Skip to main content
SpringerLink
Log in

Expression of Bmi1, FoxF1, Nanog, and γ-Catenin in Relation to Hedgehog Signaling Pathway in Human Non-small-Cell Lung Cancer

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Background

Hedgehog signaling is known to be involved in both lung organogenesis and lung carcinogenesis. The aim of this study was to examine potential downstream targets of the hedgehog signaling pathway in non-small-cell lung cancer.

Methods

Protein expression of Bmi1, FoxF1, Nanog, and γ-catenin was examined by immunohistochemistry in 80 non-small-cell lung cancer samples. Correlations with the previously immunohistochemically recovered results for sonic hedgehog, Ptch1, Smo, Gli1, and Gli2 in the same cohort of tumors as well as the clinicopathological characteristics of the tumors were also evaluated.

Results

Bmi1 was expressed in 78/80 (97.5 %) cases of non-small-cell lung cancer and correlated with male gender and expression of Gli1. Positive expression of FoxF1 was found in 62/80 (77.5 %) cases. Expression of FoxF1 correlated with lymph node metastases, Bmi1, and hedgehog pathway activation. Overexpression of Nanog was also noted in 74/80 (92.5 %) tumors and correlated with Bmi1. Cytoplasmic accumulation of γ-catenin was observed in 85 % (68/80) of the tumors and correlated with the expression of Bmi1, FoxF1, and Nanog.

Conclusion

Several developmental pathways seem to be implicated in non-small-cell lung cancer. It is also suggested that Bmi1 and FoxF1 may cooperate with hedgehog signaling in non-small-cell lung carcinogenesis.

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.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Daniel VC, Peacock CD, Watkins DN (2006) Developmental signalling pathways in lung cancer. Respirology 11(3):234–240

    Article  PubMed  Google Scholar 

  2. van Tuyl M, Post M (2000) From fruitflies to mammals: mechanisms of signalling via the Sonic hedgehog pathway in lung development. Respir Res 1(1):30–35

    Article  PubMed  Google Scholar 

  3. Velcheti V, Govindan R (2007) Hedgehog signaling pathway and lung cancer. J Thorac Oncol 2(1):7–10

    Article  PubMed  Google Scholar 

  4. Ruiz i Altaba A, Stecca B, Sánchez P, Ruiz i Altaba A, Stecca B, Sánchez P (2004) Hedgehog–Gli signaling in brain tumors: stem cells and paradevelopmental programs in cancer. Cancer Lett 204(2):145–157

    Article  PubMed  CAS  Google Scholar 

  5. Kalderon D (2000) Transducing the hedgehog signal. Cell 103(3):371–374

    Article  PubMed  CAS  Google Scholar 

  6. Mullor JL, Sánchez P, Ruiz i Altaba A (2002) Pathways and consequences: hedgehog signaling in human disease. Trends Cell Biol 12(12):562–569

    Article  PubMed  CAS  Google Scholar 

  7. Gialmanidis IP, Bravou V, Amanetopoulou SG et al (2009) Overexpression of hedgehog pathway molecules and FOXM1 in non-small cell lung carcinomas. Lung Cancer. 66(1):64–74

    Article  PubMed  Google Scholar 

  8. Michael LE, Westerman BA, Ermilov AN et al (2008) Bmi1 is required for Hedgehog pathway-driven medulloblastoma expansion. Neoplasia 10(12):1343–1349

    PubMed  Google Scholar 

  9. Zbinden M, Duquet A, Lorente-Trigos A et al (2010) NANOG regulates glioma stem cells and is essential in vivo acting in a cross-functional network with GLI1 and p53. EMBO J 29(15):2659–2674

    Article  PubMed  CAS  Google Scholar 

  10. Yoon JW, Kita Y, Frank DJ et al (2002) Gene expression profiling leads to identification of GLI1-binding elements in target genes and a role for multiple downstream pathways in GLI1-induced cell transformation. J Biol Chem 277(7):5548–5555

    Article  PubMed  CAS  Google Scholar 

  11. Jacobs JJ, Kieboom K, Marino S et al (1999) The oncogene and Polycomb-group gene bmi-1 regulates cell proliferation and senescence through the ink4a locus. Nature 397(6715):164–168

    Article  PubMed  CAS  Google Scholar 

  12. Park IK, Qian D, Kiel M et al (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423(6937):302–305

    Article  PubMed  CAS  Google Scholar 

  13. Molofsky AV, Pardal R, Iwashita T et al (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425(6961):962–967

    Article  PubMed  CAS  Google Scholar 

  14. Molofsky AV, He S, Bydon M et al (2005) Bmi-1 promotes neural stem cell self-renewal and neural development but not mouse growth and survival by repressing the p16Ink4a and p19Arf senescence pathways. Genes Dev 19(12):1432–1437

    Article  PubMed  CAS  Google Scholar 

  15. Prince ME, Sivanandan R, Kaczorowski A et al (2007) Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci U S A 104(3):973–978

    Article  PubMed  CAS  Google Scholar 

  16. Liu JH, Song LB, Zhang X et al (2008) Bmi-1 expression predicts prognosis for patients with gastric carcinoma. J Surg Oncol 97(3):267–272

    Article  PubMed  CAS  Google Scholar 

  17. Vonlanthen S, Heighway J, Altermatt HJ et al (2001) The bmi-1 oncoprotein is differentially expressed in non-small cell lung cancer and correlates with INK4A-ARF locus expression. Br J Cancer 84(10):1372–1376

    Article  PubMed  CAS  Google Scholar 

  18. Kaufmann E, Knöchel W (1996) Five years on the wings of fork head. Mech Dev 57(1):3–20

    Article  PubMed  CAS  Google Scholar 

  19. Stankiewicz P, Sen P, Bhatt SS et al (2009) Genomic and genic deletions of the FOX gene cluster on 16q24.1 and inactivating mutations of FOXF1 cause alveolar capillary dysplasia and other malformations. Am J Hum Genet 84(6):780–791

    Article  PubMed  CAS  Google Scholar 

  20. Yamaguchi S, Kimura H, Tada M et al (2005) Nanog expression in mouse germ cell development. Gene Expr Patterns 5(5):639–646

    Article  PubMed  CAS  Google Scholar 

  21. Chiou SH, Wang ML, Chou YT et al (2010) Coexpression of Oct4 and Nanog enhances malignancy in lung adenocarcinoma by inducing cancer stem cell-like properties and epithelial-mesenchymal transdifferentiation. Cancer Res 70(24):10433–10444

    Article  PubMed  CAS  Google Scholar 

  22. Barker N, Clevers H (2000) Catenins. Wnt signaling and cancer. Bioessays 22(11):961–965

    Article  CAS  Google Scholar 

  23. Wendling DS, Lück C, von Schweinitz D et al (2008) Characteristic overexpression of the forkhead box transcription factor Foxf1 in Patched-associated tumors. Int J Mol Med 22(6):787–792

    PubMed  CAS  Google Scholar 

  24. Dlugosz AA, Talpaz M (2009) Following the hedgehog to new cancer therapies. N Engl J Med 361(12):1202–1205

    Article  PubMed  CAS  Google Scholar 

  25. Xu F, Yang R, Wu L et al (2012) Overexpression of BMI1 confers clonal cells resistance to apoptosis and contributes to adverse prognosis in myelodysplastic syndrome. Cancer Lett 317(1):33–40

    Article  PubMed  CAS  Google Scholar 

  26. Lo PK, Lee JS, Liang X et al (2010) Epigenetic inactivation of the potential tumor suppressor gene FOXF1 in breast cancer. Cancer Res 70(14):6047–6058

    Article  PubMed  CAS  Google Scholar 

  27. Saito RA, Micke P, Paulsson J et al (2010) Forkhead box F1 regulates tumor-promoting properties of cancer-associated fibroblasts in lung cancer. Cancer Res 70(7):2644–2654

    Article  PubMed  CAS  Google Scholar 

  28. Maeda Y, Davé V, Whitsett JA (2007) Transcriptional control of lung morphogenesis. Physiol Rev 87(1):219–244

    Article  PubMed  CAS  Google Scholar 

  29. Shakhova O, Leung C, Marino S (2005) Bmi1 in development and tumorigenesis of the central nervous system. J Mol Med 83(8):596–600

    Article  PubMed  CAS  Google Scholar 

  30. Grinstein E, Mahotka C (2009) Stem cell divisions controlled by the proto-oncogene BMI-1. J Stem Cells 4(3):141–146

    PubMed  Google Scholar 

  31. Kalinichenko VV, Gusarova GA, Kim IM et al (2004) Foxf1 haploinsufficiency reduces Notch-2 signaling during mouse lung development. Am J Physiol Lung Cell Mol Physiol 286(3):L521–L530

    Article  PubMed  CAS  Google Scholar 

  32. Mahlapuu M, Enerbäck S, Carlsson P (2001) Haploinsufficiency of the forkhead gene Foxf1, a target for sonic hedgehog signaling, causes lung and foregut malformations. Development 128(12):2397–2406

    PubMed  CAS  Google Scholar 

  33. Teglund S (1805) Toftgård R (2010) Hedgehog beyond medulloblastoma and basal cell carcinoma. Biochim Biophys Acta 2:181–208

    Google Scholar 

  34. Liu S, Dontu G, Mantle ID et al (2006) Hedgehog signaling and Bmi-1 regulate self-renewal of normal and malignant human mammary stem cells. Cancer Res 66(12):6063–6071

    Article  PubMed  CAS  Google Scholar 

  35. Nirasawa S, Kobayashi D, Tsuji N et al (2009) Diagnostic relevance of overexpressed Nanog gene in early lung cancers. Oncol Rep 22(3):587–591

    PubMed  CAS  Google Scholar 

  36. Yuan P, Kadara H, Behrens C et al (2010) Sex determining region Y-Box 2 (SOX2) is a potential cell-lineage gene highly expressed in the pathogenesis of squamous cell carcinomas of the lung. PLoS ONE 5(2):e9112

    Article  PubMed  Google Scholar 

  37. Leung EL, Fiscus RR, Tung JW et al (2010) Non-small cell lung cancer cells expressing CD44 are enriched for stem cell-like properties. PLoS ONE 5(11):e14062

    Article  PubMed  Google Scholar 

  38. Forte A, Schettino MT, Finicelli M et al (2009) Expression pattern of stemness-related genes in human endometrial and endometriotic tissues. Mol Med 15(11–12):392–401

    PubMed  CAS  Google Scholar 

  39. Melone MA, Giuliano M, Squillaro T et al (2009) Genes involved in regulation of stem cell properties: studies on their expression in a small cohort of neuroblastoma patients. Cancer Biol Ther 8(13):1300–1306

    Article  PubMed  CAS  Google Scholar 

  40. Mathieu J, Zhang Z, Zhou W et al (2011) HIF induces human embryonic stem cell markers in cancer cells. Cancer Res 71(13):4640–4652

    Article  PubMed  CAS  Google Scholar 

  41. Aktary Z, Pasdar M (2012) Plakoglobin: role in tumorigenesis and metastasis. Int J Cell Biol 2012:189521

    PubMed  Google Scholar 

  42. Nagel JM, Kriegl L, Horst D et al (2010) γ-Catenin is an independent prognostic marker in early stage colorectal cancer. Int J Colorectal Dis 25(11):1301–1309

    Article  PubMed  Google Scholar 

  43. Shahi MH, Afzal M, Sinha S et al (2010) Regulation of sonic hedgehog-GLI1 downstream target genes PTCH1, Cyclin D2, Plakoglobin, PAX6 and NKX2.2 and their epigenetic status in medulloblastoma and astrocytoma. BMC Cancer 10:614

    Article  PubMed  CAS  Google Scholar 

  44. Kolligs FT, Kolligs B, Hajra KM et al (2000) γ-Catenin is regulated by the APC tumor suppressor and its oncogenic activity is distinct from that of beta-catenin. Genes Dev 14(11):1319–1331

    PubMed  CAS  Google Scholar 

  45. Chikaishi Y, Uramoto H, Tanaka F (2011) The EMT status in the primary tumor does not predict postoperative recurrence or disease-free survival in lung adenocarcinoma. Anticancer Res 31(12):4451–4456

    PubMed  Google Scholar 

  46. Yamashita T, Uramoto H, Onitsuka T et al (2010) Association between lymphangiogenesis-/micrometastasis- and adhesion-related molecules in resected stage I NSCLC. Lung Cancer 70(3):320–328

    Article  PubMed  Google Scholar 

  47. Winn RA, Bremnes RM, Bemis L et al (2002) γ-Catenin expression is reduced or absent in a subset of human lung cancers and re-expression inhibits transformed cell growth. Oncogene 21(49):7497–7506

    Article  PubMed  CAS  Google Scholar 

  48. Shahi MH, Schiapparelli P, Afzal M et al (2011) Expression and epigenetic modulation of sonic hedgehog-GLI1 pathway genes in neuroblastoma cell lines and tumors. Tumour Biol 32(1):113–127

    Article  PubMed  CAS  Google Scholar 

Download references

Conflict of interest

The authors have conflicts of interest to disclose.

Author information

Authors and Affiliations

  1. Department of Anatomy, School of Medicine, University of Patras, 26500, Rio Patras, Greece

    Ioannis P. Gialmanidis, Vasiliki Bravou, Ilias Petrou, Ioannis Lilis & Helen Papadaki

  2. Department of Pathology, School of Medicine, University of Patras, 26500, Rio Patras, Greece

    Helen Kourea

  3. Southport and Ormskirk Hospital NHS Trust, Southport, Merseyside, PR8 6PN, UK

    Alexandros Mathioudakis

Authors
  1. Ioannis P. Gialmanidis
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Vasiliki Bravou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ilias Petrou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Helen Kourea
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Alexandros Mathioudakis
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Ioannis Lilis
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Helen Papadaki
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Ioannis P. Gialmanidis.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gialmanidis, I.P., Bravou, V., Petrou, I. et al. Expression of Bmi1, FoxF1, Nanog, and γ-Catenin in Relation to Hedgehog Signaling Pathway in Human Non-small-Cell Lung Cancer. Lung 191, 511–521 (2013). https://doi.org/10.1007/s00408-013-9490-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-013-9490-4

Keywords

Search

Navigation