KEGG   PATHWAY: oaa05225
Entry
oaa05225                    Pathway                                
Name
Hepatocellular carcinoma - Ornithorhynchus anatinus (platypus)
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
oaa05225  Hepatocellular carcinoma
oaa05225

Disease
H00048  Hepatocellular carcinoma
Organism
Ornithorhynchus anatinus (platypus) [GN:oaa]
Gene
100073788  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
100073902  ARID1B; LOW QUALITY PROTEIN: AT-rich interactive domain-containing protein 1B [KO:K11653]
100074117  WNT9A; protein Wnt-9a [KO:K01064]
100074181  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
100074273  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100074365  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]
100074437  ARID2; AT-rich interactive domain-containing protein 2 isoform X1 [KO:K11765]
100074671  NRAS; GTPase NRas [KO:K07828]
100074840  TGFB3; transforming growth factor beta-3 proprotein [KO:K13377]
100074892  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
100075081  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
100075238  WNT4; protein Wnt-4 [KO:K00408]
100075326  GSTP1; glutathione S-transferase P [KO:K23790]
100075806  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
100075894  EGFR; epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
100075994  WNT7A; protein Wnt-7a [KO:K00572]
100076415  TXNRD1; thioredoxin reductase 1, cytoplasmic [KO:K22182] [EC:1.8.1.9]
100076676  CSNK1A1; casein kinase I isoform X1 [KO:K08957] [EC:2.7.11.1]
100076776  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
100076956  MGST3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
100076965  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
100077094  NQO1; NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
100077136  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
100077194  LRP6; low-density lipoprotein receptor-related protein 6 [KO:K03068]
100077423  POLK; DNA polymerase kappa isoform X2 [KO:K03511] [EC:2.7.7.7]
100077556  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
100077640  WNT2; protein Wnt-2 precursor [KO:K00182]
100077932  AXIN2; axin-2 [KO:K04385]
100077974  WNT16; protein Wnt-16 [KO:K01558]
100078089  BRD7; bromodomain-containing protein 7 isoform X1 [KO:K11723]
100078653  [KO:K00799] [EC:2.5.1.18]
100078757  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
100078852  RPS6KB1; ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
100078865  ACTB; actin, cytoplasmic 1 [KO:K05692]
100078989  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
100079107  PRKCA; protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
100079345  MET; hepatocyte growth factor receptor precursor [KO:K05099] [EC:2.7.10.1]
100079391  MYC; myc proto-oncogene protein [KO:K04377]
100079751  MTOR; serine/threonine-protein kinase mTOR isoform X1 [KO:K07203] [EC:2.7.11.1]
100079818  LEF1; lymphoid enhancer-binding factor 1 isoform X1 [KO:K04492]
100079874  WNT8B; protein Wnt-8b [KO:K00714]
100080176  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
100080187  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
100080214  FZD9; frizzled-9 [KO:K02842]
100080362  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
100080628  CTNNB1; catenin beta-1 [KO:K02105]
100080633  TCF7L2; transcription factor 7-like 2 isoform X1 [KO:K04491]
100080710  FZD6; frizzled-6 [KO:K02376]
100080994  FZD4; frizzled-4 [KO:K02354]
100081397  SHC2; SHC-transforming protein 2 [KO:K17447]
100081473  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
100081645  GSTO1; glutathione S-transferase omega-1 [KO:K00799] [EC:2.5.1.18]
100081741  MGST2; microsomal glutathione S-transferase 2 [KO:K00799] [EC:2.5.1.18]
100081844  SMARCB1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 isoform X1 [KO:K11648]
100081860  FZD7; frizzled-7 [KO:K02432]
100081893  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
100082075  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
100082114  APC; adenomatous polyposis coli protein isoform X1 [KO:K02085]
100082332  TCF7; transcription factor 7 isoform X1 [KO:K02620]
100082582  GAB1; GRB2-associated-binding protein 1 isoform X1 [KO:K09593]
100082608  SMARCD3; LOW QUALITY PROTEIN: SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 [KO:K11650]
100083320  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
100083537  RB1; retinoblastoma-associated protein [KO:K06618]
100083932  [KO:K06621]
100084423  ARAF; serine/threonine-protein kinase A-Raf isoform X1 [KO:K08845] [EC:2.7.11.1]
100084645  SOS2; son of sevenless homolog 2 isoform X1 [KO:K03099]
100084704  [KO:K00799] [EC:2.5.1.18]
100084721  [KO:K00799] [EC:2.5.1.18]
100084872  NFE2L2; nuclear factor erythroid 2-related factor 2 isoform X1 [KO:K05638]
100085053  E2F2; transcription factor E2F2 [KO:K09389]
100085078  ACTG1; actin, cytoplasmic 2 [KO:K05692]
100085162  SMARCC2; SWI/SNF complex subunit SMARCC2 isoform X1 [KO:K11649]
100085213  [KO:K00799] [EC:2.5.1.18]
100085218  PHF10; PHD finger protein 10 isoform X3 [KO:K22197]
100085356  ACTL8; actin-like protein 8 [KO:K05692]
100085370  WNT8A; protein Wnt-8a [KO:K00714]
100085430  KRAS; GTPase KRas isoform X1 [KO:K07827]
100085442  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
100085480  MAPK1; mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
100085809  WNT5B; protein Wnt-5b [KO:K00444]
100085963  SMAD3; mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
100086058  FZD3; frizzled-3 [KO:K02329]
100086270  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
100086380  BRAF; serine/threonine-protein kinase B-raf isoform X2 [KO:K04365] [EC:2.7.11.1]
100086487  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
100086761  SMARCE1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 isoform X1 [KO:K11651]
100087014  E2F1; transcription factor E2F1 [KO:K17454]
100087253  WNT2B; protein Wnt-2b [KO:K00182]
100087780  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
100087859  SMARCC1; SWI/SNF complex subunit SMARCC1 [KO:K11649]
100087942  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
100088212  DDB2; DNA damage-binding protein 2 [KO:K10140]
100088897  WNT5A; protein Wnt-5a [KO:K00444]
100088910  [KO:K00572]
100089075  ACTL6B; actin-like protein 6B isoform X1 [KO:K11652]
100089243  KEAP1; kelch-like ECH-associated protein 1 [KO:K10456]
100089456  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
100089547  FZD5; LOW QUALITY PROTEIN: frizzled-5 [KO:K02375]
100089786  WNT6; protein Wnt-6 [KO:K00445]
100089867  DVL2; segment polarity protein dishevelled homolog DVL-2 [KO:K02353]
100090103  WNT3A; LOW QUALITY PROTEIN: protein Wnt-3a [KO:K00312]
100090267  AKT2; RAC-beta serine/threonine-protein kinase isoform X2 [KO:K04456] [EC:2.7.11.1]
100090413  TGFA; protransforming growth factor alpha [KO:K08774]
100090475  E2F3; transcription factor E2F3 isoform X1 [KO:K06620]
100090556  TXNRD3; thioredoxin reductase 3 [KO:K22182] [EC:1.8.1.9]
100090678  WNT10A; protein Wnt-10a [KO:K01357]
100090775  FZD2; frizzled-2 [KO:K02235]
100091043  [KO:K00799] [EC:2.5.1.18]
100091700  WNT11; protein Wnt-11 [KO:K01384]
100091822  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
100091844  FZD10; frizzled-10 [KO:K02842]
100091980  DVL3; segment polarity protein dishevelled homolog DVL-3 isoform X1 [KO:K02353]
100092089  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
100092358  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
100092493  [KO:K05692]
100092556  [KO:K00799] [EC:2.5.1.18]
100092810  ACTL6A; actin-like protein 6A [KO:K11340]
100092816  SMARCA4; transcription activator BRG1 isoform X1 [KO:K11647] [EC:5.6.2.-]
100092821  TP53; cellular tumor antigen p53 [KO:K04451]
100093450  AXIN1; axin-1 [KO:K02157]
100093588  WNT7B; protein Wnt-7b [KO:K00572]
100681387  [KO:K00799] [EC:2.5.1.18]
100681469  ELK1; ETS domain-containing protein Elk-1 isoform X1 [KO:K04375]
100681615  DVL1; segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353]
100682203  APC2; adenomatous polyposis coli protein 2 [KO:K02085]
102060413  TERT; telomerase reverse transcriptase [KO:K11126] [EC:2.7.7.49]
103165190  TXNRD2; thioredoxin reductase 2, mitochondrial isoform X1 [KO:K22182] [EC:1.8.1.9]
103166093  PBRM1; protein polybromo-1 isoform X1 [KO:K11757]
103167126  PIK3R1; phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
103167718  ARID1A; LOW QUALITY PROTEIN: AT-rich interactive domain-containing protein 1A [KO:K11653]
103168620  DPF3; zinc finger protein DPF3 [KO:K22198]
107546921  BCL2L1; bcl-2-like protein 1 [KO:K04570]
107547159  WNT10B; protein Wnt-10b [KO:K01357]
107547327  [KO:K00799] [EC:2.5.1.18]
107547784  HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
114808180  SHC1; SHC-transforming protein 1 [KO:K06279]
114809992  HRAS; GTPase HRas [KO:K02833]
114810030  BAD; bcl2-associated agonist of cell death [KO:K02158]
114810222  [KO:K03096]
114812004  DPF1; zinc finger protein neuro-d4 isoform X1 [KO:K22198]
114812005  TGFB1; transforming growth factor beta-1 proprotein [KO:K13375]
114813305  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
114813317  BAK1; bcl-2 homologous antagonist/killer isoform X1 [KO:K14021]
114813907  FZD1; frizzled-1 [KO:K02432]
114814562  WNT1; proto-oncogene Wnt-1 [KO:K03209]
114814649  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
114814784  SMARCD1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 isoform X1 [KO:K11650]
114815138  SMARCD2; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 [KO:K11650]
114816216  FZD8; frizzled-8 [KO:K02375]
114817945  MGST1; microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]
114817948  TCF7L1; transcription factor 7-like 1 [KO:K04490]
791102  IGF2; insulin-like growth factor II [KO:K13769]
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.
  Journal
Gastroenterology 149:1226-1239.e4 (2015)
DOI:10.1053/j.gastro.2015.05.061
Reference
PMID:17295177
  Authors
Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM.
  Title
Genomics and signaling pathways in hepatocellular carcinoma.
  Journal
Semin Liver Dis 27:55-76 (2007)
DOI:10.1055/s-2006-960171
Reference
PMID:16799620
  Authors
Breuhahn K, Longerich T, Schirmacher P
  Title
Dysregulation of growth factor signaling in human hepatocellular carcinoma.
  Journal
Oncogene 25:3787-800 (2006)
DOI:10.1038/sj.onc.1209556
Reference
PMID:19387255
  Authors
Minguez B, Tovar V, Chiang D, Villanueva A, Llovet JM
  Title
Pathogenesis of hepatocellular carcinoma and molecular therapies.
  Journal
Curr Opin Gastroenterol 25:186-94 (2009)
DOI:10.1097/MOG.0b013e32832962a1
Reference
PMID:21829020
  Authors
Kudo M
  Title
Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma.
  Journal
Dig Dis 29:289-302 (2011)
DOI:10.1159/000327562
Reference
PMID:23994386
  Authors
Nault JC, Zucman-Rossi J
  Title
Genetics of hepatocellular carcinoma: the next generation.
  Journal
J Hepatol 60:224-6 (2014)
DOI:10.1016/j.jhep.2013.08.019
Reference
PMID:11935086
  Authors
Rocken C, Carl-McGrath S.
  Title
Pathology and pathogenesis of hepatocellular carcinoma.
  Journal
Dig Dis 19:269-78 (2001)
DOI:10.1159/000050693
Reference
PMID:21303380
  Authors
Cornella H, Alsinet C, Villanueva A
  Title
Molecular pathogenesis of hepatocellular carcinoma.
  Journal
Alcohol Clin Exp Res 35:821-5 (2011)
DOI:10.1111/j.1530-0277.2010.01406.x
Reference
PMID:27895396
  Authors
Niu ZS, Niu XJ, Wang WH
  Title
Genetic alterations in hepatocellular carcinoma: An update.
  Journal
World J Gastroenterol 22:9069-9095 (2016)
DOI:10.3748/wjg.v22.i41.9069
Reference
PMID:11956813
  Authors
Tannapfel A, Wittekind C
  Title
Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis.
  Journal
Virchows Arch 440:345-52 (2002)
DOI:10.1007/s00428-002-0617-x
Reference
PMID:23426905
  Authors
Shiraha H, Yamamoto K, Namba M
  Title
Human hepatocyte carcinogenesis (review).
  Journal
Int J Oncol 42:1133-8 (2013)
DOI:10.3892/ijo.2013.1829
Reference
PMID:23887712
  Authors
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.
  Journal
Nat Commun 4:2218 (2013)
DOI:10.1038/ncomms3218
Reference
PMID:22561517
  Authors
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
  Title
Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.
  Journal
Nat Genet 44:694-8 (2012)
DOI:10.1038/ng.2256
Reference
  Authors
Praslicka BJ, Kerins MJ, Ooi A
  Title
The complex role of NRF2 in cancer: a genomic view
  Journal
Curr Opin Toxicol 1:37-45 (2016)
DOI:10.1016/j.cotox.2016.09.003
Reference
PMID:24024136
  Authors
Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL
  Title
The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer.
  Journal
Redox Biol 1:45-9 (2013)
DOI:10.1016/j.redox.2012.10.001
Reference
PMID:21251164
  Authors
Taguchi K, Motohashi H, Yamamoto M
  Title
Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution.
  Journal
Genes Cells 16:123-40 (2011)
DOI:10.1111/j.1365-2443.2010.01473.x
Reference
PMID:20019356
  Authors
Klaunig JE, Kamendulis LM, Hocevar BA
  Title
Oxidative stress and oxidative damage in carcinogenesis.
  Journal
Toxicol Pathol 38:96-109 (2010)
DOI:10.1177/0192623309356453
Reference
PMID:11193292
  Authors
Krupp G, Bonatz G, Parwaresch R
  Title
Telomerase, immortality and cancer.
  Journal
Biotechnol Annu Rev 6:103-40 (2000)
DOI:10.1016/S1387-2656(00)06020-8
Reference
PMID:27323951
  Authors
Jafri MA, Ansari SA, Alqahtani MH, Shay JW
  Title
Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.
  Journal
Genome Med 8:69 (2016)
DOI:10.1186/s13073-016-0324-x
Reference
PMID:27029895
  Authors
Shay JW
  Title
Role of Telomeres and Telomerase in Aging and Cancer.
  Journal
Cancer Discov 6:584-93 (2016)
DOI:10.1158/2159-8290.CD-16-0062
Reference
PMID:27508192
  Authors
Granito A, Guidetti E, Gramantieri L
  Title
c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma.
  Journal
J Hepatocell Carcinoma 2:29-38 (2015)
DOI:10.2147/JHC.S77038
Reference
PMID:16934487
  Authors
Vita M, Henriksson M
  Title
The Myc oncoprotein as a therapeutic target for human cancer.
  Journal
Semin Cancer Biol 16:318-30 (2006)
DOI:10.1016/j.semcancer.2006.07.015
Reference
PMID:24096051
  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
oaa04010  MAPK signaling pathway
oaa04020  Calcium signaling pathway
oaa04110  Cell cycle
oaa04115  p53 signaling pathway
oaa04151  PI3K-Akt signaling pathway
oaa04310  Wnt signaling pathway
oaa04350  TGF-beta signaling pathway
oaa04932  Non-alcoholic fatty liver disease
oaa04936  Alcoholic liver disease
oaa05160  Hepatitis C
oaa05161  Hepatitis B
KO pathway
ko05225   

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