KEGG   PATHWAY: ko05225
Entry
ko05225                     Pathway                                
Name
Hepatocellular carcinoma
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
ko05225  Hepatocellular carcinoma
ko05225

Disease
H00048  Hepatocellular carcinoma
Orthology
K00182  WNT2; wingless-type MMTV integration site family, member 2
K00312  WNT3; wingless-type MMTV integration site family, member 3
K00355  NQO1; NAD(P)H dehydrogenase (quinone) [EC:1.6.5.2]
K00408  WNT4; wingless-type MMTV integration site family, member 4
K00444  WNT5; wingless-type MMTV integration site family, member 5
K00445  WNT6; wingless-type MMTV integration site family, member 6
K00510  HMOX1; heme oxygenase 1 [EC:1.14.14.18]
K00572  WNT7; wingless-type MMTV integration site family, member 7
K00714  WNT8; wingless-type MMTV integration site family, member 8
K00799  GST; glutathione S-transferase [EC:2.5.1.18]
K00922  PIK3CA_B_D; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:2.7.1.153]
K01064  WNT9; wingless-type MMTV integration site family, member 9
K01110  PTEN; phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:3.1.3.16 3.1.3.48 3.1.3.67]
K01116  PLCG1; phosphatidylinositol phospholipase C, gamma-1 [EC:3.1.4.11]
K01357  WNT10; wingless-type MMTV integration site family, member 10
K01384  WNT11; wingless-type MMTV integration site family, member 11
K01558  WNT16; wingless-type MMTV integration site family, member 16
K02085  APC; adenomatosis polyposis coli protein
K02089  CDK4; cyclin-dependent kinase 4 [EC:2.7.11.22]
K02091  CDK6; cyclin-dependent kinase 6 [EC:2.7.11.22]
K02105  CTNNB1; catenin beta 1
K02157  AXIN1; axin 1
K02158  BAD; Bcl-2-antagonist of cell death
K02159  BAX; apoptosis regulator BAX
K02235  FZD2; frizzled 2
K02329  FZD3; frizzled 3
K02353  DVL; segment polarity protein dishevelled
K02354  FZD4, fz4, CD344; frizzled 4
K02375  FZD5_8, fz2; frizzled 5/8
K02376  FZD6; frizzled 6
K02432  FZD1_7, fz; frizzled 1/7
K02620  TCF7, TCF-1; transcription factor 7
K02649  PIK3R1_2_3; phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K02677  PRKCA; classical protein kinase C alpha type [EC:2.7.11.13]
K02833  HRAS; GTPase HRas
K02842  FZD9_10, CD349_50; frizzled 9/10
K03068  LRP5_6; low density lipoprotein receptor-related protein 5/6
K03069  FRAT1; frequently rearranged in advanced T-cell lymphomas 1
K03083  GSK3B; glycogen synthase kinase 3 beta [EC:2.7.11.26]
K03096  FRAT2; frequently rearranged in advanced T-cell lymphomas 2
K03099  SOS; son of sevenless
K03209  WNT1; wingless-type MMTV integration site family, member 1
K03511  POLK; DNA polymerase kappa [EC:2.7.7.7]
K04361  EGFR, ERBB1; epidermal growth factor receptor [EC:2.7.10.1]
K04364  GRB2; growth factor receptor-bound protein 2
K04365  BRAF; B-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04366  RAF1; RAF proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K04368  MAP2K1, MEK1; mitogen-activated protein kinase kinase 1 [EC:2.7.12.2]
K04369  MAP2K2, MEK2; mitogen-activated protein kinase kinase 2 [EC:2.7.12.2]
K04371  ERK, MAPK1_3; mitogen-activated protein kinase 1/3 [EC:2.7.11.24]
K04375  ELK1; ETS domain-containing protein Elk-1
K04377  MYC; Myc proto-oncogene protein
K04385  AXIN2; axin 2
K04388  TGFBR2; TGF-beta receptor type-2 [EC:2.7.11.30]
K04402  GADD45; growth arrest and DNA-damage-inducible protein
K04451  TP53, P53; tumor protein p53
K04456  AKT; RAC serine/threonine-protein kinase [EC:2.7.11.1]
K04490  TCF7L1; transcription factor 7-like 1
K04491  TCF7L2; transcription factor 7-like 2
K04492  LEF1; lymphoid enhancer-binding factor 1
K04500  SMAD2; mothers against decapentaplegic homolog 2
K04501  SMAD4; mothers against decapentaplegic homolog 4
K04503  CCND1; G1/S-specific cyclin-D1
K04570  BCL2L1, bcl-xL; Bcl-2-like 1 (apoptosis regulator Bcl-X)
K04674  TGFBR1, ALK5; TGF-beta receptor type-1 [EC:2.7.11.30]
K04688  RPS6KB; ribosomal protein S6 kinase beta [EC:2.7.11.1]
K05087  IGF1R, CD221; insulin-like growth factor 1 receptor [EC:2.7.10.1]
K05099  MET, HGFR; proto-oncogene tyrosine-protein kinase Met [EC:2.7.10.1]
K05460  HGF; hepatocyte growth factor
K05638  NFE2L2, NRF2; nuclear factor erythroid 2-related factor 2
K05692  ACTB_G1; actin beta/gamma 1
K05859  PLCG2; phosphatidylinositol phospholipase C, gamma-2 [EC:3.1.4.11]
K06279  SHC1; SHC-transforming protein 1
K06618  RB1; retinoblastoma-associated protein
K06620  E2F3; transcription factor E2F3
K06621  CDKN2A, P16, INK4A; cyclin-dependent kinase inhibitor 2A
K06625  CDKN1A, P21, CIP1; cyclin-dependent kinase inhibitor 1A
K07203  MTOR, FRAP, TOR; serine/threonine-protein kinase mTOR [EC:2.7.11.1]
K07827  KRAS, KRAS2; GTPase KRas
K07828  NRAS; GTPase NRas
K08774  TGFA; transforming growth factor, alpha
K08845  ARAF, ARAF1; A-Raf proto-oncogene serine/threonine-protein kinase [EC:2.7.11.1]
K08957  CSNK1A; casein kinase 1, alpha [EC:2.7.11.1]
K09389  E2F2; transcription factor E2F2
K09593  GAB1; GRB2-associated-binding protein 1
K10140  DDB2; DNA damage-binding protein 2
K10456  KLHL19, KEAP1, INRF2; kelch-like protein 19
K11126  TERT, EST2; telomerase reverse transcriptase [EC:2.7.7.49]
K11340  ACTL6A, INO80K; actin-like protein 6A
K11647  SMARCA2_4; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2/4 [EC:5.6.2.-]
K11648  SMARCB1, SNF5, INI1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1
K11649  SMARCC; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C
K11650  SMARCD; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D
K11651  SMARCE1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1
K11652  ACTL6B; actin-like protein 6B
K11653  ARID1; AT-rich interactive domain-containing protein 1
K11723  BRD7; bromodomain-containing protein 7
K11757  PBRM1, PB1; protein polybromo-1
K11765  ARID2; AT-rich interactive domain-containing protein 2
K13375  TGFB1; transforming growth factor beta-1
K13376  TGFB2; transforming growth factor beta-2
K13377  TGFB3; transforming growth factor beta-3
K13769  IGF2; insulin-like growth factor 2
K14021  BAK, BAK1; Bcl-2 homologous antagonist/killer
K17447  SHC2; SHC-transforming protein 2
K17448  SHC3; SHC-transforming protein 3
K17449  SHC4; SHC-transforming protein 4
K17454  E2F1; transcription factor E2F1
K19662  PRKCB; classical protein kinase C beta type [EC:2.7.11.13]
K19663  PRKCG; classical protein kinase C gamma type [EC:2.7.11.13]
K22182  TXNRD; thioredoxin reductase (NADPH) [EC:1.8.1.9]
K22183  TERC; telomerase RNA component
K22197  BAF45A, PHF10; BRG1-associated factor 45A
K22198  DPF1_3; zinc finger protein neuro-d4/cer-d4
K23605  SMAD3; mothers against decapentaplegic homolog 3
K23790  GSTP; glutathione S-transferase P
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
ko04010  MAPK signaling pathway
ko04020  Calcium signaling pathway
ko04110  Cell cycle
ko04115  p53 signaling pathway
ko04151  PI3K-Akt signaling pathway
ko04310  Wnt signaling pathway
ko04350  TGF-beta signaling pathway
ko04932  Non-alcoholic fatty liver disease
ko04936  Alcoholic liver disease
ko05160  Hepatitis C
ko05161  Hepatitis B

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