KEGG   PATHWAY: ko05225
ko05225                     Pathway                                
Hepatocellular carcinoma
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.
Human Diseases; Cancer: specific types
Pathway map
ko05225  Hepatocellular carcinoma

H00048  Hepatocellular carcinoma
K08774  transforming growth factor, alpha
K04361  epidermal growth factor receptor [EC:]
K13769  insulin-like growth factor 2
K05087  insulin-like growth factor 1 receptor [EC:]
K01116  phosphatidylinositol phospholipase C, gamma-1 [EC:]
K05859  phosphatidylinositol phospholipase C, gamma-2 [EC:]
K02677  classical protein kinase C alpha type [EC:]
K19662  classical protein kinase C beta type [EC:]
K19663  classical protein kinase C gamma type [EC:]
K04375  ETS domain-containing protein Elk-1
K06279  SHC-transforming protein 1
K17447  SHC-transforming protein 2
K17448  SHC-transforming protein 3
K17449  SHC-transforming protein 4
K04364  growth factor receptor-bound protein 2
K03099  son of sevenless
K02833  GTPase HRas
K07827  GTPase KRas
K07828  GTPase NRas
K08845  A-Raf proto-oncogene serine/threonine-protein kinase [EC:]
K04365  B-Raf proto-oncogene serine/threonine-protein kinase [EC:]
K04366  RAF proto-oncogene serine/threonine-protein kinase [EC:]
K04368  mitogen-activated protein kinase kinase 1 [EC:]
K04369  mitogen-activated protein kinase kinase 2 [EC:]
K04371  mitogen-activated protein kinase 1/3 [EC:]
K00922  phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha/beta/delta [EC:]
K02649  phosphoinositide-3-kinase regulatory subunit alpha/beta/delta
K01110  phosphatidylinositol-3,4,5-trisphosphate 3-phosphatase and dual-specificity protein phosphatase PTEN [EC:]
K04456  RAC serine/threonine-protein kinase [EC:]
K07203  serine/threonine-protein kinase mTOR [EC:]
K04688  ribosomal protein S6 kinase beta [EC:]
K02158  Bcl-2-antagonist of cell death
K04570  Bcl-2-like 1 (apoptosis regulator Bcl-X)
K04377  Myc proto-oncogene protein
K06618  retinoblastoma-associated protein
K17454  transcription factor E2F1
K09389  transcription factor E2F2
K06620  transcription factor E2F3
K11126  telomerase reverse transcriptase [EC:]
K22183  telomerase RNA component
K04451  tumor protein p53
K06625  cyclin-dependent kinase inhibitor 1A
K04402  growth arrest and DNA-damage-inducible protein
K02159  apoptosis regulator BAX
K14021  Bcl-2 homologous antagonist/killer
K10140  DNA damage-binding protein 2
K03511  DNA polymerase kappa [EC:]
K06621  cyclin-dependent kinase inhibitor 2A
K02089  cyclin-dependent kinase 4 [EC:]
K02091  cyclin-dependent kinase 6 [EC:]
K04503  G1/S-specific cyclin-D1
K13375  transforming growth factor beta-1
K13376  transforming growth factor beta-2
K13377  transforming growth factor beta-3
K04674  TGF-beta receptor type-1 [EC:]
K04388  TGF-beta receptor type-2 [EC:]
K04500  mothers against decapentaplegic homolog 2
K23605  mothers against decapentaplegic homolog 3
K04501  mothers against decapentaplegic homolog 4
K03209  wingless-type MMTV integration site family, member 1
K00182  wingless-type MMTV integration site family, member 2
K00312  wingless-type MMTV integration site family, member 3
K00408  wingless-type MMTV integration site family, member 4
K00444  wingless-type MMTV integration site family, member 5
K00445  wingless-type MMTV integration site family, member 6
K00572  wingless-type MMTV integration site family, member 7
K00714  wingless-type MMTV integration site family, member 8
K01064  wingless-type MMTV integration site family, member 9
K01357  wingless-type MMTV integration site family, member 10
K01384  wingless-type MMTV integration site family, member 11
K01558  wingless-type MMTV integration site family, member 16
K02432  frizzled 1/7
K02235  frizzled 2
K02329  frizzled 3
K02354  frizzled 4
K02375  frizzled 5/8
K02376  frizzled 6
K02842  frizzled 9/10
K03068  low density lipoprotein receptor-related protein 5/6
K02353  segment polarity protein dishevelled
K03069  frequently rearranged in advanced T-cell lymphomas 1
K03096  frequently rearranged in advanced T-cell lymphomas 2
K03083  glycogen synthase kinase 3 beta [EC:]
K02157  axin 1
K04385  axin 2
K02085  adenomatosis polyposis coli protein
K02105  catenin beta 1
K08957  casein kinase 1, alpha [EC:]
K02620  transcription factor 7
K04490  transcription factor 7-like 1
K04491  transcription factor 7-like 2
K04492  lymphoid enhancer-binding factor 1
K10456  kelch-like protein 19
K05638  nuclear factor erythroid 2-related factor 2
K00510  heme oxygenase 1 [EC:]
K00355  NAD(P)H dehydrogenase (quinone) [EC:]
K00799  glutathione S-transferase [EC:]
K23790  glutathione S-transferase P [EC:]
K22182  thioredoxin reductase (NADPH) [EC:]
K05460  hepatocyte growth factor
K05099  proto-oncogene tyrosine-protein kinase Met [EC:]
K09593  GRB2-associated-binding protein 1
K05692  actin beta/gamma 1
K11340  actin-like protein 6A
K11652  actin-like protein 6B
K11650  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D
K22197  BRG1-associated factor 45A
K22198  BRG1-associated factor 45B/C
K11653  AT-rich interactive domain-containing protein 1
K11651  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1
K11648  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1
K11649  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily C
K11647  SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily A member 2/4 [EC:5.6.2.-]
K11765  AT-rich interactive domain-containing protein 2
K11757  protein polybromo-1
K11723  bromodomain-containing protein 7
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
Whittaker S, Marais R, Zhu AX
The role of signaling pathways in the development and treatment of hepatocellular carcinoma.
Oncogene 29:4989-5005 (2010)
Zucman-Rossi J, Villanueva A, Nault JC, Llovet JM
Genetic Landscape and Biomarkers of Hepatocellular Carcinoma.
Gastroenterology 149:1226-1239.e4 (2015)
Villanueva A, Newell P, Chiang DY, Friedman SL, Llovet JM.
Genomics and signaling pathways in hepatocellular carcinoma.
Semin Liver Dis 27:55-76 (2007)
Breuhahn K, Longerich T, Schirmacher P
Dysregulation of growth factor signaling in human hepatocellular carcinoma.
Oncogene 25:3787-800 (2006)
Minguez B, Tovar V, Chiang D, Villanueva A, Llovet JM
Pathogenesis of hepatocellular carcinoma and molecular therapies.
Curr Opin Gastroenterol 25:186-94 (2009)
Kudo M
Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma.
Dig Dis 29:289-302 (2011)
Nault JC, Zucman-Rossi J
Genetics of hepatocellular carcinoma: the next generation.
J Hepatol 60:224-6 (2014)
Rocken C, Carl-McGrath S.
Pathology and pathogenesis of hepatocellular carcinoma.
Dig Dis 19:269-78 (2001)
Cornella H, Alsinet C, Villanueva A
Molecular pathogenesis of hepatocellular carcinoma.
Alcohol Clin Exp Res 35:821-5 (2011)
Niu ZS, Niu XJ, Wang WH
Genetic alterations in hepatocellular carcinoma: An update.
World J Gastroenterol 22:9069-9095 (2016)
Tannapfel A, Wittekind C
Genes involved in hepatocellular carcinoma: deregulation in cell cycling and apoptosis.
Virchows Arch 440:345-52 (2002)
Shiraha H, Yamamoto K, Namba M
Human hepatocyte carcinogenesis (review).
Int J Oncol 42:1133-8 (2013)
Nault JC, Mallet M, Pilati C, Calderaro J, Bioulac-Sage P, Laurent C, Laurent A, Cherqui D, Balabaud C, Zucman-Rossi J
High frequency of telomerase reverse-transcriptase promoter somatic mutations in hepatocellular carcinoma and preneoplastic lesions.
Nat Commun 4:2218 (2013)
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
Integrated analysis of somatic mutations and focal copy-number changes identifies key genes and pathways in hepatocellular carcinoma.
Nat Genet 44:694-8 (2012)
Praslicka BJ, Kerins MJ, Ooi A
The complex role of NRF2 in cancer: a genomic view
Curr Opin Toxicol 1:37-45 (2016)
Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL
The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer.
Redox Biol 1:45-9 (2013)
Taguchi K, Motohashi H, Yamamoto M
Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution.
Genes Cells 16:123-40 (2011)
Klaunig JE, Kamendulis LM, Hocevar BA
Oxidative stress and oxidative damage in carcinogenesis.
Toxicol Pathol 38:96-109 (2010)
Krupp G, Bonatz G, Parwaresch R
Telomerase, immortality and cancer.
Biotechnol Annu Rev 6:103-40 (2000)
Jafri MA, Ansari SA, Alqahtani MH, Shay JW
Roles of telomeres and telomerase in cancer, and advances in telomerase-targeted therapies.
Genome Med 8:69 (2016)
Shay JW
Role of Telomeres and Telomerase in Aging and Cancer.
Cancer Discov 6:584-93 (2016)
Granito A, Guidetti E, Gramantieri L
c-MET receptor tyrosine kinase as a molecular target in advanced hepatocellular carcinoma.
J Hepatocell Carcinoma 2:29-38 (2015)
Vita M, Henriksson M
The Myc oncoprotein as a therapeutic target for human cancer.
Semin Cancer Biol 16:318-30 (2006)
Qu A, Jiang C, Cai Y, Kim JH, Tanaka N, Ward JM, Shah YM, Gonzalez FJ
Role of Myc in hepatocellular proliferation and hepatocarcinogenesis.
J Hepatol 60:331-8 (2014)
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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