO:K07827]
113921849  ARID2; AT-rich interactive domain-containing protein 2 isoform X1 [KO:K11765]
113921881  SMARCC2; SWI/SNF complex subunit SMARCC2 isoform X1 [KO:K11649]
113921955  WNT10B; protein Wnt-10b [KO:K01357]
113921956  WNT1; proto-oncogene Wnt-1 [KO:K03209]
113922345  WNT8B; protein Wnt-8b [KO:K00714]
113922447  WNT7B; protein Wnt-7b [KO:K00572]
113922486  WNT5B; protein Wnt-5b isoform X1 [KO:K00444]
113922845  MGST1; microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]
113923025  TCF7L2; transcription factor 7-like 2 isoform X1 [KO:K04491]
113923054  FZD8; frizzled-8 [KO:K02375]
113923069  HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
113923622  GSTO2; glutathione S-transferase omega-2 isoform X1 [KO:K00799] [EC:2.5.1.18]
113923623  GSTO1; glutathione S-transferase omega-1 [KO:K00799] [EC:2.5.1.18]
113923921  WNT2B; protein Wnt-2b isoform X1 [KO:K00182]
113924221  [KO:K23790]
113924315  GAB1; GRB2-associated-binding protein 1 isoform X1 [KO:K09593]
113924417  MGST2; microsomal glutathione S-transferase 2 isoform X1 [KO:K00799] [EC:2.5.1.18]
113924444  ARID1A; AT-rich interactive domain-containing protein 1A isoform X1 [KO:K11653]
113924761  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
113925060  FZD3; frizzled-3 [KO:K02329]
113925147  [KO:K00799] [EC:2.5.1.18]
113925264  [KO:K11651]
113925268  LEF1; lymphoid enhancer-binding factor 1 isoform X1 [KO:K04492]
113926358  ARID1B; AT-rich interactive domain-containing protein 1B isoform X1 [KO:K11653]
113926410  [KO:K00799] [EC:2.5.1.18]
113926411  [KO:K00799] [EC:2.5.1.18]
113926458  PHF10; PHD finger protein 10 isoform X1 [KO:K22197]
113927082  [KO:K00799] [EC:2.5.1.18]
113927176  GSTA1; glutathione S-transferase A1 isoform X1 [KO:K00799] [EC:2.5.1.18]
113927180  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
113927327  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
113927365  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
113928377  TERT; telomerase reverse transcriptase isoform X1 [KO:K11126] [EC:2.7.7.49]
113928407  TCF7; transcription factor 7 isoform X1 [KO:K02620]
113928435  POLK; DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
113928600  WNT8A; protein Wnt-8a [KO:K00714]
113928748  APC; adenomatous polyposis coli protein isoform X1 [KO:K02085]
113928897  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
113928921  [KO:K11650]
113929507  CSNK1A1; casein kinase I isoform X1 [KO:K08957] [EC:2.7.11.1]
113929550  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
113930205  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
113930372  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
113931879  NRAS; GTPase NRas [KO:K07828]
113932035  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113932123  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
113932280  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
113932759  DVL1; segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353]
113932833  ACTB; actin, cytoplasmic 1 [KO:K05692]
113932883  ACTL6B; actin-like protein 6B isoform X1 [KO:K11652]
113932963  FZD9; LOW QUALITY PROTEIN: frizzled-9 [KO:K02842]
113932986  AXIN1; axin-1 isoform X1 [KO:K02157]
113933024  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
113933238  [KO:K11651]
113933258  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
113933469  MGST3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
113934058  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
113934266  SMARCA2; probable global transcription activator SNF2L2 isoform X1 [KO:K11647] [EC:5.6.2.-]
113934484  TGFBR1; LOW QUALITY PROTEIN: TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
113935041  SHC3; SHC-transforming protein 3 isoform X1 [KO:K17448]
113935537  AKT2; RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
113935677  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
113935771  BRD7; bromodomain-containing protein 7 isoform X1 [KO:K11723]
113935773  DPF1; zinc finger protein neuro-d4 isoform X1 [KO:K22198]
113935801  PRKCG; protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
113936075  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
113936171  [KO:K08957] [EC:2.7.11.1]
113936424  TGFB1; transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
113936428  NQO1; NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
113936575  [KO:K00799] [EC:2.5.1.18]
113936987  BCL2L1; bcl-2-like protein 1 [KO:K04570]
113937127  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
113937502  [KO:K00799] [EC:2.5.1.18]
113937552  [KO:K23790]
113938191  TGFA; protransforming growth factor alpha isoform X1 [KO:K08774]
113938298  TCF7L1; transcription factor 7-like 1 isoform X1 [KO:K04490]
113938304  PLCG1; LOW QUALITY PROTEIN: 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 [KO:K01116] [EC:3.1.4.11]
113938493  E2F1; transcription factor E2F1 [KO:K17454]
113938904  WNT9A; protein Wnt-9a [KO:K01064]
113938914  WNT3A; protein Wnt-3a [KO:K00312]
113938999  WNT3; proto-oncogene Wnt-3 [KO:K00312]
113939369  DVL2; LOW QUALITY PROTEIN: segment polarity protein dishevelled homolog DVL-2 [KO:K02353]
113939477  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
113939579  GRB2; growth factor receptor-bound protein 2 isoform X1 [KO:K04364]
113939587  TP53; cellular tumor antigen p53 isoform X1 [KO:K04451]
113939732  FZD2; frizzled-2 [KO:K02235]
113939792  ACTG1; actin, cytoplasmic 2 [KO:K05692]
113939826  SMARCE1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 isoform X1 [KO:K11651]
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
  Authors
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
  Authors
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)
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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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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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PMID:11935086
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PMID:27895396
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Niu ZS, Niu XJ, Wang WH
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World J Gastroenterol 22:9069-9095 (2016)
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Reference
PMID:11956813
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Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis.
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Virchows Arch 440:345-52 (2002)
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High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.
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Nat Genet 44:694-8 (2012)
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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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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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Telomerase, immortality and cancer.
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Biotechnol Annu Rev 6:103-40 (2000)
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Genome Med 8:69 (2016)
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Reference
PMID:27508192
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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
PMID:16934487
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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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  Authors
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
zca04010  MAPK signaling pathway
zca04020  Calcium signaling pathway
zca04110  Cell cycle
zca04115  p53 signaling pathway
zca04151  PI3K-Akt signaling pathway
zca04310  Wnt signaling pathway
zca04350  TGF-beta signaling pathway
zca04932  Non-alcoholic fatty liver disease
zca04936  Alcoholic liver disease
zca05160  Hepatitis C
zca05161  Hepatitis B
KO pathway
ko05225   

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