KEGG   PATHWAY: puc05225
Entry
puc05225                    Pathway                                
Name
Hepatocellular carcinoma - Panthera uncia (snow leopard)
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
puc05225  Hepatocellular carcinoma
puc05225

Organism
Panthera uncia (snow leopard) [GN:puc]
Gene
125937079  protransforming growth factor alpha [KO:K08774]
125929783  epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
125911611  insulin-like growth factor II [KO:K13769]
125910252  insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
125936595  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
125916347  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 isoform X1 [KO:K05859] [EC:3.1.4.11]
125927372  protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
125927972  protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
125915497  protein kinase C gamma type isoform X1 [KO:K19663] [EC:2.7.11.13]
125931642  ETS domain-containing protein Elk-1 [KO:K04375]
125925730  SHC-transforming protein 1 isoform X1 [KO:K06279]
125928763  SHC-transforming protein 2 isoform X1 [KO:K17447]
125929330  SHC-transforming protein 3 [KO:K17448]
125909988  SHC-transforming protein 4 [KO:K17449]
125926370  growth factor receptor-bound protein 2 [KO:K04364]
125909520  son of sevenless homolog 2 isoform X1 [KO:K03099]
125917913  son of sevenless homolog 1 [KO:K03099]
125917917  son of sevenless homolog 1 [KO:K03099]
125937753  GTPase HRas isoform X1 [KO:K02833]
125918906  GTPase KRas isoform X1 [KO:K07827]
125912218  GTPase NRas [KO:K07828]
125931647  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
125930477  serine/threonine-protein kinase B-raf [KO:K04365] [EC:2.7.11.1]
125930728  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
125910082  dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
125918032  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
125918034  dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
125914884  mitogen-activated protein kinase 1 isoform X1 [KO:K04371] [EC:2.7.11.24]
125928028  mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
125921850  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
125913143  LOW QUALITY PROTEIN: phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
125921289  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
125913493  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
125935698  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
125929237  phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
125933550  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]
125915806  RAC-beta serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
125909102  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
125925091  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
125913121  serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
125930574  ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
125926762  ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
125931741  bcl2-associated agonist of cell death [KO:K02158]
125936704  bcl-2-like protein 1 isoform X1 [KO:K04570]
125924410  myc proto-oncogene protein [KO:K04377]
125933773  retinoblastoma-associated protein isoform X1 [KO:K06618]
125936106  transcription factor E2F1 [KO:K17454]
125912975  transcription factor E2F2 [KO:K09389]
125908499  transcription factor E2F3 [KO:K06620]
125934745  telomerase reverse transcriptase [KO:K11126] [EC:2.7.7.49]
125927023  LOW QUALITY PROTEIN: cellular tumor antigen p53 [KO:K04451]
125938307  cyclin-dependent kinase inhibitor 1 [KO:K06625]
125929753  growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
125930526  growth arrest and DNA damage-inducible protein GADD45 beta isoform X1 [KO:K04402]
125912521  growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
125915138  apoptosis regulator BAX isoform X1 [KO:K02159]
125938359  bcl-2 homologous antagonist/killer [KO:K14021]
125933993  DNA damage-binding protein 2 isoform X1 [KO:K10140]
125935748  DNA polymerase kappa isoform X1 [KO:K03511] [EC:2.7.7.7]
125919257  cyclin-dependent kinase 4 isoform X1 [KO:K02089] [EC:2.7.11.22]
125930419  cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
125930010  G1/S-specific cyclin-D1 [KO:K04503]
125915432  transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
125925521  transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
125908676  transforming growth factor beta-3 proprotein [KO:K13377]
125920171  TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
125921386  TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
125914628  mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
125910090  mothers against decapentaplegic homolog 3 [KO:K23605]
125914595  mothers against decapentaplegic homolog 4 isoform X1 [KO:K04501]
125920405  proto-oncogene Wnt-1 [KO:K03209]
125930076  protein Wnt-2 [KO:K00182]
125912240  protein Wnt-2b [KO:K00182]
125934822  protein Wnt-3a [KO:K00312]
125927692  proto-oncogene Wnt-3 [KO:K00312]
125913720  protein Wnt-4 [KO:K00408]
125929490  protein Wnt-5a [KO:K00444]
125920070  protein Wnt-5b [KO:K00444]
125911162  LOW QUALITY PROTEIN: protein Wnt-6 [KO:K00445]
125929663  protein Wnt-7a isoform X1 [KO:K00572]
125919709  protein Wnt-7b [KO:K00572]
125933437  protein Wnt-8b [KO:K00714]
125935540  protein Wnt-8a [KO:K00714]
125911171  protein Wnt-10a [KO:K01357]
125920404  protein Wnt-10b [KO:K01357]
125914412  protein Wnt-11 [KO:K01384]
125931011  protein Wnt-16 [KO:K01558]
125929896  frizzled-1 [KO:K02432]
125911307  frizzled-7 [KO:K02432]
125926635  frizzled-2 [KO:K02235]
125923798  frizzled-3 isoform X1 [KO:K02329]
125938072  frizzled-4 [KO:K02354]
125911259  frizzled-5 [KO:K02375]
125919776  frizzled-8 [KO:K02375]
125924487  frizzled-6 [KO:K02376]
125915041  frizzled-10 [KO:K02842]
125928505  frizzled-9 [KO:K02842]
125911115  low-density lipoprotein receptor-related protein 5 [KO:K03068]
125920089  low-density lipoprotein receptor-related protein 6 [KO:K03068]
125927067  LOW QUALITY PROTEIN: segment polarity protein dishevelled homolog DVL-2 [KO:K02353]
125913233  LOW QUALITY PROTEIN: segment polarity protein dishevelled homolog DVL-1 [KO:K02353]
125921126  segment polarity protein dishevelled homolog DVL-3 [KO:K02353]
125932834  proto-oncogene FRAT1 [KO:K03069]
125932835  GSK-3-binding protein FRAT2 [KO:K03096]
125921776  glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
125928387  axin-1 isoform X1 [KO:K02157]
125917039  adenomatous polyposis coli protein 2-like isoform X1 [KO:K02085]
125917782  adenomatous polyposis coli protein 2-like isoform X1 [KO:K02085]
125934374  adenomatous polyposis coli protein isoform X1 [KO:K02085]
125921400  catenin beta-1 [KO:K02105]
125934572  casein kinase I isoform X1 [KO:K08957] [EC:2.7.11.1]
125935489  transcription factor 7 isoform X1 [KO:K02620]
125937396  transcription factor 7-like 1 isoform X1 [KO:K04490]
125932981  transcription factor 7-like 2 isoform X1 [KO:K04491]
125923001  lymphoid enhancer-binding factor 1 isoform X1 [KO:K04492]
125930546  kelch-like ECH-associated protein 1 [KO:K10456]
125911807  nuclear factor erythroid 2-related factor 2 isoform X1 [KO:K05638]
125919536  heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
125916299  NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
125914029  glutathione S-transferase theta-1 isoform X1 [KO:K00799] [EC:2.5.1.18]
125914031  glutathione S-transferase theta-3-like [KO:K00799] [EC:2.5.1.18]
125914033  glutathione S-transferase theta-1-like [KO:K00799] [EC:2.5.1.18]
125914034  glutathione S-transferase theta-4-like [KO:K00799] [EC:2.5.1.18]
125914630  LOW QUALITY PROTEIN: glutathione S-transferase theta-2B-like [KO:K00799] [EC:2.5.1.18]
125938214  glutathione S-transferase-like [KO:K00799] [EC:2.5.1.18]
125938572  LOW QUALITY PROTEIN: glutathione S-transferase A4-like [KO:K00799] [EC:2.5.1.18]
125938573  glutathione S-transferase A2 [KO:K00799] [EC:2.5.1.18]
125938574  glutathione S-transferase A4 [KO:K00799] [EC:2.5.1.18]
125938576  glutathione S-transferase alpha M14-like [KO:K00799] [EC:2.5.1.18]
125923708  microsomal glutathione S-transferase 2 [KO:K00799] [EC:2.5.1.18]
125932940  glutathione S-transferase omega-1 isoform X1 [KO:K00799] [EC:2.5.1.18]
125932941  glutathione S-transferase omega-2 isoform X1 [KO:K00799] [EC:2.5.1.18]
125925943  microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
125918878  microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]
125912286  glutathione S-transferase Mu 3 [KO:K00799] [EC:2.5.1.18]
125912288  glutathione S-transferase Mu 4-like [KO:K00799] [EC:2.5.1.18]
125930454  glutathione S-transferase P [KO:K23790] [EC:2.5.1.18]
125930390  thioredoxin reductase 3 [KO:K22182] [EC:1.8.1.9]
125914911  thioredoxin reductase 2, mitochondrial isoform X1 [KO:K22182] [EC:1.8.1.9]
125919914  thioredoxin reductase 1, cytoplasmic [KO:K22182] [EC:1.8.1.9]
125929849  hepatocyte growth factor isoform X1 [KO:K05460]
125930874  hepatocyte growth factor receptor [KO:K05099] [EC:2.7.10.1]
125923729  GRB2-associated-binding protein 1 isoform X1 [KO:K09593]
125926261  actin, cytoplasmic 2 [KO:K05692]
125928308  actin, cytoplasmic 1 [KO:K05692]
125921857  actin-like protein 6A isoform X1 [KO:K11340]
125928665  actin-like protein 6B [KO:K11652]
125930316  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 isoform X1 [KO:K11650]
125926673  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 isoform X1 [KO:K11650]
125920225  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 [KO:K11650]
125939069  PHD finger protein 10 isoform X1 [KO:K22197]
125909371  zinc finger protein DPF3 isoform X1 [KO:K22198]
125918359  zinc finger protein neuro-d4-like [KO:K22198]
125918362  zinc finger protein neuro-d4 [KO:K22198]
125938058  AT-rich interactive domain-containing protein 1B isoform X1 [KO:K11653]
125912888  AT-rich interactive domain-containing protein 1A isoform X1 [KO:K11653]
125937641  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1-like [KO:K11651]
125926507  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 isoform X1 [KO:K11651]
125914870  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 isoform X1 [KO:K11648]
125920245  SWI/SNF complex subunit SMARCC2 isoform X1 [KO:K11649]
125928760  SWI/SNF complex subunit SMARCC1 [KO:K11649]
125932366  probable global transcription activator SNF2L2 isoform X1 [KO:K11647] [EC:5.6.2.-]
125928991  transcription activator BRG1 isoform X1 [KO:K11647] [EC:5.6.2.-]
125919836  AT-rich interactive domain-containing protein 2 [KO:K11765]
125929452  protein polybromo-1 isoform X1 [KO:K11757]
125915413  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
  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
puc04010  MAPK signaling pathway
puc04020  Calcium signaling pathway
puc04110  Cell cycle
puc04115  p53 signaling pathway
puc04151  PI3K-Akt signaling pathway
puc04310  Wnt signaling pathway
puc04350  TGF-beta signaling pathway
puc04932  Non-alcoholic fatty liver disease
puc04936  Alcoholic liver disease
puc05160  Hepatitis C
puc05161  Hepatitis B
KO pathway
ko05225   
LinkDB

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