KEGG   PATHWAY: setr05225
Entry
setr05225                   Pathway                                
Name
Hepatocellular carcinoma - Suncus etruscus (white-toothed pygmy 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
setr05225  Hepatocellular carcinoma
setr05225

Disease
H00048  Hepatocellular carcinoma
Organism
Suncus etruscus (white-toothed pygmy shrew) [GN:setr]
Gene
125994798  [KO:K03069]
125994817  GSTO1; glutathione S-transferase omega-1 [KO:K00799] [EC:2.5.1.18]
125994820  [KO:K03096]
125994848  WNT8B; protein Wnt-8b [KO:K00714]
125994905  TCF7L2; transcription factor 7-like 2 isoform X1 [KO:K04491]
125995088  TXNRD2; thioredoxin reductase 2, mitochondrial isoform X1 [KO:K22182] [EC:1.8.1.9]
125995101  PTEN; 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]
125996177  E2F3; transcription factor E2F3 [KO:K06620]
125996343  BAK1; bcl-2 homologous antagonist/killer [KO:K14021]
125996373  ARID1B; AT-rich interactive domain-containing protein 1B isoform X1 [KO:K11653]
125996497  CDKN1A; cyclin-dependent kinase inhibitor 1 [KO:K06625]
125997181  MYC; myc proto-oncogene protein [KO:K04377]
125997360  [KO:K00799] [EC:2.5.1.18]
125997361  [KO:K00799] [EC:2.5.1.18]
125997363  [KO:K00799] [EC:2.5.1.18]
125997364  [KO:K00799] [EC:2.5.1.18]
125997372  NRAS; GTPase NRas [KO:K07828]
125997382  WNT2B; protein Wnt-2b [KO:K00182]
125997398  [KO:K00799] [EC:2.5.1.18]
125997897  TGFBR2; TGF-beta receptor type-2 [KO:K04388] [EC:2.7.11.30]
125998008  DVL2; segment polarity protein dishevelled homolog DVL-2 [KO:K02353]
125998025  TP53; LOW QUALITY PROTEIN: cellular tumor antigen p53 [KO:K04451]
125998044  RAF1; RAF proto-oncogene serine/threonine-protein kinase isoform X1 [KO:K04366] [EC:2.7.11.1]
125998256  TXNRD3; thioredoxin reductase 3 [KO:K22182] [EC:1.8.1.9]
125998259  WNT7A; protein Wnt-7a [KO:K00572]
125998802  [KO:K08957] [EC:2.7.11.1]
125998822  [KO:K08957] [EC:2.7.11.1]
125999018  SOS2; son of sevenless homolog 2 [KO:K03099]
125999215  ELK1; ETS domain-containing protein Elk-1 [KO:K04375]
125999333  ARAF; serine/threonine-protein kinase A-Raf [KO:K08845] [EC:2.7.11.1]
125999360  [KO:K08957] [EC:2.7.11.1]
126000852  AXIN1; LOW QUALITY PROTEIN: axin-1 [KO:K02157]
126000870  WNT10A; protein Wnt-10a [KO:K01357]
126000878  WNT6; protein Wnt-6 [KO:K00445]
126001478  POLK; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
126001552  PIK3R1; LOW QUALITY PROTEIN: phosphatidylinositol 3-kinase regulatory subunit alpha [KO:K02649]
126001801  TERT; telomerase reverse transcriptase [KO:K11126] [EC:2.7.7.49]
126001825  FZD1; frizzled-1 [KO:K02432]
126001866  [KO:K00444]
126002025  FZD10; frizzled-10 [KO:K02842]
126002884  GSTP1; LOW QUALITY PROTEIN: glutathione S-transferase P [KO:K23790]
126003348  TGFB2; transforming growth factor beta-2 proprotein isoform X1 [KO:K13376]
126003375  SHC3; SHC-transforming protein 3 [KO:K17448]
126003398  GADD45G; growth arrest and DNA damage-inducible protein GADD45 gamma [KO:K04402]
126003551  GRB2; growth factor receptor-bound protein 2 [KO:K04364]
126003919  TGFBR1; TGF-beta receptor type-1 [KO:K04674] [EC:2.7.11.30]
126004037  TGFB3; transforming growth factor beta-3 proprotein isoform X1 [KO:K13377]
126004044  DPF3; zinc finger protein DPF3 [KO:K22198]
126004441  GAB1; GRB2-associated-binding protein 1 [KO:K09593]
126004442  MGST2; microsomal glutathione S-transferase 2 [KO:K00799] [EC:2.5.1.18]
126004843  MET; hepatocyte growth factor receptor isoform X1 [KO:K05099] [EC:2.7.10.1]
126004925  WNT2; protein Wnt-2 [KO:K00182]
126005800  FZD3; frizzled-3 [KO:K02329]
126005833  WNT16; protein Wnt-16 [KO:K01558]
126006279  WNT7B; protein Wnt-7b [KO:K00572]
126006302  HMOX1; heme oxygenase 1 [KO:K00510] [EC:1.14.14.18]
126006378  RPS6KB1; ribosomal protein S6 kinase beta-1 [KO:K04688] [EC:2.7.11.1]
126008496  HGF; hepatocyte growth factor isoform X1 [KO:K05460]
126008919  FZD5; frizzled-5 [KO:K02375]
126008922  FZD7; frizzled-7 [KO:K02432]
126009063  NFE2L2; nuclear factor erythroid 2-related factor 2 isoform X1 [KO:K05638]
126009440  FZD6; frizzled-6 [KO:K02376]
126009952  SMARCA2; LOW QUALITY PROTEIN: probable global transcription activator SNF2L2 [KO:K11647] [EC:5.6.2.-]
126010754  BRAF; serine/threonine-protein kinase B-raf isoform X1 [KO:K04365] [EC:2.7.11.1]
126010817  GADD45A; growth arrest and DNA damage-inducible protein GADD45 alpha [KO:K04402]
126010910  DVL1; segment polarity protein dishevelled homolog DVL-1 isoform X1 [KO:K02353]
126011086  PIK3R3; phosphatidylinositol 3-kinase regulatory subunit gamma isoform X1 [KO:K02649]
126011154  E2F2; transcription factor E2F2 [KO:K09389]
126011385  ARID1A; AT-rich interactive domain-containing protein 1A [KO:K11653]
126011494  MTOR; serine/threonine-protein kinase mTOR [KO:K07203] [EC:2.7.11.1]
126011501  PIK3CD; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit delta isoform [KO:K00922] [EC:2.7.1.153]
126011761  WNT4; protein Wnt-4 [KO:K00408]
126011777  [KO:K08957] [EC:2.7.11.1]
126011810  [KO:K08957] [EC:2.7.11.1]
126011842  [KO:K08957] [EC:2.7.11.1]
126012017  [KO:K11723]
126012035  PIK3CB; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit beta isoform [KO:K00922] [EC:2.7.1.153]
126012036  PIK3CA; phosphatidylinositol 4,5-bisphosphate 3-kinase catalytic subunit alpha isoform [KO:K00922] [EC:2.7.1.153]
126012051  DVL3; segment polarity protein dishevelled homolog DVL-3 [KO:K02353]
126012067  ACTL6A; actin-like protein 6A [KO:K11340]
126012206  APC; adenomatous polyposis coli protein isoform X1 [KO:K02085]
126013194  PBRM1; protein polybromo-1 [KO:K11757]
126013216  WNT5A; protein Wnt-5a [KO:K00444]
126013384  FZD8; frizzled-8 [KO:K02375]
126013417  AKT3; RAC-gamma serine/threonine-protein kinase isoform X1 [KO:K04456] [EC:2.7.11.1]
126013497  MGST3; microsomal glutathione S-transferase 3 [KO:K00799] [EC:2.5.1.18]
126013539  ACTG1; actin, cytoplasmic 2 [KO:K05692]
126013756  [KO:K00799] [EC:2.5.1.18]
126013757  [KO:K00799] [EC:2.5.1.18]
126013822  [KO:K00799] [EC:2.5.1.18]
126013961  EGFR; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
126014024  SMARCC1; SWI/SNF complex subunit SMARCC1 [KO:K11649]
126015278  SMARCD3; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 3 isoform X1 [KO:K11650]
126015505  SMAD3; mothers against decapentaplegic homolog 3 [KO:K23605]
126015509  WNT3A; protein Wnt-3a [KO:K00312]
126015547  WNT9A; protein Wnt-9a [KO:K01064]
126016198  RB1; retinoblastoma-associated protein isoform X1 [KO:K06618]
126017276  PLCG1; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-1 isoform X1 [KO:K01116] [EC:3.1.4.11]
126017297  PRKCA; protein kinase C alpha type [KO:K02677] [EC:2.7.11.13]
126017437  BCL2L1; bcl-2-like protein 1 [KO:K04570]
126017556  E2F1; transcription factor E2F1 [KO:K17454]
126017563  SMARCD2; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 2 [KO:K11650]
126017658  DDB2; DNA damage-binding protein 2 [KO:K10140]
126017861  BAD; bcl2-associated agonist of cell death [KO:K02158]
126017963  FZD4; frizzled-4 [KO:K02354]
126018112  SMARCE1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily E member 1 isoform X1 [KO:K11651]
126018176  WNT11; protein Wnt-11 [KO:K01384]
126018332  FZD2; frizzled-2 [KO:K02235]
126018525  WNT3; proto-oncogene Wnt-3 [KO:K00312]
126019034  RPS6KB2; ribosomal protein S6 kinase beta-2 isoform X1 [KO:K04688] [EC:2.7.11.1]
126019044  LRP5; low-density lipoprotein receptor-related protein 5 [KO:K03068]
126019074  CCND1; G1/S-specific cyclin-D1 [KO:K04503]
126019084  HRAS; GTPase HRas [KO:K02833]
126019086  IGF2; insulin-like growth factor II isoform X1 [KO:K13769]
126020007  SHC4; SHC-transforming protein 4 [KO:K17449]
126020077  SMAD4; mothers against decapentaplegic homolog 4 [KO:K04501]
126020080  SMAD2; mothers against decapentaplegic homolog 2 [KO:K04500]
126020238  AXIN2; axin-2 [KO:K04385]
126020709  SHC1; SHC-transforming protein 1 isoform X1 [KO:K06279]
126020938  CTNNB1; catenin beta-1 [KO:K02105]
126021814  IGF1R; insulin-like growth factor 1 receptor [KO:K05087] [EC:2.7.10.1]
126021920  MAP2K1; dual specificity mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
126022042  LRP6; low-density lipoprotein receptor-related protein 6 [KO:K03068]
126022162  [KO:K02376]
126022235  CDK4; cyclin-dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
126022319  TXNRD1; thioredoxin reductase 1, cytoplasmic [KO:K22182] [EC:1.8.1.9]
126022357  WNT5B; LOW QUALITY PROTEIN: protein Wnt-5b [KO:K00444]
126022499  SMARCD1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily D member 1 [KO:K11650]
126022551  WNT10B; protein Wnt-10b [KO:K01357]
126022557  WNT1; proto-oncogene Wnt-1 [KO:K03209]
126022720  MGST1; microsomal glutathione S-transferase 1 [KO:K00799] [EC:2.5.1.18]
126022764  ARID2; AT-rich interactive domain-containing protein 2 [KO:K11765]
126022823  KRAS; GTPase KRas isoform X1 [KO:K07827]
126022961  SMARCC2; SWI/SNF complex subunit SMARCC2 isoform X1 [KO:K11649]
126023864  SOS1; son of sevenless homolog 1 isoform X1 [KO:K03099]
126024450  CDK6; cyclin-dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
126024487  TCF7L1; transcription factor 7-like 1 [KO:K04490]
126024677  TGFA; protransforming growth factor alpha [KO:K08774]
126024729  PHF10; PHD finger protein 10 [KO:K22197]
126024736  CSNK1A1; casein kinase I isoform X1 [KO:K08957] [EC:2.7.11.1]
126025839  [KO:K08957] [EC:2.7.11.1]
126026205  GSK3B; glycogen synthase kinase-3 beta isoform X1 [KO:K03083] [EC:2.7.11.26]
126027129  BRD7; bromodomain-containing protein 7 isoform X1 [KO:K11723]
126027215  BAX; apoptosis regulator BAX isoform X1 [KO:K02159]
126027269  PLCG2; 1-phosphatidylinositol 4,5-bisphosphate phosphodiesterase gamma-2 [KO:K05859] [EC:3.1.4.11]
126027429  NQO1; NAD(P)H dehydrogenase [quinone] 1 [KO:K00355] [EC:1.6.5.2]
126027625  DPF1; zinc finger protein neuro-d4 isoform X1 [KO:K22198]
126027752  TCF7; LOW QUALITY PROTEIN: transcription factor 7 [KO:K02620]
126027890  LEF1; lymphoid enhancer-binding factor 1 isoform X1 [KO:K04492]
126027978  PRKCG; protein kinase C gamma type [KO:K19663] [EC:2.7.11.13]
126028133  AKT2; RAC-beta serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126028183  TGFB1; transforming growth factor beta-1 proprotein [KO:K13375]
126028350  WNT8A; protein Wnt-8a [KO:K00714]
126029574  FZD9; frizzled-9 [KO:K02842]
126029610  APC2; adenomatous polyposis coli protein 2 isoform X1 [KO:K02085]
126029670  MAP2K2; dual specificity mitogen-activated protein kinase kinase 2 [KO:K04369] [EC:2.7.12.2]
126029893  MAPK3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
126030200  PIK3R2; phosphatidylinositol 3-kinase regulatory subunit beta [KO:K02649]
126030288  KEAP1; kelch-like ECH-associated protein 1 [KO:K10456]
126030444  ACTB; actin, cytoplasmic 1 [KO:K05692]
126030823  SMARCA4; transcription activator BRG1 isoform X1 [KO:K11647] [EC:5.6.2.-]
126030826  SHC2; SHC-transforming protein 2 [KO:K17447]
126030861  PRKCB; protein kinase C beta type isoform X1 [KO:K19662] [EC:2.7.11.13]
126031124  ACTL6B; actin-like protein 6B [KO:K11652]
126031185  GADD45B; growth arrest and DNA damage-inducible protein GADD45 beta [KO:K04402]
126033346  AKT1; RAC-alpha serine/threonine-protein kinase [KO:K04456] [EC:2.7.11.1]
126033381  [KO:K00799] [EC:2.5.1.18]
126033443  [KO:K00799] [EC:2.5.1.18]
126033699  SMARCB1; SWI/SNF-related matrix-associated actin-dependent regulator of chromatin subfamily B member 1 isoform X1 [KO:K11648]
126033704  MAPK1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
126033721  [KO:K00799] [EC:2.5.1.18]
126033722  [KO:K00799] [EC:2.5.1.18]
126033724  [KO:K00799] [EC:2.5.1.18]
126033726  [KO:K00799] [EC:2.5.1.18]
126033734  [KO:K00799] [EC:2.5.1.18]
126033736  [KO:K00799] [EC:2.5.1.18]
126033761  [KO:K00799] [EC:2.5.1.18]
126033773  [KO:K00799] [EC:2.5.1.18]
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.
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Oncogene 25:3787-800 (2006)
DOI:10.1038/sj.onc.1209556
Reference
PMID:19387255
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Minguez B, Tovar V, Chiang D, Villanueva A, Llovet JM
  Title
Pathogenesis of hepatocellular carcinoma and molecular therapies.
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Curr Opin Gastroenterol 25:186-94 (2009)
DOI:10.1097/MOG.0b013e32832962a1
Reference
PMID:21829020
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  Title
Signaling pathway and molecular-targeted therapy for hepatocellular carcinoma.
  Journal
Dig Dis 29:289-302 (2011)
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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
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Cornella H, Alsinet C, Villanueva A
  Title
Molecular pathogenesis of hepatocellular carcinoma.
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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.
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Virchows Arch 440:345-52 (2002)
DOI:10.1007/s00428-002-0617-x
Reference
PMID:23426905
  Authors
Shiraha H, Yamamoto K, Namba M
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Human hepatocyte carcinogenesis (review).
  Journal
Int J Oncol 42:1133-8 (2013)
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Reference
PMID:23887712
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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)
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Reference
PMID:22561517
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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
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Praslicka BJ, Kerins MJ, Ooi A
  Title
The complex role of NRF2 in cancer: a genomic view
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Curr Opin Toxicol 1:37-45 (2016)
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Reference
PMID:24024136
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Kansanen E, Kuosmanen SM, Leinonen H, Levonen AL
  Title
The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer.
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Redox Biol 1:45-9 (2013)
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Reference
PMID:21251164
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Taguchi K, Motohashi H, Yamamoto M
  Title
Molecular mechanisms of the Keap1-Nrf2 pathway in stress response and cancer evolution.
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Genes Cells 16:123-40 (2011)
DOI:10.1111/j.1365-2443.2010.01473.x
Reference
PMID:20019356
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Klaunig JE, Kamendulis LM, Hocevar BA
  Title
Oxidative stress and oxidative damage in carcinogenesis.
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Toxicol Pathol 38:96-109 (2010)
DOI:10.1177/0192623309356453
Reference
PMID:11193292
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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
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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
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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.
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Semin Cancer Biol 16:318-30 (2006)
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Reference
PMID:24096051
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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
setr04010  MAPK signaling pathway
setr04020  Calcium signaling pathway
setr04110  Cell cycle
setr04115  p53 signaling pathway
setr04151  PI3K-Akt signaling pathway
setr04310  Wnt signaling pathway
setr04350  TGF-beta signaling pathway
setr04932  Non-alcoholic fatty liver disease
setr04936  Alcoholic liver disease
setr05160  Hepatitis C
setr05161  Hepatitis B
KO pathway
ko05225   

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