KEGG   PATHWAY: mthb05225
Entry
mthb05225                   Pathway                                
Name
Hepatocellular carcinoma - Macaca thibetana thibetana (Pere David's macaque)
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
mthb05225  Hepatocellular carcinoma
mthb05225

Organism
Macaca thibetana thibetana (Pere David's macaque) [GN:mthb]
Gene
126934085  protransforming growth factor alpha isoform X1 [KO:K08774]
126950202  epidermal growth factor receptor isoform X1 [KO:K04361] [EC:2.7.10.1]
126935883  insulin-like growth factor II [KO:K13769]
126959327  insulin-like growth factor 1 receptor isoform X1 [KO:K05087] [EC:2.7.10.1]
126963902  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
126943961  1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
126938340  protein kinase C alpha type isoform X1 [KO:K02677] [EC:2.7.11.13]
126944386  protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
126943319  protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
126944416  LOW QUALITY PROTEIN: ETS domain-containing protein Elk-1-like [KO:K04375]
126945587  ETS domain-containing protein Elk-1 [KO:K04375]
126934689  LOW QUALITY PROTEIN: ETS domain-containing protein Elk-1-like [KO:K04375]
126933571  SHC-transforming protein 1 isoform X1 [KO:K06279]
126942949  SHC-transforming protein 2 [KO:K17447]
126937656  SHC-transforming protein 3 [KO:K17448]
126958692  SHC-transforming protein 4 [KO:K17449]
126939255  growth factor receptor-bound protein 2 [KO:K04364]
126933534  son of sevenless homolog 1 isoform X1 [KO:K03099]
126958499  son of sevenless homolog 2 isoform X1 [KO:K03099]
126935869  GTPase HRas isoform X1 [KO:K02833]
126931572  GTPase KRas [KO:K07827]
126930824  GTPase NRas [KO:K07828]
126945567  serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
126949633  serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
126949054  RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
126957976  dual specificity mitogen-activated protein kinase kinase 1 isoform X1 [KO:K04368] [EC:2.7.12.2]
126942673  dual specificity mitogen-activated protein kinase kinase 2 isoform X1 [KO:K04369] [EC:2.7.12.2]
126944456  mitogen-activated protein kinase 3 isoform X1 [KO:K04371] [EC:2.7.11.24]
126929669  mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
126947557  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
126952893  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform isoform X1 [KO:K00922] [EC:2.7.1.153]
126948170  phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
126961422  phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
126956531  phosphatidylinositol 3-kinase regulatory subunit alpha isoform X1 [KO:K02649]
126942202  phosphatidylinositol 3-kinase regulatory subunit beta isoform X1 [KO:K02649]
126963336  phosphatidylinositol 3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN isoform X1 [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
126943096  RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
126959416  RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126942032  RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126952739  serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
126939388  ribosomal protein S6 kinase beta-1 isoform X1 [KO:K04688] [EC:2.7.11.1]
126935360  ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
126935617  bcl2-associated agonist of cell death [KO:K02158]
126964283  bcl-2-like protein 1 isoform X1 [KO:K04570]
126960612  myc proto-oncogene protein [KO:K04377]
126940411  retinoblastoma-associated protein isoform X1 [KO:K06618]
126964352  transcription factor E2F1 [KO:K17454]
126955302  transcription factor E2F2 [KO:K09389]
126953853  transcription factor E2F3 isoform X1 [KO:K06620]
126957402  telomerase reverse transcriptase isoform X1 [KO:K11126] [EC:2.7.7.49]
126939707  cellular tumor antigen p53 isoform X1 [KO:K04451]
126952813  cyclin-dependent kinase inhibitor 1 [KO:K06625]
126942832  growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
126937334  growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
126939469  growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
126943600  apoptosis regulator BAX isoform X1 [KO:K02159]
126952802  bcl-2 homologous antagonist/killer [KO:K14021]
126936385  DNA damage-binding protein 2 isoform X1 [KO:K10140]
126957066  DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
126937619  cyclin-dependent kinase inhibitor 2A isoform X1 [KO:K06621]
126930400  cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
126951304  cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
126935963  G1/S-specific cyclin-D1 [KO:K04503]
126941768  transforming growth factor beta-1 proprotein isoform X1 [KO:K13375]
126948495  transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
126959539  transforming growth factor beta-3 proprotein [KO:K13377]
126938052  TGF-beta receptor type-1 isoform X1 [KO:K04674] [EC:2.7.11.30]
126946646  TGF-beta receptor type-2 isoform X1 [KO:K04388] [EC:2.7.11.30]
126941494  mothers against decapentaplegic homolog 2 isoform X1 [KO:K04500]
126957972  mothers against decapentaplegic homolog 3 isoform X1 [KO:K23605]
126941313  mothers against decapentaplegic homolog 4 [KO:K04501]
126930178  proto-oncogene Wnt-1 [KO:K03209]
126930501  protein Wnt-2b [KO:K00182]
126951195  protein Wnt-2 [KO:K00182]
126936033  protein Wnt-3a [KO:K00312]
126938314  proto-oncogene Wnt-3 [KO:K00312]
126956796  protein Wnt-4 [KO:K00408]
126930247  protein Wnt-5b [KO:K00444]
126947624  protein Wnt-5a isoform X1 [KO:K00444]
126933008  protein Wnt-6 isoform X1 [KO:K00445]
126949140  protein Wnt-7a [KO:K00572]
126963624  protein Wnt-7b isoform X1 [KO:K00572]
126963076  protein Wnt-8b [KO:K00714]
126957556  protein Wnt-8a [KO:K00714]
126938932  protein Wnt-9b isoform X1 [KO:K01064]
126935947  protein Wnt-9a isoform X1 [KO:K01064]
126930177  protein Wnt-10b [KO:K01357]
126933003  protein Wnt-10a [KO:K01357]
126935098  protein Wnt-11 isoform X1 [KO:K01384]
126950813  protein Wnt-16 [KO:K01558]
126932182  frizzled-7 [KO:K02432]
126949919  frizzled-1 [KO:K02432]
126938678  frizzled-2 [KO:K02235]
126961767  frizzled-3 isoform X1 [KO:K02329]
126934903  frizzled-4 isoform X1 [KO:K02354]
126962319  LOW QUALITY PROTEIN: frizzled-8 [KO:K02375]
126933089  frizzled-5 [KO:K02375]
126960879  frizzled-6 isoform X1 [KO:K02376]
126930546  frizzled-10 [KO:K02842]
126950358  frizzled-9 [KO:K02842]
126930738  low-density lipoprotein receptor-related protein 6 [KO:K03068]
126935940  low-density lipoprotein receptor-related protein 5 isoform X1 [KO:K03068]
126939681  segment polarity protein dishevelled homolog DVL-2 isoform X1 [KO:K02353]
126951679  segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353]
126948407  segment polarity protein dishevelled homolog DVL-3 [KO:K02353]
126962089  proto-oncogene FRAT1 [KO:K03069]
126962094  GSK-3-binding protein FRAT2 [KO:K03096]
126949239  glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
126944825  axin-1 isoform X1 [KO:K02157]
126938336  axin-2 isoform X1 [KO:K04385]
126942456  LOW QUALITY PROTEIN: adenomatous polyposis coli protein 2 [KO:K02085]
126956213  adenomatous polyposis coli protein isoform X1 [KO:K02085]
126948505  catenin beta-1 isoform X1 [KO:K02105]
126956791  casein kinase I isoform X1 [KO:K08957] [EC:2.7.11.1]
126940310  casein kinase I [KO:K08957] [EC:2.7.11.1]
126955989  transcription factor 7 isoform X1 [KO:K02620]
126933391  transcription factor 7-like 1 isoform X1 [KO:K04490]
126962827  transcription factor 7-like 2 isoform X1 [KO:K04491]
126954934  lymphoid enhancer-binding factor 1 isoform X1 [KO:K04492]
126932076  nuclear factor erythroid 2-related factor 2 isoform X1 [KO:K05638]
126964018  heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
126944082  NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
126930060  glutathione S-transferase Mu 1 isoform X1 [KO:K00799] [EC:2.5.1.18]
126930154  glutathione S-transferase Mu 3 [KO:K00799] [EC:2.5.1.18]
126930168  glutathione S-transferase Mu 5 [KO:K00799] [EC:2.5.1.18]
126954620  microsomal glutathione S-transferase 2 isoform X1 [KO:K00799] [EC:2.5.1.18]
126931359  microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]
126963047  glutathione S-transferase omega-1 [KO:K00799] [EC:2.5.1.18]
126963049  glutathione S-transferase omega-2 [KO:K00799] [EC:2.5.1.18]
126946285  glutathione S-transferase omega-1-like [KO:K00799] [EC:2.5.1.18]
126952227  glutathione S-transferase A1-like [KO:K00799] [EC:2.5.1.18]
126941935  microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
126929522  glutathione S-transferase theta-4-like [KO:K00799] [EC:2.5.1.18]
126929523  glutathione S-transferase theta-2B [KO:K00799] [EC:2.5.1.18]
126929524  glutathione S-transferase theta-4 [KO:K00799] [EC:2.5.1.18]
126929525  glutathione S-transferase theta-1 isoform X1 [KO:K00799] [EC:2.5.1.18]
126953690  glutathione S-transferase A1 isoform X1 [KO:K00799] [EC:2.5.1.18]
126953691  glutathione S-transferase A4 [KO:K00799] [EC:2.5.1.18]
126953692  glutathione S-transferase A4-like [KO:K00799] [EC:2.5.1.18]
126949123  thioredoxin reductase 3 isoform X1 [KO:K22182] [EC:1.8.1.9]
126930901  thioredoxin reductase 1, cytoplasmic isoform X1 [KO:K22182] [EC:1.8.1.9]
126929633  thioredoxin reductase 2, mitochondrial isoform X1 [KO:K22182] [EC:1.8.1.9]
126949900  hepatocyte growth factor isoform X1 [KO:K05460]
126951204  hepatocyte growth factor receptor [KO:K05099] [EC:2.7.10.1]
126954977  GRB2-associated-binding protein 1 isoform X1 [KO:K09593]
126932601  actin, cytoplasmic 2 [KO:K05692]
126939111  actin, cytoplasmic 2 [KO:K05692]
126950494  actin, cytoplasmic 1 isoform X1 [KO:K05692]
126958358  LOW QUALITY PROTEIN: actin-like [KO:K05692]
126948386  actin-like protein 6A isoform X1 [KO:K11340]
126950369  actin-like protein 6B isoform X1 [KO:K11652]
126931017  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 isoform X1 [KO:K11650]
126939548  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 isoform X1 [KO:K11650]
126951604  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 isoform X1 [KO:K11650]
126952468  PHD finger protein 10 isoform X1 [KO:K22197]
126959544  zinc finger protein DPF3 [KO:K22198]
126942046  zinc finger protein neuro-d4 isoform X1 [KO:K22198]
126956941  AT-rich interactive domain-containing protein 1A isoform X1 [KO:K11653]
126952280  AT-rich interactive domain-containing protein 1B isoform X1 [KO:K11653]
126938503  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 isoform X1 [KO:K11651]
126929509  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 isoform X1 [KO:K11648]
126931199  SWI/SNF complex subunit SMARCC2 isoform X1 [KO:K11649]
126948636  SWI/SNF complex subunit SMARCC1 isoform X1 [KO:K11649]
126942462  transcription activator BRG1 isoform X1 [KO:K11647] [EC:5.6.2.-]
126937894  LOW QUALITY PROTEIN: probable global transcription activator SNF2L2 [KO:K11647] [EC:5.6.2.-]
126930147  AT-rich interactive domain-containing protein 2 [KO:K11765]
126947607  protein polybromo-1 isoform X1 [KO:K11757]
126944908  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
mthb04010  MAPK signaling pathway
mthb04020  Calcium signaling pathway
mthb04110  Cell cycle
mthb04115  p53 signaling pathway
mthb04151  PI3K-Akt signaling pathway
mthb04310  Wnt signaling pathway
mthb04350  TGF-beta signaling pathway
mthb04932  Non-alcoholic fatty liver disease
mthb04936  Alcoholic liver disease
mthb05160  Hepatitis C
mthb05161  Hepatitis B
KO pathway
ko05225   
LinkDB

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