KEGG   PATHWAY: tup05225
Entry
tup05225                    Pathway                                
Name
Hepatocellular carcinoma - Tupaia chinensis (Chinese tree shrew)
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
tup05225  Hepatocellular carcinoma
tup05225

Disease
H00048  Hepatocellular carcinoma
Organism
Tupaia chinensis (Chinese tree shrew) [GN:tup]
Gene
102467720  WNT5B; Wnt family member 5B [KO:K00444]
102467923  ARID1B; AT-rich interaction domain 1B [KO:K11653]
102468229  WNT8B; Wnt family member 8B [KO:K00714]
102468765  [KO:K23790]
102468994  DVL1; dishevelled segment polarity protein 1 [KO:K02353]
102469271  PRKCB; protein kinase C beta [KO:K19662] [EC:2.7.11.13]
102469399  AXIN1; axin 1 [KO:K02157]
102469401  PIK3R2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
102469468  TERT; telomerase reverse transcriptase [KO:K11126] [EC:2.7.7.49]
102469651  PLCG1; phospholipase C gamma 1 [KO:K01116] [EC:3.1.4.11]
102470052  APC2; APC2, WNT signaling pathway regulator [KO:K02085]
102470193  [KO:K23790]
102470932  MGST2; microsomal glutathione S-transferase 2 [KO:K00799] [EC:2.5.1.18]
102471776  BAX; BCL2 associated X, apoptosis regulator [KO:K02159]
102472172  AKT2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
102472217  SMARCA4; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4 [KO:K11647] [EC:5.6.2.-]
102472295  SHC3; SHC adaptor protein 3 [KO:K17448]
102472352  DVL3; dishevelled segment polarity protein 3 [KO:K02353]
102472614  DDB2; damage specific DNA binding protein 2 [KO:K10140]
102472740  CTNNB1; catenin beta 1 [KO:K02105]
102472810  TCF7L2; transcription factor 7 like 2 [KO:K04491]
102473158  SMAD3; SMAD family member 3 [KO:K23605]
102473447  LRP5L; LDL receptor related protein 5 like [KO:K03068]
102473496  IGF1R; insulin like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
102474297  AKT3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
102474621  LEF1; lymphoid enhancer binding factor 1 [KO:K04492]
102474832  ARID2; AT-rich interaction domain 2 [KO:K11765]
102474963  FZD3; frizzled class receptor 3 [KO:K02329]
102475157  FZD5; frizzled class receptor 5 [KO:K02375]
102475242  SMARCD1; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 1 [KO:K11650]
102475423  RPS6KB2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
102475793  NFE2L2; nuclear factor erythroid 2-related factor 2 [KO:K05638]
102476038  GSK3B; glycogen synthase kinase 3 beta [KO:K03083] [EC:2.7.11.26]
102476496  MAP2K1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
102476523  GADD45B; growth arrest and DNA damage inducible beta [KO:K04402]
102476690  BAK1; BCL2 antagonist/killer 1 [KO:K14021]
102476700  TGFBR1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
102477020  [KO:K00799] [EC:2.5.1.18]
102477222  SOS2; SOS Ras/Rho guanine nucleotide exchange factor 2 [KO:K03099]
102477389  BRAF; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
102477705  [KO:K00799] [EC:2.5.1.18]
102477916  ACTL6B; actin like 6B [KO:K11652]
102478173  SMARCA2; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 2 [KO:K11647] [EC:5.6.2.-]
102478253  [KO:K00799] [EC:2.5.1.18]
102478748  MGST1; microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]
102479291  GSTM1; glutathione S-transferase Mu 2 [KO:K00799] [EC:2.5.1.18]
102479307  FZD2; frizzled class receptor 2 [KO:K02235]
102479454  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
102479635  MGST3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
102479669  E2F2; E2F transcription factor 2 [KO:K09389]
102479734  SHC4; SHC adaptor protein 4 [KO:K17449]
102479813  FZD10; frizzled class receptor 10 [KO:K02842]
102479831  WNT2B; Wnt family member 2B [KO:K00182]
102479926  ACTB; actin beta [KO:K05692]
102480006  [KO:K00799] [EC:2.5.1.18]
102480504  PHF10; PHD finger protein 10 [KO:K22197]
102481002  SHC1; SHC adaptor protein 1 [KO:K06279]
102481011  FZD9; frizzled class receptor 9 [KO:K02842]
102481112  GSTM3; glutathione S-transferase Mu 3 [KO:K00799] [EC:2.5.1.18]
102481394  TCF7L1; transcription factor 7 like 1 [KO:K04490]
102481567  WNT10B; Wnt family member 10B [KO:K01357]
102481608  IGF2; insulin like growth factor 2 [KO:K13769]
102481863  SHC2; SHC adaptor protein 2 [KO:K17447]
102481953  [KO:K00799] [EC:2.5.1.18]
102483057  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
102483253  WNT10A; Wnt family member 10A [KO:K01357]
102483329  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
102483550  [KO:K00799] [EC:2.5.1.18]
102483667  WNT6; Wnt family member 6 [KO:K00445]
102483689  HGF; hepatocyte growth factor [KO:K05460]
102483700  MAP2K2; mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
102483771  GSTO2; glutathione S-transferase omega-2 [KO:K00799] [EC:2.5.1.18]
102483786  PLCG2; phospholipase C gamma 2 [KO:K05859] [EC:3.1.4.11]
102483867  WNT2; Wnt family member 2 [KO:K00182]
102484318  TCF7; transcription factor 7 (T-cell specific, HMG-box) [KO:K02620]
102484353  WNT7A; Wnt family member 7A [KO:K00572]
102484444  PIK3R3; phosphoinositide-3-kinase regulatory subunit 3 [KO:K02649]
102484500  PIK3R1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
102484573  ACTL6A; actin like 6A [KO:K11340]
102484832  E2F1; E2F transcription factor 1 [KO:K17454]
102484859  APC; APC, WNT signaling pathway regulator [KO:K02085]
102485262  MTOR; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
102485304  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
102485388  ARID1A; AT-rich interaction domain 1A [KO:K11653]
102485749  DVL2; dishevelled segment polarity protein 2 [KO:K02353]
102485781  HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
102485847  MET; MET proto-oncogene, receptor tyrosine kinase [KO:K05099] [EC:2.7.10.1]
102485880  GSTO1; glutathione S-transferase omega 1 [KO:K00799] [EC:2.5.1.18]
102486356  [KO:K00799] [EC:2.5.1.18]
102486518  TGFBR2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
102486626  BCL2L1; BCL2 like 1 [KO:K04570]
102487480  FZD8; frizzled class receptor 8 [KO:K02375]
102487582  GSTA1; glutathione S-transferase A1 [KO:K00799] [EC:2.5.1.18]
102487868  SMARCB1; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily b, member 1 [KO:K11648]
102487962  CSNK1A1; casein kinase 1 alpha 1 [KO:K08957] [EC:2.7.11.1]
102487997  [KO:K00799] [EC:2.5.1.18]
102488432  CDK6; cyclin dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
102488524  TGFB1; transforming growth factor beta 1 [KO:K13375]
102489001  WNT3; Wnt family member 3 [KO:K00312]
102489031  DPF1; double PHD fingers 1 [KO:K22198]
102489114  PTEN; phosphatase and tensin homolog [KO:K01110] [EC:3.1.3.16 3.1.3.48 3.1.3.67]
102489417  WNT9B; Wnt family member 9B [KO:K01064]
102489573  WNT5A; Wnt family member 5A [KO:K00444]
102490159  CDKN1A; cyclin dependent kinase inhibitor 1A [KO:K06625]
102490209  WNT8A; Wnt family member 8A [KO:K00714]
102490230  [KO:K00799] [EC:2.5.1.18]
102490651  CCND1; cyclin D1 [KO:K04503]
102490659  [KO:K00799] [EC:2.5.1.18]
102490837  KEAP1; kelch like ECH associated protein 1 [KO:K10456]
102491074  [KO:K00799] [EC:2.5.1.18]
102491333  DPF3; double PHD fingers 3 [KO:K22198]
102491949  FZD4; frizzled class receptor 4 [KO:K02354]
102492163  FZD7; frizzled class receptor 7 [KO:K02432]
102492375  FZD6; frizzled class receptor 6 [KO:K02376]
102492549  SMARCC2; SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 2 [KO:K11649]
102492771  AKT1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
102493020  SMARCC1; SWI/SNF related, matrix associated, actin dependent regulator of chromatin subfamily c member 1 [KO:K11649]
102493080  GRB2; growth factor receptor bound protein 2 [KO:K04364]
102493152  RPS6KB1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
102493230  HRAS; HRas proto-oncogene, GTPase [KO:K02833]
102493239  ARAF; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
102493291  CDK4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
102493340  WNT4; Wnt family member 4 [KO:K00408]
102493581  NQO1; NAD(P)H quinone dehydrogenase 1 [KO:K00355] [EC:1.6.5.2]
102493766  AXIN2; axin 2 [KO:K04385]
102493831  PBRM1; polybromo 1 [KO:K11757]
102493944  TXNRD2; thioredoxin reductase 2 [KO:K22182] [EC:1.8.1.9]
102494008  SMAD4; SMAD family member 4 [KO:K04501]
102494041  SMARCD2; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 2 [KO:K11650]
102494629  SOS1; SOS Ras/Rac guanine nucleotide exchange factor 1 [KO:K03099]
102494763  ELK1; ELK1, ETS transcription factor [KO:K04375]
102494826  WNT11; Wnt family member 11 [KO:K01384]
102495954  PRKCA; protein kinase C alpha [KO:K02677] [EC:2.7.11.13]
102496226  WNT9A; Wnt family member 9A [KO:K01064]
102496453  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
102496534  NRAS; neuroblastoma RAS viral oncogene homolog [KO:K07828]
102496861  GADD45G; growth arrest and DNA damage inducible gamma [KO:K04402]
102497004  BRD7; bromodomain containing 7 [KO:K11723]
102497029  TGFB3; transforming growth factor beta 3 [KO:K13377]
102497204  PRKCG; protein kinase C gamma [KO:K19663] [EC:2.7.11.13]
102497215  [KO:K00799] [EC:2.5.1.18]
102497468  GAB1; GRB2 associated binding protein 1 [KO:K09593]
102497488  RAF1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
102497530  WNT16; Wnt family member 16 [KO:K01558]
102497711  [KO:K22182] [EC:1.8.1.9]
102497817  TGFA; transforming growth factor alpha [KO:K08774]
102498069  BAD; BCL2 associated agonist of cell death [KO:K02158]
102498431  ACTG1; actin gamma 1 [KO:K05692]
102499190  WNT1; Wnt family member 1 [KO:K03209]
102499195  FZD1; frizzled class receptor 1 [KO:K02432]
102499416  E2F3; E2F transcription factor 3 [KO:K06620]
102499507  RB1; RB transcriptional corepressor 1 [KO:K06618]
102499541  SMAD2; SMAD family member 2 [KO:K04500]
102499658  TXNRD1; thioredoxin reductase 1 [KO:K22182] [EC:1.8.1.9]
102500004  WNT7B; Wnt family member 7B [KO:K00572]
102500069  KRAS; KRAS proto-oncogene, GTPase [KO:K07827]
102500482  TGFB2; transforming growth factor beta 2 [KO:K13376]
102500530  PIK3CD; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
102501022  SMARCE1; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily e, member 1 [KO:K11651]
102501247  SMARCD3; SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily d, member 3 [KO:K11650]
102501628  WNT3A; Wnt family member 3A [KO:K00312]
102501999  MYC; v-myc avian myelocytomatosis viral oncogene homolog [KO:K04377]
102502071  LRP6; LDL receptor related protein 6 [KO:K03068]
102502163  PIK3CB; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
102502702  TXNRD3; thioredoxin reductase 3 [KO:K22182] [EC:1.8.1.9]
102502813  GADD45A; growth arrest and DNA damage inducible alpha [KO:K04402]
102503238  TP53; tumor protein p53 [KO:K04451]
106733134  [KO:K00799] [EC:2.5.1.18]
106735193  [KO:K05638]
106736453  [KO:K00922] [EC:2.7.1.153]
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
tup04010  MAPK signaling pathway
tup04020  Calcium signaling pathway
tup04110  Cell cycle
tup04115  p53 signaling pathway
tup04151  PI3K-Akt signaling pathway
tup04310  Wnt signaling pathway
tup04350  TGF-beta signaling pathway
tup04932  Non-alcoholic fatty liver disease
tup04936  Alcoholic liver disease
tup05160  Hepatitis C
tup05161  Hepatitis B
KO pathway
ko05225   

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