Skip to main content

Advertisement

SpringerLink
Log in

PDCD4/miR-21 dysregulation in inflammatory bowel disease-associated carcinogenesis

  • Original Article
  • Published:
Virchows Archiv Aims and scope Submit manuscript

Abstract

Inflammatory bowel diseases (IBDs; both ulcerative colitis [UC] and Crohn’s colitis [CC]) are well-established predisposing pathological conditions for colorectal cancer (CRC) development. In IBDs, both the endoscopy and the histology assessment of CRC precursors (i.e., dysplasia, also defined as intraepithelial neoplasia) are associated with low interobserver consistency, and no reliable dysplasia-specific biomarker is available. The programmed cell death 4 (PDCD4) tumor suppressor gene is involved in sporadic colorectal oncogenesis, but scanty information is available on its involvement in IBD-associated colorectal oncogenesis. One hundred twenty tissue samples representative of active and inactive IBD and of flat dysplasia were obtained from 30 cases of UC and 30 of CC who undergone colectomy. Twenty additional biopsy samples obtained from patients with irritable bowel syndrome acted as normal controls. PDCD4 expression was assessed by immunohistochemistry; the expression of miR-21 (a major PDCD4 regulator) was investigated by quantitative real-time PCR and in situ hybridization in different series of a hundred samples. Tissue specimens from both controls and inactive IBD consistently featured strong PDCD4 nuclear immunostain; conversely, lower PDCD4 nuclear expression was featured by both active IBD and IBD-associated dysplastic lesions. Significant PDCD4 down-regulation distinguished IBD-associated dysplasia (p < 0.001) versus active IBD. In both active IBD and dysplasia, PDCD4 down-regulation was significantly associated with miR-21 up-regulation. PDCD4 nuclear down-regulation (which parallels miR-21 up-regulation) is involved in the molecular pathway of IBD-associated carcinogenesis. PDCD4 nuclear expression may be usefully applied as ancillary maker in the histological assessment of IBD-associated dysplastic lesions.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Abbreviations

IHC:

Immunohistochemistry

IBD:

Inflammatory bowel disease

PDCD4:

Programmed cell death 4

UC:

Ulcerative colitis

CC:

Crohn’s colitis

References

  1. Fiocchi C (1998) Inflammatory bowel disease: etiology and pathogenesis. Gastroenterology 115:182–205

    Article  PubMed  CAS  Google Scholar 

  2. Crohn BB (1925) The sigmoidoscopic picture of chronic ulcerative colitis (non-specific). Am J Med Sci 170:220–228

    Article  Google Scholar 

  3. Munkholm P (2003) The incidence and prevalence of colorectal cancer in inflammatory bowel disease. Aliment Pharmacol Ther 18(S2):1–5

    Article  PubMed  Google Scholar 

  4. Feagins LA, Souza RF, Spechler SJ (2009) Carcinogenesis in IBD: potential targets for the prevention of colorectal cancer. Nat Rev Gastroenterol Hepatol 6(5):297–305

    Article  PubMed  CAS  Google Scholar 

  5. Goel GA, Kandiel A, Achkar JP et al (2011) Molecular pathways underlying IBD-associated colorectal neoplasia: therapeutic implications. Am J Gastroenterol 106(4):719–730

    Article  PubMed  Google Scholar 

  6. Hamilton SR, Bosman FT, Boffetta P et al (2010) Carcinoma of the colon and rectum. In: Bosman FT, Carneiro F, Hruban R, Theise ND (eds) WHO classification of tumours of the digestive system, 4th edn. International Agency for Research on Cancer, Lyon, France, pp 134–182

    Google Scholar 

  7. Neumann H, Vieth M, Langner C et al (2011) Cancer risk in IBD: how to diagnose and how to manage DALM and ALM. World J Gastroenterol 17(27):3184–3191

    PubMed  Google Scholar 

  8. Eaden J, Abrams K, McKay H et al (2001) Inter-observer variation between general and specialist gastrointestinal pathologists when grading dysplasia in ulcerative colitis. J Pathol 194(2):152–157

    Article  PubMed  CAS  Google Scholar 

  9. Eaden J (2004) Colorectal carcinoma and inflammatory bowel disease. Aliment Pharmacol Ther 20(S4):24–30

    Article  PubMed  Google Scholar 

  10. Bohm M, Sawicka K, Siebrasse JP et al (2003) The transformation suppressor protein Pdcd4 shuttles between nucleus and cytoplasm and binds RNA. Oncogene 22:4905–4910

    Article  PubMed  Google Scholar 

  11. Yang HS, Cho MH, Zakowicz H et al (2004) A novel function of the MA-3 domains in transformation and translation suppressor Pdcd4 is essential for its binding to eukaryotic translation initiation factor 4A. Mol Cell Biol 24:3894–3906

    Article  PubMed  CAS  Google Scholar 

  12. Afonja O, Juste D, Das S et al (2004) 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 23:8135–8145

    Article  PubMed  CAS  Google Scholar 

  13. Bitomsky N, Bohm M, Klempnauer KH (2004) Transformation suppressor protein Pdcd4 interferes with JNK-mediated phosphorylation of c-Jun and recruitment of the coactivator p300 by c-Jun. Oncogene 23:7484–7493

    Article  PubMed  CAS  Google Scholar 

  14. Zakowicz H, Yang HS, Stark C et al (2005) Mutational analysis of the DEAD-box RNA helicase eIF4AII characterizes its interaction with transformation suppressor Pdcd4 and eIF4GI. RNA 11:261–274

    Article  PubMed  CAS  Google Scholar 

  15. Jansen AP, Camalier CE, Colburn NH (2005) Epidermal expression of the translation inhibitor programmed cell death 4 suppresses tumorigenesis. Cancer Res 65:6034–6041

    Article  PubMed  CAS  Google Scholar 

  16. Dorrello NV, Peschiaroli A, Guardavaccaro D et al (2006) S6K1-and betaTRCP-mediated degradation of PDCD4 promotes protein translation and cell growth. Science 314:467–471

    Article  PubMed  CAS  Google Scholar 

  17. Bitomsky N, Wethkamp N, Marikkannu R et al (2008) SiRNA-mediated knockdown of Pdcd4 expression causes upregulation of p21(Waf1/Cip1) expression. Oncogene 27:4820–4829

    Article  PubMed  CAS  Google Scholar 

  18. Carayol N, Katsoulidis E, Sassano A et al (2008) Suppression of programmed cell death 4 (PDCD4) protein expression by BCRABL-regulated engagement of the mTOR/p70 S6 kinase pathway. J Biol Chem 283:8601–8610

    Article  PubMed  CAS  Google Scholar 

  19. Mudduluru G, Medved F, Grobholz R et al (2007) 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 110:1697–1707

    Article  PubMed  CAS  Google Scholar 

  20. Allgayer H (2010) Pdcd4, a colon cancer prognostic that is regulated by a microRNA. Crit Rev Oncol Hematol 73:185–191

    Article  PubMed  Google Scholar 

  21. Fassan M, Pizzi M, Battaglia G et al (2010) Programmed cell death 4 (PDCD4) expression during multistep Barrett’s carcinogenesis. J Clin Pathol 63:692–696

    Article  PubMed  CAS  Google Scholar 

  22. Chen Y, Knosel T, Kristiansen G et al (2003) Loss of PDCD4 expression in human lung cancer correlates with tumour progression and prognosis. J Pathol 200:640–646

    Article  PubMed  CAS  Google Scholar 

  23. Zhang H, Ozaki I, Mizuta T et al (2006) Involvement of programmed cell death 4 in transforming growth factor-beta1-induced apoptosis in human hepatocellular carcinoma. Oncogene 25:6101–6112

    Article  PubMed  CAS  Google Scholar 

  24. Wang Q, Sun Z, Yang HS (2008) Downregulation of tumor suppressor Pdcd4 promotes invasion and activates both betacatenin/Tcf and AP-1-dependent transcription in colon carcinoma cells. Oncogene 27:1527–1535

    Article  PubMed  CAS  Google Scholar 

  25. Baffa R, Fassan M, Volinia S et al (2009) MicroRNA expression profiling of human metastatic cancers identifies cancer gene targets. J Pathol 219:214–221

    Article  PubMed  CAS  Google Scholar 

  26. Yamamichi N, Shimomura R, Inada K et al (2009) Locked nucleic acid in situ hybridization analysis of miR-21 expression during colorectal cancer development. Clin Cancer Res 15:4009–4016

    Article  PubMed  CAS  Google Scholar 

  27. Fassan M, Cagol M, Pennelli G et al (2010) Programmed cell death 4 (PDCD4) protein in esophageal cancer. Oncol Rep 24:135–139

    PubMed  CAS  Google Scholar 

  28. Goke R, Barth P, Schmidt A et al (2004) Programmed cell death protein 4 suppresses CDK1/cdc2 via induction of p21 (Waf1/Cip1). Am J Physiol Cell Physiol 287:C1541–C1546

    Article  PubMed  CAS  Google Scholar 

  29. Dalal SR, Kwon JH (2010) The role of microRNA in inflammatory bowel disease. Gastroenterol Hepatol (NY) 6:714–722

    Google Scholar 

  30. Wu F, Zhang S, Dassopoulos T, Harris ML et al (2010) Identification of microRNAs associated with ileal and colonic Crohn’s disease. Inflamm Bowel Dis 16:1729–1738

    Article  PubMed  Google Scholar 

  31. Okubo M, Tahara T, Shibita T et al (2011) Association study of common genetic variants in pre-microRNAs in patients with ulcerative colitis. J Clin Immunol 31:69–73

    Article  PubMed  CAS  Google Scholar 

  32. Goldman H (1994) Interpretation of large intestinal mucosal biopsy specimens. Hum Pathol 25(11):1150–1159

    Article  PubMed  CAS  Google Scholar 

  33. Cornaggia M, Leutner M, Mescoli C et al (2011) Chronic idiopathic inflammatory bowel diseases: the histology report. Dig Liver Dis 43(4):293–303

    Article  Google Scholar 

  34. Rugge M, Correa P, Dixon MF (2000) Padova classification gastric dysplasia: the Padova international classification. Am J Surg Pathol 24(2):167–176, Review

    Article  PubMed  CAS  Google Scholar 

  35. Rugge M, Fassan M, Clemente R et al (2008) Bronchopulmonary carcinoid: phenotype and long-term outcome in a single institution series of Italian patients. Clin Cancer Res 14:149–154

    Article  PubMed  CAS  Google Scholar 

  36. Yoshinaga H, Matsuhashi S, Fujiyama C et al (1999) Novel human PDCD4 (H731) gene expressed in proliferative cells is expressed in the small duct epithelial cells of the breast as revealed by an anti-H731 antibody. Pathol Int 49:1067–1077

    Article  PubMed  CAS  Google Scholar 

  37. Fassan M, Volinia S, Palatini J et al (2011) MicroRNA expression profiling in human Barrett’s carcinogenesis. Int J Cancer 129(7):1661–1670

    Article  PubMed  CAS  Google Scholar 

  38. Fassan M, Pizzi M, Giacomelli L et al (2011) PDCD4 nuclear loss inversely correlates with miR-21 levels in colon carcinogenesis. Virchows Arch 458(4):413–419

    Article  PubMed  CAS  Google Scholar 

  39. Chang KH, Miller N, Kheirelseid EA et al (2011) MicroRNA-21 and PDCD4 expression in colorectal cancer. Eur J Surg Oncol 37(7):597–603

    Article  PubMed  CAS  Google Scholar 

  40. Yu Y, Kanwar SS, Patel BB et al (2012) MicroRNA-21 induces stemness by downregulating transforming growth factor beta receptor 2 (TGFβR2) in colon cancer cells. Carcinogenesis 33(1):68–76

    Article  PubMed  CAS  Google Scholar 

  41. Itzkowitz SH (2006) Molecular biology of dysplasia and cancer in inflammatory bowel disease. Gastroenterol Clin North Am 35(3):553–571

    Article  PubMed  Google Scholar 

  42. Gerrits MM, Chen M, Theeuwes M et al (2011) Biomarker-based prediction of inflammatory bowel disease-related colorectal cancer: a case–control study. Cell Oncol (Dordr) 34(2):107–117

    CAS  Google Scholar 

  43. Hiyoshi Y, Kamohara H, Karashima R et al (2009) Micro-RNA-21 regulates the proliferation and invasion in esophageal squamous cell carcinoma. Clin Cancer Res 15(6):1915–1922

    Article  PubMed  CAS  Google Scholar 

  44. Gerrits MM, Chen M, Theeuwes M et al (2011) Biomarker-based prediction of inflammatory bowel disease-related colorectal cancer: a case–control study. Cell Oncol 34:107–117

    Article  CAS  Google Scholar 

  45. Rutter M, Saunders B, Wilkinson K et al (2004) Severity of inflammation is a risk factor for colorectal neoplasia in ulcerative colitis. Gastroenterology 126:451–459

    Article  PubMed  Google Scholar 

  46. Brest P, Lapaquette P, Souidi M et al (2011) A synonymous variant in IRGM alters a binding site for miR-196 and causes deregulation of IRGM-dependent xenophagy in Crohn's disease. Nat Genet 43(3):242–245

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We wish to acknowledge the continuous support of the “G. Berlucchi” and the “G.B. Morgagni” Foundations. This work was partially supported by an AIRC Regional grant (2008). We also thank Dr. Cristiano Lanza, Dr. Vincenza Guzzardo, and Dr. Vanni Lazzarin for their excellent technical support. All authors of this research paper participated directly in the planning and execution of the study and in the analysis of the results.

Conflict of interest

The authors have no competing interests to declare.

Author information

Authors and Affiliations

  1. Department of Medicine (DIMED), Surgical Pathology and Cytopathology Unit, University of Padua, Padua, Italy

    Kathrin Ludwig, Matteo Fassan, Claudia Mescoli, Marco Pizzi, Mariangela Balistreri & Laura Albertoni

  2. Department of Surgical Oncology and Gastroenterological Sciences (DiSCOG), General Oncology Unit, University of Padua, Padua, Italy

    Matteo Fassan

  3. Department of Surgical Oncology and Gastroenterological Sciences (DiSCOG), Clinica Chirurgica II, University of Padua, Padua, Italy

    Salvatore Pucciarelli

  4. Oncological Surgery Unit, Veneto Institute of Oncology (IOV–IRCCS), Padua, Italy

    Marco Scarpa & Imerio Angriman

  5. Department of Surgical Oncology and Gastroenterological Sciences (DiSCOG), Gastroenterology Unit, University of Padua, Padua, Italy

    Giacomo Carlo Sturniolo

  6. Surgical Pathology Unit, Veneto Institute of Oncology (IOV–IRCCS), Padua, Italy

    Massimo Rugge

  7. Department of Medical Diagnostic Sciences and Special Therapies, University of Padua, Via Aristide Gabelli, 61, 35121, Padua, Italy

    Massimo Rugge

Authors
  1. Kathrin Ludwig
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Matteo Fassan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Claudia Mescoli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marco Pizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mariangela Balistreri
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Laura Albertoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Salvatore Pucciarelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Marco Scarpa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Giacomo Carlo Sturniolo
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Imerio Angriman
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Massimo Rugge
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Massimo Rugge.

Additional information

Kathrin Ludwig and Matteo Fassan contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ludwig, K., Fassan, M., Mescoli, C. et al. PDCD4/miR-21 dysregulation in inflammatory bowel disease-associated carcinogenesis. Virchows Arch 462, 57–63 (2013). https://doi.org/10.1007/s00428-012-1345-5

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00428-012-1345-5

Keywords

Search

Navigation