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Tumor Biology

, Volume 36, Issue 1, pp 111–119 | Cite as

SMAD4 and its role in pancreatic cancer

  • Xiang Xia
  • Weidong Wu
  • Chen Huang
  • Gang Cen
  • Tao Jiang
  • Jun Cao
  • Kejian Huang
  • Zhengjun Qiu
Review

Abstract

Transforming growth factor-β (TGF-β) regulates cell functions and has key roles in pancreatic cancer development. SMAD4, as one of the Smads family of signal transducer from TGF-β, mediates pancreatic cell proliferation and apoptosis and is specifically inactivated in half of advanced pancreatic cancers. In recent years, many advances concerning SMAD4 had tried to unravel the complex signaling mechanisms of TGF-β and its dual role of tumor-suppressive and tumor-promoting efforts in pancreatic cancer initiation and progression through SMAD4-dependent TGF-β signaling and SMAD4-independent TGF-β signaling pathways. Meanwhile, its potential prognostic value based on immunohistochemical expression in surgical sample was variably reported by several studies and short of a systematic analysis. This review aimed to discuss the structure, functions, and regulation of this principal protein and its effects in determining the progression and prognosis of pancreatic cancer.

Keywords

Pancreatic cancer TGF-β signaling pathway Loss of SMAD4 Prognosis 

Notes

Acknowledgments

This study was supported by grants from the National Natural Science Foundation of China (No. 81372640 (to QZJ)) and (No. 81101844 and No. 81210108027 (to C. Huang)), Shanghai Municipal Human Resources and Social Security Bureau (No. 2012040 and No. 13PJD024 (to C. Huang)), and Shanghai Municipal Health Bureau (No. XYQ2013092 (to C. Huang)). This is an original article and is not being considered for publication elsewhere. All of the authors contributed to the article and are aware of and agree to its submission for publication.

Conflicts of interest

None

Author’s contribution

XX, WW, CH, GC, TJ, and JC conceived and designed the study. XX, KH, and ZQ performed the experiments. XX and WW analyzed the data. XX and ZQ wrote the manuscript. All authors read and approved the final manuscript.

References

  1. 1.
    Singh P, Srinivasan R, Wig JD. Major molecular markers in pancreatic ductal adenocarcinoma and their roles in screening, diagnosis, prognosis, and treatment. Pancreas. 2011;40:644–52.CrossRefPubMedGoogle Scholar
  2. 2.
    Hilbig A, Oettle H. Transforming growth factor beta in pancreatic cancer. Curr Pharm Biotechnol. 2011;12:2158–64.CrossRefPubMedGoogle Scholar
  3. 3.
    Bilimoria KY, Bentrem DJ, Ko CY, Ritchey J, Stewart AK, et al. Validation of the 6th edition AJCC pancreatic cancer staging system: report from the National Cancer Database. Cancer. 2007;110:738–44.CrossRefPubMedGoogle Scholar
  4. 4.
    Goggins M, Kern SE, Offerhaus JA, Hruban RH. Progress in cancer genetics: lessons from pancreatic cancer. Ann Oncol. 1999;10 Suppl 4:4–8.CrossRefPubMedGoogle Scholar
  5. 5.
    Iacobuzio-Donahue CA, Song J, Parmiagiani G, Yeo CJ, Hruban RH, et al. Missense mutations of MADH4: characterization of the mutational hot spot and functional consequences in human tumors. Clin Cancer Res. 2004;10:1597–604.CrossRefPubMedGoogle Scholar
  6. 6.
    Kang Y, Ling J, Suzuki R, Roife D, Chopin-Laly X, et al. SMAD4 regulates cell motility through transcription of N-cadherin in human pancreatic ductal epithelium. PLoS One. 2014;9:e107948.CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Saiki Y, Horii A. Molecular pathology of pancreatic cancer. Pathol Int. 2014;64:10–9.CrossRefPubMedGoogle Scholar
  8. 8.
    Derynck R, Akhurst RJ, Balmain A. TGF-beta signaling in tumor suppression and cancer progression. Nat Genet. 2001;29:117–29.CrossRefPubMedGoogle Scholar
  9. 9.
    Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signalling. Nature. 2003;425:577–84.CrossRefPubMedGoogle Scholar
  10. 10.
    Principe DR, Doll JA, Bauer J, Jung B, Munshi HG, et al. (2014) TGF-beta: duality of function between tumor prevention and carcinogenesis. J Natl Cancer Inst 106: djt369.Google Scholar
  11. 11.
    Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, et al. DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996;271:350–3.CrossRefPubMedGoogle Scholar
  12. 12.
    Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, Gelbart WM. Genetic characterization and cloning of mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics. 1995;139:1347–58.PubMedPubMedCentralGoogle Scholar
  13. 13.
    Derynck R, Gelbart WM, Harland RM, Heldin CH, Kern SE, et al. Nomenclature: vertebrate mediators of TGFbeta family signals. Cell. 1996;87:173.CrossRefPubMedGoogle Scholar
  14. 14.
    Singh P, Wig JD, Srinivasan R. The Smad family and its role in pancreatic cancer. Indian J Cancer. 2011;48:351–60.CrossRefPubMedGoogle Scholar
  15. 15.
    Wu G, Chen YG, Ozdamar B, Gyuricza CA, Chong PA, et al. Structural basis of Smad2 recognition by the Smad anchor for receptor activation. Science. 2000;287:92–7.CrossRefPubMedGoogle Scholar
  16. 16.
    Massague J, Wotton D. Transcriptional control by the TGF-beta/Smad signaling system. EMBO J. 2000;19:1745–54.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Shi Y, Hata A, Lo RS, Massague J, Pavletich NP. A structural basis for mutational inactivation of the tumour suppressor Smad4. Nature. 1997;388:87–93.CrossRefPubMedGoogle Scholar
  18. 18.
    Watanabe M, Masuyama N, Fukuda M, Nishida E. Regulation of intracellular dynamics of Smad4 by its leucine-rich nuclear export signal. EMBO Rep. 2000;1:176–82.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Kurisaki A, Kose S, Yoneda Y, Heldin CH, Moustakas A. Transforming growth factor-beta induces nuclear import of Smad3 in an importin-beta1 and Ran-dependent manner. Mol Biol Cell. 2001;12:1079–91.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Pierreux CE, Nicolas FJ, Hill CS. Transforming growth factor beta-independent shuttling of Smad4 between the cytoplasm and nucleus. Mol Cell Biol. 2000;20:9041–54.CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Inman GJ, Nicolas FJ, Hill CS. Nucleocytoplasmic shuttling of Smads 2, 3, and 4 permits sensing of TGF-beta receptor activity. Mol Cell. 2002;10:283–94.CrossRefPubMedGoogle Scholar
  22. 22.
    Shi Y, Massague J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685–700.CrossRefPubMedGoogle Scholar
  23. 23.
    Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411:342–8.CrossRefPubMedGoogle Scholar
  24. 24.
    Lecanda J, Ganapathy V, D′Aquino-Ardalan C, Evans B, Cadacio C, et al. TGFbeta prevents proteasomal degradation of the cyclin-dependent kinase inhibitor p27kip1 for cell cycle arrest. Cell Cycle. 2009;8:742–56.CrossRefPubMedGoogle Scholar
  25. 25.
    Massague J, Blain SW, Lo RS. TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000;103:295–309.CrossRefPubMedGoogle Scholar
  26. 26.
    Bauer J, Sporn JC, Cabral J, Gomez J, Jung B. Effects of activin and TGFbeta on p21 in colon cancer. PLoS One. 2012;7:e39381.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Alvarez C, Bass BL. Role of transforming growth factor-beta in growth and injury response of the pancreatic duct epithelium in vitro. J Gastrointest Surg. 1999;3:178–84.CrossRefPubMedGoogle Scholar
  28. 28.
    Tachibana I, Imoto M, Adjei PN, Gores GJ, Subramaniam M, et al. Overexpression of the TGFbeta-regulated zinc finger encoding gene, TIEG, induces apoptosis in pancreatic epithelial cells. J Clin Invest. 1997;99:2365–74.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Biswas S, Criswell TL, Wang SE, Arteaga CL. Inhibition of transforming growth factor-beta signaling in human cancer: targeting a tumor suppressor network as a therapeutic strategy. Clin Cancer Res. 2006;12:4142–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Jakowlew SB. Transforming growth factor-beta in cancer and metastasis. Cancer Metastasis Rev. 2006;25:435–57.CrossRefPubMedGoogle Scholar
  31. 31.
    Wagner M, Kleeff J, Lopez ME, Bockman I, Massaque J, et al. Transfection of the type I TGF-beta receptor restores TGF-beta responsiveness in pancreatic cancer. Int J Cancer. 1998;78:255–60.CrossRefPubMedGoogle Scholar
  32. 32.
    Furukawa T, Sunamura M, Horii A. Molecular mechanisms of pancreatic carcinogenesis. Cancer Sci. 2006;97:1–7.CrossRefPubMedGoogle Scholar
  33. 33.
    Xu J, Attisano L. Mutations in the tumor suppressors Smad2 and Smad4 inactivate transforming growth factor beta signaling by targeting Smads to the ubiquitin-proteasome pathway. Proc Natl Acad Sci U S A. 2000;97:4820–5.CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Duda DG, Sunamura M, Lefter LP, Furukawa T, Yokoyama T, et al. Restoration of SMAD4 by gene therapy reverses the invasive phenotype in pancreatic adenocarcinoma cells. Oncogene. 2003;22:6857–64.CrossRefPubMedGoogle Scholar
  35. 35.
    Yasutome M, Gunn J, Korc M. Restoration of Smad4 in BxPC3 pancreatic cancer cells attenuates proliferation without altering angiogenesis. Clin Exp Metastasis. 2005;22:461–73.CrossRefPubMedGoogle Scholar
  36. 36.
    Shen W, Tao GQ, Li DC, Zhu XG, Bai X, et al. Inhibition of pancreatic carcinoma cell growth in vitro by DPC4 gene transfection. World J Gastroenterol. 2008;14:6254–60.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Derynck R, Jarrett JA, Chen EY, Eaton DH, Bell JR, et al. Human transforming growth factor-beta complementary DNA sequence and expression in normal and transformed cells. Nature. 1985;316:701–5.CrossRefPubMedGoogle Scholar
  38. 38.
    Levy L, Hill CS. Smad4 dependency defines two classes of transforming growth factor {beta} (TGF-{beta}) target genes and distinguishes TGF-{beta}-induced epithelial-mesenchymal transition from its antiproliferative and migratory responses. Mol Cell Biol. 2005;25:8108–25.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Moustakas A, Heldin CH. Non-Smad TGF-beta signals. J Cell Sci. 2005;118:3573–84.CrossRefPubMedGoogle Scholar
  40. 40.
    Chow JY, Quach KT, Cabrera BL, Cabral JA, Beck SE, et al. RAS/ERK modulates TGFbeta-regulated PTEN expression in human pancreatic adenocarcinoma cells. Carcinogenesis. 2007;28:2321–7.CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Chow JY, Ban M, Wu HL, Nguyen F, Huang M, et al. TGF-beta downregulates PTEN via activation of NF-kappaB in pancreatic cancer cells. Am J Physiol Gastrointest Liver Physiol. 2010;298:G275–82.CrossRefPubMedGoogle Scholar
  42. 42.
    Li H, Huang C, Huang K, Wu W, Jiang T, et al. STAT3 knockdown reduces pancreatic cancer cell invasiveness and matrix metalloproteinase-7 expression in nude mice. PLoS One. 2011;6:e25941.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Yang G, Huang C, Cao J, Huang KJ, Jiang T, et al. Lentivirus-mediated shRNA interference targeting STAT3 inhibits human pancreatic cancer cell invasion. World J Gastroenterol. 2009;15:3757–66.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Huang C, Jiang T, Zhu L, Liu J, Cao J, et al. STAT3-targeting RNA interference inhibits pancreatic cancer angiogenesis in vitro and in vivo. Int J Oncol. 2011;38:1637–44.PubMedGoogle Scholar
  45. 45.
    Zhao S, Venkatasubbarao K, Lazor JW, Sperry J, Jin C, et al. Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells. Cancer Res. 2008;68:4221–8.CrossRefPubMedGoogle Scholar
  46. 46.
    Zhao S, Ammanamanchi S, Brattain M, Cao L, Thangasamy A, et al. Smad4-dependent TGF-beta signaling suppresses RON receptor tyrosine kinase-dependent motility and invasion of pancreatic cancer cells. J Biol Chem. 2008;283:11293–301.CrossRefPubMedPubMedCentralGoogle Scholar
  47. 47.
    Vincent DF, Yan KP, Treilleux I, Gay F, Arfi V, et al. Inactivation of TIF1gamma cooperates with Kras to induce cystic tumors of the pancreas. PLoS Genet. 2009;5:e1000575.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Ligr M, Wu X, Daniels G, Zhang D, Wang H, et al. Imbalanced expression of Tif1gamma inhibits pancreatic ductal epithelial cell growth. Am J Cancer Res. 2014;4:196–210.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Vincent DF, Gout J, Chuvin N, Arfi V, Pommier RM, et al. Tif1gamma suppresses murine pancreatic tumoral transformation by a Smad4-independent pathway. Am J Pathol. 2012;180:2214–21.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Thiery JP, Acloque H, Huang RY, Nieto MA. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–90.CrossRefPubMedGoogle Scholar
  51. 51.
    Polyak K, Weinberg RA. Transitions between epithelial and mesenchymal states: acquisition of malignant and stem cell traits. Nat Rev Cancer. 2009;9:265–73.CrossRefPubMedGoogle Scholar
  52. 52.
    Krantz SB, Shields MA, Dangi-Garimella S, Munshi HG, Bentrem DJ. Contribution of epithelial-to-mesenchymal transition and cancer stem cells to pancreatic cancer progression. J Surg Res. 2012;173:105–12.CrossRefPubMedGoogle Scholar
  53. 53.
    Ikushima H, Miyazono K. TGFbeta signalling: a complex web in cancer progression. Nat Rev Cancer. 2010;10:415–24.CrossRefPubMedGoogle Scholar
  54. 54.
    Lamouille S, Derynck R. Cell size and invasion in TGF-beta-induced epithelial to mesenchymal transition is regulated by activation of the mTOR pathway. J Cell Biol. 2007;178:437–51.CrossRefPubMedPubMedCentralGoogle Scholar
  55. 55.
    Lamouille S, Connolly E, Smyth JW, Akhurst RJ, Derynck R. TGF-beta-induced activation of mTOR complex 2 drives epithelial-mesenchymal transition and cell invasion. J Cell Sci. 2012;125:1259–73.CrossRefPubMedPubMedCentralGoogle Scholar
  56. 56.
    Bardeesy N, Cheng KH, Berger JH, Chu GC, Pahler J, et al. Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer. Genes Dev. 2006;20:3130–46.CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Vincent T, Neve EP, Johnson JR, Kukalev A, Rojo F, et al. A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-beta mediated epithelial-mesenchymal transition. Nat Cell Biol. 2009;11:943–50.CrossRefPubMedPubMedCentralGoogle Scholar
  58. 58.
    Bracken CP, Gregory PA, Kolesnikoff N, Bert AG, Wang J, et al. A double-negative feedback loop between ZEB1-SIP1 and the microRNA-200 family regulates epithelial-mesenchymal transition. Cancer Res. 2008;68:7846–54.CrossRefPubMedGoogle Scholar
  59. 59.
    Katsuno Y, Lamouille S, Derynck R. TGF-beta signaling and epithelial-mesenchymal transition in cancer progression. Curr Opin Oncol. 2013;25:76–84.CrossRefPubMedGoogle Scholar
  60. 60.
    Deer EL, Gonzalez-Hernandez J, Coursen JD, Shea JE, Ngatia J, et al. Phenotype and genotype of pancreatic cancer cell lines. Pancreas. 2010;39:425–35.CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Loukopoulos P, Kanetaka K, Takamura M, Shibata T, Sakamoto M, et al. Orthotopic transplantation models of pancreatic adenocarcinoma derived from cell lines and primary tumors and displaying varying metastatic activity. Pancreas. 2004;29:193–203.CrossRefPubMedGoogle Scholar
  62. 62.
    Sun C, Yamato T, Furukawa T, Ohnishi Y, Kijima H, et al. Characterization of the mutations of the K-ras, p53, p16, and SMAD4 genes in 15 human pancreatic cancer cell lines. Oncol Rep. 2001;8:89–92.PubMedGoogle Scholar
  63. 63.
    Aoki Y, Hosaka S, Tachibana N, Karasawa Y, Kawa S, et al. Reassessment of K-ras mutations at codon 12 by direct PCR and sequencing from tissue microdissection in human pancreatic adenocarcinomas. Pancreas. 2000;21:152–7.CrossRefPubMedGoogle Scholar
  64. 64.
    Chen WB, Lenschow W, Tiede K, Fischer JW, Kalthoff H, et al. Smad4/DPC4-dependent regulation of biglycan gene expression by transforming growth factor-beta in pancreatic tumor cells. J Biol Chem. 2002;277:36118–28.CrossRefPubMedGoogle Scholar
  65. 65.
    Schutte M, Hruban RH, Hedrick L, Cho KR, Nadasdy GM, et al. DPC4 gene in various tumor types. Cancer Res. 1996;56:2527–30.PubMedGoogle Scholar
  66. 66.
    Moore PS, Sipos B, Orlandini S, Sorio C, Real FX, et al. Genetic profile of 22 pancreatic carcinoma cell lines. Analysis of K-ras, p53, p16 and DPC4/Smad4. Virchows Arch. 2001;439:798–802.CrossRefPubMedGoogle Scholar
  67. 67.
    Maitra A, Adsay NV, Argani P, Iacobuzio-Donahue C, De Marzo A, et al. Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray. Mod Pathol. 2003;16:902–12.CrossRefPubMedGoogle Scholar
  68. 68.
    Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, et al. Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 2001;25:579–86.CrossRefPubMedGoogle Scholar
  69. 69.
    Kloppel G, Luttges J. The pathology of ductal-type pancreatic carcinomas and pancreatic intraepithelial neoplasia: insights for clinicians. Curr Gastroenterol Rep. 2004;6:111–8.CrossRefPubMedGoogle Scholar
  70. 70.
    Longnecker DS, Adsay NV, Fernandez-del Castillo C, Hruban RH, Kasugai T, et al. Histopathological diagnosis of pancreatic intraepithelial neoplasia and intraductal papillary-mucinous neoplasms: interobserver agreement. Pancreas. 2005;31:344–9.CrossRefPubMedGoogle Scholar
  71. 71.
    Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, et al. Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000;60:2002–6.PubMedGoogle Scholar
  72. 72.
    Biankin AV, Biankin SA, Kench JG, Morey AL, Lee CS, et al. Aberrant p16(INK4A) and DPC4/Smad4 expression in intraductal papillary mucinous tumours of the pancreas is associated with invasive ductal adenocarcinoma. Gut. 2002;50:861–8.CrossRefPubMedPubMedCentralGoogle Scholar
  73. 73.
    Iacobuzio-Donahue CA, Klimstra DS, Adsay NV, Wilentz RE, Argani P, et al. Dpc-4 protein is expressed in virtually all human intraductal papillary mucinous neoplasms of the pancreas: comparison with conventional ductal adenocarcinomas. Am J Pathol. 2000;157:755–61.CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Wilentz RE, Su GH, Dai JL, Sparks AB, Argani P, et al. Immunohistochemical labeling for dpc4 mirrors genetic status in pancreatic adenocarcinomas : a new marker of DPC4 inactivation. Am J Pathol. 2000;156:37–43.CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Yonezawa S, Higashi M, Yamada N, Goto M. Precursor lesions of pancreatic cancer. Gut Live. 2008;2:137–54.CrossRefGoogle Scholar
  76. 76.
    Maitra A, Fukushima N, Takaori K, Hruban RH. Precursors to invasive pancreatic cancer. Adv Anat Pathol. 2005;12:81–91.CrossRefPubMedGoogle Scholar
  77. 77.
    Singh M, Maitra A. Precursor lesions of pancreatic cancer: molecular pathology and clinical implications. Pancreatology. 2007;7:9–19.CrossRefPubMedGoogle Scholar
  78. 78.
    Perez-Mancera PA, Guerra C, Barbacid M, Tuveson DA. What we have learned about pancreatic cancer from mouse models. Gastroenterology. 2012;142:1079–92.CrossRefPubMedGoogle Scholar
  79. 79.
    Ijichi H, Chytil A, Gorska AE, Aakre ME, Fujitani Y, et al. Aggressive pancreatic ductal adenocarcinoma in mice caused by pancreas-specific blockade of transforming growth factor-beta signaling in cooperation with active Kras expression. Genes Dev. 2006;20:3147–60.CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Izeradjene K, Combs C, Best M, Gopinathan A, Wagner A, et al. Kras(G12D) and Smad4/Dpc4 haploinsufficiency cooperate to induce mucinous cystic neoplasms and invasive adenocarcinoma of the pancreas. Cancer Cell. 2007;11:229–43.CrossRefPubMedGoogle Scholar
  81. 81.
    Leung L, Radulovich N, Zhu CQ, Wang D, To C, et al. Loss of canonical Smad4 signaling promotes KRAS driven malignant transformation of human pancreatic duct epithelial cells and metastasis. PLoS One. 2013;8:e84366.CrossRefPubMedPubMedCentralGoogle Scholar
  82. 82.
    Voorneveld PW, Stache V, Jacobs RJ, Smolders E, Sitters AI, et al. Reduced expression of bone morphogenetic protein receptor IA in pancreatic cancer is associated with a poor prognosis. Br J Cancer. 2013;109:1805–12.CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Toga T, Nio Y, Hashimoto K, Higami T, Maruyama R. The dissociated expression of protein and messenger RNA of DPC4 in human invasive ductal carcinoma of the pancreas and their implication for patient outcome. Anticancer Res. 2004;24:1173–8.PubMedGoogle Scholar
  84. 84.
    Tascilar M, Skinner HG, Rosty C, Sohn T, Wilentz RE, et al. The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2001;7:4115–21.PubMedGoogle Scholar
  85. 85.
    Singh P, Srinivasan R, Wig JD. SMAD4 genetic alterations predict a worse prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas. 2012;41:541–6.CrossRefPubMedGoogle Scholar
  86. 86.
    Hua Z, Zhang YC, Hu XM, Jia ZG. Loss of DPC4 expression and its correlation with clinicopathological parameters in pancreatic carcinoma. World J Gastroenterol. 2003;9:2764–7.CrossRefPubMedPubMedCentralGoogle Scholar
  87. 87.
    Khorana AA, Hu YC, Ryan CK, Komorowski RA, Hostetter G, et al. Vascular endothelial growth factor and DPC4 predict adjuvant therapy outcomes in resected pancreatic cancer. J Gastrointest Surg. 2005;9:903–11.CrossRefPubMedGoogle Scholar
  88. 88.
    Biankin AV, Morey AL, Lee CS, Kench JG, Biankin SA, et al. DPC4/Smad4 expression and outcome in pancreatic ductal adenocarcinoma. J Clin Oncol. 2002;20:4531–42.CrossRefPubMedGoogle Scholar
  89. 89.
    Blackford A, Serrano OK, Wolfgang CL, Parmigiani G, Jones S, et al. SMAD4 gene mutations are associated with poor prognosis in pancreatic cancer. Clin Cancer Res. 2009;15:4674–9.CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Iacobuzio-Donahue CA, Fu B, Yachida S, Luo M, Abe H, et al. DPC4 gene status of the primary carcinoma correlates with patterns of failure in patients with pancreatic cancer. J Clin Oncol. 2009;27:1806–13.CrossRefPubMedPubMedCentralGoogle Scholar
  91. 91.
    Maitra A, Molberg K, Albores-Saavedra J, Lindberg G. Loss of Dpc4 expression in colonic adenocarcinomas correlates with the presence of metastatic disease. Am J Pathol. 2000;157:1105–11.CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Sohn TA, Su GH, Ryu B, Yeo CJ, Kern SE. High-throughput drug screening of the DPC4 tumor-suppressor pathway in human pancreatic cancer cells. Ann Surg. 2001;233:696–703.CrossRefPubMedPubMedCentralGoogle Scholar
  93. 93.
    Wang H, Han H, Von Hoff DD. Identification of an agent selectively targeting DPC4 (deleted in pancreatic cancer locus 4)-deficient pancreatic cancer cells. Cancer Res. 2006;66:9722–30.CrossRefPubMedGoogle Scholar
  94. 94.
    Wang H, Stephens B, Von Hoff DD, Han H. Identification and characterization of a novel anticancer agent with selectivity against deleted in pancreatic cancer locus 4 (DPC4)-deficient pancreatic and colon cancer cells. Pancreas. 2009;38:551–7.CrossRefPubMedGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2014

Authors and Affiliations

  • Xiang Xia
    • 1
  • Weidong Wu
    • 1
  • Chen Huang
    • 1
  • Gang Cen
    • 1
  • Tao Jiang
    • 1
  • Jun Cao
    • 1
  • Kejian Huang
    • 1
  • Zhengjun Qiu
    • 1
  1. 1.Department of General SurgeryShanghai Jiaotong University Affiliated First People’s HospitalShanghaiPeople’s Republic of China

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