Tumor Biology

, Volume 34, Issue 6, pp 3879–3885 | Cite as

Downregulation of programmed cell death 4 (PDCD4) in tumorigenesis and progression of human digestive tract cancers

  • Gang MaEmail author
  • Hao Zhang
  • Ming Dong
  • Xinyu Zheng
  • Iwata Ozaki
  • Sachiko Matsuhashi
  • Kejian Guo
Research Article


Nowadays, digestive tract cancers become the commonest neoplasia and one of the leading causes of cancer deaths worldwide. The development of diagnosis and therapy is urgently required. Programmed cell death 4 (PDCD4), a new tumor suppressor, has been documented to be a potential diagnostic tool and treatment target for neoplasia due to the inhabitation of tumor promotion/progression and metastasis. However, its role in human digestive tract cancers is few available up to now. In this study, we examined the expression of PDCD4 in human digestive tract cancers (61 gastric cancer, 65 colorectal cancer, and 69 pancreatic cancer patients) by Western blot analysis, reverse transcription (RT)-PCR, and immunohistochemistry. Western blot, RT-PCR, and immunohistochemistry examination showed that expressions of PDCD4 were significantly lower in cancers specimens than in noncancerous tissues. Among the different differentiated cancer tissues, PDCD4 expression was significantly lower in moderately or poorly differentiated cancers than in well-differentiated cancers (p < 0.05). Our findings suggested that PDCD4 might be a potentially valuable molecular target in diagnosis and therapy for human digestive tract cancers.


PDCD4 Digestive tract cancers Western blot RT-PCR Immunohistochemistry 



This work was supported by the National Natural Science Foundation of China (No.30572114).

Conflict of interest

The authors declare that they have no conflict of interests.


  1. 1.
    Wong HY, Yau T. Management of gastric cancer: the Chinese perspective. Transl Gastrointest Cancer. 2012;1:181–5.Google Scholar
  2. 2.
    Chandanos E, Lagergren J. Oestrogen and the enigmatic male predominance of gastric cancer. Eur J Cancer. 2008;44:2397–403.PubMedCrossRefGoogle Scholar
  3. 3.
    Chen WQ, Zheng RS, Zhang SW, Li N, Zhao P, Li GL, et al. Report of incidence and mortality in China cancer registries, 2008. Chin J Cancer Res. 2012;24:171–80.PubMedCrossRefGoogle Scholar
  4. 4.
    Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57:43–66.PubMedCrossRefGoogle Scholar
  5. 5.
    Ke L. Mortality and incidence trends from esophagus cancer in selected geographic areas of China circa 1970–1990. Int J Cancer. 2002;102:271–4.PubMedCrossRefGoogle Scholar
  6. 6.
    Chen W, Zheng R, Zhang S, Zhao P, Li G, Wu L, et al. Report of incidence and mortality in China cancer registries, 2009. Chin J Cancer Res. 2013;25:10–21.PubMedGoogle Scholar
  7. 7.
    Chen W, He Y, Zheng R, Zhang S, Zeng H, Zou X, et al. Esophageal cancer incidence and mortality in China, 2009. J Thorac Dis. 2013;5:19–26.PubMedGoogle Scholar
  8. 8.
    Lankat-Buttgereit B, Göke R. The tumour suppressor Pdcd4: recent advances in the elucidation of function and regulation. Biol Cell. 2009;101:309–17.PubMedCrossRefGoogle Scholar
  9. 9.
    Chang JH, Cho YH, Sohn SY, Choi JM, Kim A, Kim YC, et al. Crystal structure of the eIF4A–PDCD4 complex. Proc Natl Acad Sci U S A. 2009;106:3148–53.PubMedCrossRefGoogle Scholar
  10. 10.
    Suzuki C, Garces RG, Edmonds KA, Hiller S, Hyberts SG, Marintchev A, et al. PDCD4 inhibits translation initiation by binding to eIF4A using both its MA3 domains. Proc Natl Acad Sci U S A. 2008;105:3274–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Zhang S, Li J, Jiang Y, Xu Y, Qin C. Programmed cell death 4 (PDCD4) suppresses metastastic potential of human hepatocellular carcinoma cells. J Exp Clin Cancer Res. 2009;28:71.PubMedCrossRefGoogle Scholar
  12. 12.
    Nieves-Alicea R, Colburn NH, Simeone AM, Tari AM. Programmed cell death 4 inhibits breast cancer cell invasion by increasing tissue inhibitor of metalloproteinases-2 expression. Breast Cancer Res Treat. 2009;114:203–9.PubMedCrossRefGoogle Scholar
  13. 13.
    Yang HS, Knies JL, Stark C, Colburn NH. PDCD4 suppresses tumor phenotype in JB6 cells by inhibiting AP-1 transactivation. Oncogene. 2003;22:3712–20.PubMedCrossRefGoogle Scholar
  14. 14.
    Yang HS, Jansen AP, Komar AA, Zheng X, Merrick WC, Costes S, et al. The transformation suppressor PDCD4 is a novel eukaryotic translation initiation factor 4A binding protein that inhibits translation. Mol Cell Biol. 2003;23:26–37.PubMedCrossRefGoogle Scholar
  15. 15.
    Leupold JH, Yang HS, Colburn NH, Asangani I, Post S, Allgayer H. Tumor suppressor PDCD4 inhibits invasion/intravasation and regulates urokinase receptor (u-PAR) gene expression via Sp-transcription factors. Oncogene. 2007;26:4550–62.PubMedCrossRefGoogle Scholar
  16. 16.
    Yang HS, Matthews CP, Clair T, Wang Q, Baker AR, Li CC, et al. Tumorigenesis suppressor PDCD4 downregulates mitogen-activated protein kinase kinase kinase kinase 1 expression to suppress colon carcinoma cell invasion. Mol Cell Biol. 2006;26:1297–306.PubMedCrossRefGoogle Scholar
  17. 17.
    Shibahara K, Asano M, Ishida Y, Aoki T, Koike T, Honjo T. Isolation of a novel mouse gene MA-3 that is induced upon programmed cell death. Gene. 1995;166:297–301.PubMedCrossRefGoogle Scholar
  18. 18.
    Yang HS, Jansen AP, Nair R, Shibahara K, Verma AK, Cmarik JL, et al. A novel transformation suppressor, PDCD4, inhibits AP-1 transaction but not NF-κB or ODC transactivation. Oncogene. 2001;20:669–76.PubMedCrossRefGoogle Scholar
  19. 19.
    Cmarik JL, Min H, Hegamyer G, Zhan S, Kulesz-Martin M, Yoshinaga H, et al. Differentially expressed protein PDCD4 inhibits tumor promoter-induced neoplastic transformation. Proc Natl Acad Sci USA. 1999;96:14037–42.PubMedCrossRefGoogle Scholar
  20. 20.
    Liu X, Cheng Y, Yang J, Krall TJ, Huo Y, Zhang C. An essential role of PDCD4 in vascular smooth muscle cell apoptosis and proliferation: implications for vascular disease. Am J Physiol Cell Physiol. 2010;298(6):C1481–8.PubMedCrossRefGoogle Scholar
  21. 21.
    Wedeken L, Ohnheiser J, Hirschi B, Wethkamp N, Klempnauer KH. Association of tumor suppressor protein Pdcd4 with ribosomes is mediated by protein-protein and protein-RNA interactions. Genes Cancer. 2010;1(3):293–301.PubMedCrossRefGoogle Scholar
  22. 22.
    Hiyoshi Y, Kamohara H, Karashima R. Micro-RNA-21 regulates the proliferation and invasion in esophageal squamous cell carcinoma. Clin Cancer Res. 2009;15:1915–22.PubMedCrossRefGoogle Scholar
  23. 23.
    Jansen AP, Camalier CE, Stark C, Colburn NH. Characterization of programmed cell death 4 in multiple human cancers reveals a novel enhancer of drug sensitivity. Mol Cancer Ther. 2004;3:103–10.PubMedGoogle Scholar
  24. 24.
    Chen Y, Knosel T, Kristiansen G, Pietas A, Garber ME, Matsuhashi S, et al. Loss of PDCD4 expression in human lung cancer correlates with tumor progression and prognosis. J Pathol. 2003;200:640–6.PubMedCrossRefGoogle Scholar
  25. 25.
    Ma G, Guo KJ, Zhang H, Ozaki I, Matsuhashi S, Zheng XY, et al. Expression of programmed cell death 4 and its clinicopathological significance in human pancreatic cancer. Zhongguo Yi Xue Ke Xue Yuan Xue Bao. 2005;27:597–600 [Article in Chinese].PubMedGoogle Scholar
  26. 26.
    Zhang H, Ozaki I, Mizuta T, Hamajima H, Yasutake T, Eguchi Y, et al. Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma. Oncogene. 2006;25:6101–12.PubMedCrossRefGoogle Scholar
  27. 27.
    Mudduluru G, Medved F, Grobholz R, Jost C, Gruber A, Leupold JH, et al. Loss of programmed cell death 4 expression marks adenoma-carcinoma transition, correlates inversely with phosphorylated protein kinase B, and is an independent prognostic factor in resected colorectal cancer. Cancer. 2007;110:1697–707.PubMedCrossRefGoogle Scholar
  28. 28.
    Gao F, Zhang P, Zhou C, Li J, Wang Q, Zhu F, et al. Frequent loss of PDCD4 expression in human glioma: possible role in the tumorigenesis of glioma. Oncol Rep. 2007;17:123–8.PubMedGoogle Scholar
  29. 29.
    Walter BA, Gómez-Macias G, Valera VA, Sobel M, Merino MJ. miR-21 expression in pregnancy-associated breast cancer: a possible marker of poor prognosis. J Cancer. 2011;2:67–75.PubMedCrossRefGoogle Scholar
  30. 30.
    Zhang Z, DuBois RN. Detection of differentially expressed genes in human colon carcinoma cells treated with a selective COX-2 inhibitor. Oncogene. 2001;20:4450–6.PubMedCrossRefGoogle Scholar
  31. 31.
    Afonja O, Juste D, Das S, Matsuhashi S, Samuels HH. Induction of PDCD4 tumor suppressor gene expression by RAR agonists, antiestrogen and HER-2/neu antagonist in breast cancer cells. Evidence for a role in apoptosis. Oncogene. 2004;23:8135–45.PubMedCrossRefGoogle Scholar
  32. 32.
    Jansen AP, Camalier CE, Colburn NH. Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Cancer Res. 2005;65:6034–41.PubMedCrossRefGoogle Scholar
  33. 33.
    Fassan M, Cagol M, Pennelli G. Programmed cell death 4 (PDCD4) protein in esophageal cancer. Oncol Rep. 2010;24:135–9.PubMedGoogle Scholar
  34. 34.
    Göke A, Göke R, Knolle A, Trusheim H, Schmidt H, Wilmen A, et al. DUG is a novel homologue of translation initiation factor 4G that binds eIF4A. Biochem Biophys Res Commun. 2002;297:78–82.PubMedCrossRefGoogle Scholar
  35. 35.
    Kang MJ, Ahn HS, Lee JY, Matsuhashi S, Park WY. Upregulation of PDCD4 in senescent human diploid fibroblasts. Biochem Biophys Res Commun. 2002;293:617–21.PubMedCrossRefGoogle Scholar
  36. 36.
    Ponting CP. Novel eIF4G domain homologues linking mRNA translation with nonsense-mediated mRNA decay. Trends Biochem Sci. 2000;25:423–6.PubMedCrossRefGoogle Scholar
  37. 37.
    Roth W, Reed JC. Apoptosis and cancer: when BAX is TRAILing away. Nat Med. 2002;8:216–8.PubMedCrossRefGoogle Scholar
  38. 38.
    Nguyen DX, McCance DJ. Role of the retinoblastoma tumor suppressor protein in cellular differentiation. J Cell Biochem. 2005;94:870–9.PubMedCrossRefGoogle Scholar
  39. 39.
    Wang Q, Sun Z, Yang HS. Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both beta-catenin/Tcf and AP-1-dependent transcription in colon carcinoma cells. Oncogene. 2008;27:1527–35.PubMedCrossRefGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Gang Ma
    • 1
    Email author
  • Hao Zhang
    • 1
  • Ming Dong
    • 1
  • Xinyu Zheng
    • 1
  • Iwata Ozaki
    • 2
  • Sachiko Matsuhashi
    • 3
  • Kejian Guo
    • 1
  1. 1.Department of Surgery, First Affiliated HospitalChina Medical UniversityShenyangPeople’s Republic of China
  2. 2.Division of Hepatology and Metabolism, Department of internal Medicine, Saga Medical SchoolSaga UniversitySagaJapan
  3. 3.Health Administration Center, Saga Medical SchoolSaga UniversitySagaJapan

Personalised recommendations