KEGG   PATHWAY: hgl05212
Entry
hgl05212                    Pathway                                

Name
Pancreatic cancer - Heterocephalus glaber (naked mole rat)
Description
Infiltrating ductal adenocarcinoma is the most common malignancy of the pancreas. When most investigators use the term 'pancreatic cancer' they are referring to pancreatic ductal adenocarcinoma (PDA). Normal duct epithelium progresses to infiltrating cancer through a series of histologically defined precursors (PanINs). The overexpression of HER-2/neu and activating point mutations in the K-ras gene occur early, inactivation of the p16 gene at an intermediate stage, and the inactivation of p53, SMAD4, and BRCA2 occur relatively late. Activated K-ras engages multiple effector pathways. Although EGF receptors are conventionally regarded as upstream activators of RAS proteins, they can also act as RAS signal transducers via RAS-induced autocrine activation of the EGFR family ligands. Moreover, PDA shows extensive genomic instability and aneuploidy. Telomere attrition and mutations in p53 and BRCA2 are likely to contribute to these phenotypes. Inactivation of the SMAD4 tumour suppressor gene leads to loss of the inhibitory influence of the transforming growth factor-beta signalling pathway.
Class
Human Diseases; Cancer: specific types
Pathway map
hgl05212  Pancreatic cancer
hgl05212

Organism
Heterocephalus glaber (naked mole rat) [GN:hgl]
Gene
101718997  Kras; KRAS proto-oncogene, GTPase [KO:K07827]
101711934  Pik3ca; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha [KO:K00922] [EC:2.7.1.153]
101715249  Pik3cb; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta [KO:K00922] [EC:2.7.1.153]
101712941  Pik3cd; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta [KO:K00922] [EC:2.7.1.153]
101718815  Pik3r2; phosphoinositide-3-kinase regulatory subunit 2 [KO:K02649]
101717096  Pik3r3; phosphatidylinositol 3-kinase regulatory subunit gamma [KO:K02649]
101703691  Pik3r1; phosphoinositide-3-kinase regulatory subunit 1 [KO:K02649]
101700245  Arhgef6; Rac/Cdc42 guanine nucleotide exchange factor 6 [KO:K05729]
101706434  Rac1; ras-related C3 botulinum toxin substrate 1 (rho family, small GTP binding protein Rac1) [KO:K04392]
101725000  Rac2; ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) [KO:K07860]
101723777  Rac3; ras-related C3 botulinum toxin substrate 3 (rho family, small GTP binding protein Rac3) [KO:K07861]
101696485  Nfkb1; nuclear factor kappa B subunit 1 [KO:K02580]
101716738  Rela; RELA proto-oncogene, NF-kB subunit [KO:K04735]
101700695  Akt1; AKT serine/threonine kinase 1 [KO:K04456] [EC:2.7.11.1]
101719164  Akt2; AKT serine/threonine kinase 2 [KO:K04456] [EC:2.7.11.1]
101701289  Akt3; AKT serine/threonine kinase 3 [KO:K04456] [EC:2.7.11.1]
101719306  Chuk; conserved helix-loop-helix ubiquitous kinase [KO:K04467] [EC:2.7.11.10]
101711077  Ikbkb; inhibitor of nuclear factor kappa B kinase subunit beta [KO:K07209] [EC:2.7.11.10]
101712077  Ikbkg; inhibitor of nuclear factor kappa B kinase subunit gamma [KO:K07210]
101726042  Bad; BCL2 associated agonist of cell death [KO:K02158]
101713410  Bcl2l1; BCL2 like 1 [KO:K04570]
101720105  bcl-2-like protein 1 [KO:K04570]
101702898  Casp9; caspase 9 [KO:K04399] [EC:3.4.22.62]
101723157  Araf; A-Raf proto-oncogene, serine/threonine kinase [KO:K08845] [EC:2.7.11.1]
101702762  Braf; B-Raf proto-oncogene, serine/threonine kinase [KO:K04365] [EC:2.7.11.1]
101721841  Raf1; Raf-1 proto-oncogene, serine/threonine kinase [KO:K04366] [EC:2.7.11.1]
101715628  Map2k1; mitogen-activated protein kinase kinase 1 [KO:K04368] [EC:2.7.12.2]
101706099  Mapk1; mitogen-activated protein kinase 1 [KO:K04371] [EC:2.7.11.24]
101702687  Mapk3; mitogen-activated protein kinase 3 [KO:K04371] [EC:2.7.11.24]
101698286  Mapk9; mitogen-activated protein kinase 9 [KO:K04440] [EC:2.7.11.24]
101715259  Mapk8; mitogen-activated protein kinase 8 [KO:K04440] [EC:2.7.11.24]
101712980  Mapk10; mitogen-activated protein kinase 10 [KO:K04440] [EC:2.7.11.24]
101700047  Ralgds; ral guanine nucleotide dissociation stimulator [KO:K08732]
101706563  Rala; RAS like proto-oncogene A [KO:K07834]
101699253  Ralb; RAS like proto-oncogene B [KO:K07835]
101711056  Ralbp1; ralA binding protein 1 [KO:K08773]
101701374  Cdc42; cell division cycle 42 [KO:K04393]
101711269  cell division control protein 42 homolog [KO:K04393]
101700438  Pld1; phospholipase D1 [KO:K01115] [EC:3.1.4.4]
101713528  Pld2; phospholipase D2 [KO:K01115] [EC:3.1.4.4]
101723712  Tgfa; transforming growth factor alpha [KO:K08774]
106007527  Egf; epidermal growth factor [KO:K04357]
101723771  Egfr; epidermal growth factor receptor [KO:K04361] [EC:2.7.10.1]
101705227  Erbb2; erb-b2 receptor tyrosine kinase 2 [KO:K05083] [EC:2.7.10.1]
101725626  Mtor; mechanistic target of rapamycin [KO:K07203] [EC:2.7.11.1]
101702911  Rps6kb2; ribosomal protein S6 kinase B2 [KO:K04688] [EC:2.7.11.1]
101724077  Rps6kb1; ribosomal protein S6 kinase B1 [KO:K04688] [EC:2.7.11.1]
101710283  Jak1; Janus kinase 1 [KO:K11217] [EC:2.7.10.2]
101721899  Stat3; signal transducer and activator of transcription 3 [KO:K04692]
101718902  Stat1; signal transducer and activator of transcription 1 [KO:K11220]
101702403  Vegfa; vascular endothelial growth factor A [KO:K05448]
101702608  Cdk4; cyclin dependent kinase 4 [KO:K02089] [EC:2.7.11.22]
101719908  Cdk6; cyclin dependent kinase 6 [KO:K02091] [EC:2.7.11.22]
101712621  Ccnd1; cyclin D1 [KO:K04503]
101703701  Rb1; RB transcriptional corepressor 1 [KO:K06618]
101717980  E2f1; E2F transcription factor 1 [KO:K17454]
101711793  E2f2; E2F transcription factor 2 [KO:K09389]
101698963  E2f3; E2F transcription factor 3 [KO:K06620]
101701769  Tp53; tumor protein p53 [KO:K04451]
101710552  Cdkn1a; cyclin dependent kinase inhibitor 1A [KO:K06625]
101725746  Gadd45a; growth arrest and DNA damage inducible alpha [KO:K04402]
101711314  Gadd45g; growth arrest and DNA damage inducible gamma [KO:K04402]
101710909  Gadd45b; growth arrest and DNA damage inducible beta [KO:K04402]
101713575  Bax; BCL2 associated X, apoptosis regulator [KO:K02159]
101707336  Bak1; BCL2 antagonist/killer 1 [KO:K14021]
101715591  Ddb2; damage specific DNA binding protein 2 [KO:K10140]
101718580  Polk; DNA polymerase kappa [KO:K03511] [EC:2.7.7.7]
101704230  Tgfb1; transforming growth factor beta 1 [KO:K13375]
101707457  Tgfb2; transforming growth factor beta 2 [KO:K13376]
101712904  Tgfb3; transforming growth factor beta 3 [KO:K13377]
101718090  Tgfbr1; transforming growth factor beta receptor 1 [KO:K04674] [EC:2.7.11.30]
101704397  Tgfbr2; transforming growth factor beta receptor 2 [KO:K04388] [EC:2.7.11.30]
101714203  Smad2; SMAD family member 2 [KO:K04500]
101713378  Smad3; SMAD family member 3 [KO:K23605]
101703764  Smad4; SMAD family member 4 [KO:K04501]
101698015  Brca2; BRCA2, DNA repair associated [KO:K08775]
101715048  Rad51; RAD51 recombinase [KO:K04482]
Compound
C00416  Phosphatidate
C05981  Phosphatidylinositol-3,4,5-trisphosphate
Reference
  Authors
Von Hoff D, Evans D, Hruban R (ed).
  Title
Pancreatic cancer
  Journal
Jones and Bartlett publishers (2005)
Reference
(Japanese)
  Authors
Niitsu Y, Yokota J (ed).
  Title
[Oncogenes and Tumor Suppressor Genes for Medical Oncologist] (In Japanese)
  Journal
Nankodo (1999)
Reference
  Authors
Bardeesy N, DePinho RA.
  Title
Pancreatic cancer biology and genetics.
  Journal
Nat Rev Cancer 2:897-909 (2002)
DOI:10.1038/nrc949
Reference
  Authors
Bardeesy N, Sharpless NE, DePinho RA, Merlino G.
  Title
The genetics of pancreatic adenocarcinoma: a roadmap for a mouse model.
  Journal
Semin Cancer Biol 11:201-18 (2001)
DOI:10.1006/scbi.2000.0371
Reference
  Authors
Cowgill SM, Muscarella P.
  Title
The genetics of pancreatic cancer.
  Journal
Am J Surg 186:279-86 (2003)
DOI:10.1016/S0002-9610(03)00226-5
Reference
  Authors
Hezel AF, Kimmelman AC, Stanger BZ, Bardeesy N, Depinho RA.
  Title
Genetics and biology of pancreatic ductal adenocarcinoma.
  Journal
Genes Dev 20:1218-49 (2006)
DOI:10.1101/gad.1415606
Reference
  Authors
Shields JM, Pruitt K, McFall A, Shaub A, Der CJ.
  Title
Understanding Ras: 'it ain't over 'til it's over'.
  Journal
Trends Cell Biol 10:147-54 (2000)
DOI:10.1016/S0962-8924(00)01740-2
Reference
  Authors
Holbro T, Civenni G, Hynes NE.
  Title
The ErbB receptors and their role in cancer progression.
  Journal
Exp Cell Res 284:99-110 (2003)
DOI:10.1016/S0014-4827(02)00099-X
Reference
  Authors
Marmor MD, Skaria KB, Yarden Y.
  Title
Signal transduction and oncogenesis by ErbB/HER receptors.
  Journal
Int J Radiat Oncol Biol Phys 58:903-13 (2004)
DOI:10.1016/j.ijrobp.2003.06.002
Reference
  Authors
DeArmond D, Brattain MG, Jessup JM, Kreisberg J, Malik S, Zhao S, Freeman JW.
  Title
Autocrine-mediated ErbB-2 kinase activation of STAT3 is required for growth factor independence of pancreatic cancer cell lines.
  Journal
Oncogene 22:7781-95 (2003)
DOI:10.1038/sj.onc.1206966
Reference
  Authors
Wei D, Le X, Zheng L, Wang L, Frey JA, Gao AC, Peng Z, Huang S, Xiong HQ, Abbruzzese JL, Xie K.
  Title
Stat3 activation regulates the expression of vascular endothelial growth factor and human pancreatic cancer angiogenesis and metastasis.
  Journal
Oncogene 22:319-29 (2003)
DOI:10.1038/sj.onc.1206122
Reference
  Authors
Toyonaga T, Nakano K, Nagano M, Zhao G, Yamaguchi K, Kuroki S, Eguchi T, Chijiiwa K, Tsuneyoshi M, Tanaka M.
  Title
Blockade of constitutively activated Janus kinase/signal transducer and activator of transcription-3 pathway inhibits growth of human pancreatic cancer.
  Journal
Cancer Lett 201:107-16 (2003)
DOI:10.1016/S0304-3835(03)00482-8
Reference
  Authors
Schmid RM.
  Title
Genetic basis of pancreatic cancer.
  Journal
Best Pract Res Clin Gastroenterol 16:421-33 (2002)
DOI:10.1053/bega.2002.0316
Reference
  Authors
Elliott RL, Blobe GC.
  Title
Role of transforming growth factor Beta in human cancer.
  Journal
J Clin Oncol 23:2078-93 (2005)
DOI:10.1200/JCO.2005.02.047
Reference
  Authors
Rudkin TM, Foulkes WD.
  Title
BRCA2: breaks, mistakes and failed separations.
  Journal
Trends Mol Med 11:145-8 (2005)
DOI:10.1016/j.molmed.2005.02.003
Reference
  Authors
Venkitaraman AR.
  Title
Functions of BRCA1 and BRCA2 in the biological response to DNA damage.
  Journal
J Cell Sci 114:3591-8 (2001)
Reference
  Authors
Chang Z, Li Z, Wang X, Kang Y, Yuan Y, Niu J, Wang H, Chatterjee D, Fleming JB, Li M, Abbruzzese JL, Chiao PJ
  Title
Deciphering the mechanisms of tumorigenesis in human pancreatic ductal epithelial cells.
  Journal
Clin Cancer Res 19:549-59 (2013)
DOI:10.1158/1078-0432.CCR-12-0032
Related
pathway
hgl04010  MAPK signaling pathway
hgl04012  ErbB signaling pathway
hgl04110  Cell cycle
hgl04115  p53 signaling pathway
hgl04151  PI3K-Akt signaling pathway
hgl04210  Apoptosis
hgl04350  TGF-beta signaling pathway
hgl04370  VEGF signaling pathway
hgl04630  JAK-STAT signaling pathway
KO pathway
ko05212   
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