Skip to main content

Advertisement

Log in

Decreased TAp63 and ΔNp63 mRNA Levels in Most Human Pituitary Adenomas Are Correlated with Notch3/Jagged1 Relative Expression

  • Published:
Endocrine Pathology Aims and scope Submit manuscript

Abstract

Despite recent advances in molecular genetics, the pituitary adenoma initiation, development, progress, and the molecular basis of their unique features are still poorly understood. In this sense, it is proposed that stem cell could be involved in pituitary adenoma tumorigenesis. It is suggested that TP63 has important functions in stem cells, and it may have interplay of TP63 and Notch and its ligand Jagged in this process. This study aimed to evaluate the distinct expression of TP63 isoforms (TAp63 and ΔNp63), as well as its correlation with Notch3 receptor and its ligand Jagged1 in human pituitary adenomas at the messenger RNA (mRNA) level. We included 77 pituitary adenoma tumor samples from patients who underwent surgical resection. The expression levels of TP63 isoforms (TAp63 and ΔNp63) and Notch3 and its ligand Jagged1 were evaluated by qRT-PCR using isoform-specific primers. We also evaluated proliferation index immunohistochemically using KI-67 antibody. The expression levels were associated with clinical outcomes, as age, gender, tumor size, and tumor subtype. In summary, we found that mRNA expression of both TP63 isoforms decreased in pituitary adenomas compared with normal pituitary control. On the other hand, there was an increase of relative Notch3 and Jagged1 mRNA expression in the majority of examined samples. The mRNA expression of three genes evaluated was correlated and statistically significantly. There was no significant association between gene expression and the analyzed clinical data. The current study has provided the first time evidence that Tap63 and ΔNp63 isoforms are underexpressed in most pituitary adenomas. These results are correlated with Notch3 and its ligand Jagged1 overexpression, corroborating previous studies pointing its antagonistic interactions.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Ostrom QT, Gittleman H, Fulop J, et al. CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2008-2012. Neuro-oncology 17 Suppl 4: iv1-iv62, 2015.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Melmed S Mechanisms for pituitary tumorigenesis: the plastic pituitary. The Journal of clinical investigation 112: 1603–1618, 2003.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Ratovitski EA, Patturajan M, Hibi K, Trink B, Yamaguchi K, Sidransky D p53 associates with and targets Delta Np63 into a protein degradation pathway. Proc Natl Acad Sci U S A 98: 1817–1822, 2001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Patturajan M, Nomoto S, Sommer Met al. DeltaNp63 induces beta-catenin nuclear accumulation and signaling. Cancer cell 1: 369–379, 2002.

    Article  CAS  PubMed  Google Scholar 

  5. Graziano V, De Laurenzi V Role of p63 in cancer development. Biochim Biophys Acta 1816: 57–66, 2011.

    CAS  PubMed  Google Scholar 

  6. Zhu X, Zhang J, Tollkuhn J, et al. Sustained Notch signaling in progenitors is required for sequential emergence of distinct cell lineages during organogenesis. Genes & development 20: 2739–2753, 2006.

    Article  CAS  Google Scholar 

  7. Raetzman LT, Ross SA, Cook S, Dunwoodie SL, Camper SA, Thomas PQ Developmental regulation of Notch signaling genes in the embryonic pituitary: Prop1 deficiency affects Notch2 expression. Developmental biology 265: 329–340, 2004.

    Article  CAS  PubMed  Google Scholar 

  8. Moreno CS, Evans CO, Zhan X, Okor M, Desiderio DM, Oyesiku NM Novel molecular signaling and classification of human clinically nonfunctional pituitary adenomas identified by gene expression profiling and proteomic analyses. Cancer research 65: 10214–10222, 2005.

    Article  CAS  PubMed  Google Scholar 

  9. Chen J, Hersmus N, Van Duppen V, Caesens P, Denef C, Vankelecom H The adult pituitary contains a cell population displaying stem/progenitor cell and early embryonic characteristics. Endocrinology 146: 3985–3998, 2005.

    Article  CAS  PubMed  Google Scholar 

  10. Chen J, Gremeaux L, Fu Q, Liekens D, Van Laere S, Vankelecom H Pituitary progenitor cells tracked down by side population dissection. Stem cells 27: 1182–1195, 2009.

    Article  CAS  PubMed  Google Scholar 

  11. Chen J, Crabbe A, Van Duppen V, Vankelecom H The notch signaling system is present in the postnatal pituitary: marked expression and regulatory activity in the newly discovered side population. Molecular endocrinology 20: 3293–3307, 2006.

    Article  CAS  PubMed  Google Scholar 

  12. Nantie LB, Himes AD, Getz DR, Raetzman LT Notch signaling in postnatal pituitary expansion: proliferation, progenitors, and cell specification. Molecular endocrinology 28: 731–744, 2014.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Tando Y, Fujiwara K, Yashiro T, Kikuchi M Localization of Notch signaling molecules and their effect on cellular proliferation in adult rat pituitary. Cell and tissue research 351: 511–519, 2013.

    Article  CAS  PubMed  Google Scholar 

  14. Vankelecom H, Gremeaux L Stem cells in the pituitary gland: A burgeoning field. General and comparative endocrinology 166: 478–488, 2010.

    Article  CAS  PubMed  Google Scholar 

  15. Miao Z, Miao Y, Lin Y, Lu X Overexpression of the Notch3 receptor in non-functioning pituitary tumours. J Clin Neurosci 19: 107–110, 2012.

    Article  CAS  PubMed  Google Scholar 

  16. Lu R, Gao H, Wang H, Cao L, Bai J, Zhang Y Overexpression of the Notch3 receptor and its ligand Jagged1 in human clinically non-functioning pituitary adenomas. Oncology letters 5: 845–851, 2013.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Yalcin-Ozuysal O, Fiche M, Guitierrez M, Wagner KU, Raffoul W, Brisken C Antagonistic roles of Notch and p63 in controlling mammary epithelial cell fates. Cell Death Differ 17: 1600–1612, 2010.

    Article  CAS  PubMed  Google Scholar 

  18. Sasaki Y, Ishida S, Morimoto I, et al. The p53 family member genes are involved in the Notch signal pathway. J Biol Chem 277: 719–724, 2002.

    Article  CAS  PubMed  Google Scholar 

  19. Wu G, Nomoto S, Hoque MO, et al. DeltaNp63alpha and TAp63alpha regulate transcription of genes with distinct biological functions in cancer and development. Cancer Res 63: 2351–2357, 2003.

    CAS  PubMed  Google Scholar 

  20. Rotondo F, Vidal S, Bell D, et al. Immunohistochemical localization of amylin in human pancreas, thyroid, pituitary and their tumors. Acta histochemica 105: 303–307, 2003.

    Article  PubMed  Google Scholar 

  21. Chomczynski P A A reagent for the single-step simultaneous isolation of RNA, DNA and proteins from cell and tissue samples. BioTechniques 15: 532–534, 536-537, 1993.

    CAS  PubMed  Google Scholar 

  22. de Biase D, Morandi L, Degli Esposti R, et al. P63 short isoforms are found in invasive carcinomas only and not in benign breast conditions. Virchows Arch 456: 395–401, 2010.

    Article  PubMed  Google Scholar 

  23. Uchida K, Ross H, Lotan T, et al. DeltaNp63 (p40) expression in prostatic adenocarcinoma with diffuse p63 positivity. Hum Pathol 46: 384–389, 2015.

    Article  CAS  PubMed  Google Scholar 

  24. Baig MK, Hassan U, Mansoor S Role of p63 in differentiating morphologically ambiguous lesions of prostate. Journal of the College of Physicians and Surgeons--Pakistan : JCPSP 22: 773–777, 2012.

    PubMed  Google Scholar 

  25. Du Z, Li J, Wang L, et al. Overexpression of DeltaNp63alpha induces a stem cell phenotype in MCF7 breast carcinoma cell line through the Notch pathway. Cancer Sci 101: 2417–2424, 2010.

    Article  CAS  PubMed  Google Scholar 

  26. Bustin SA, Benes V, Garson JA, et al. The MIQE guidelines: minimum information for publication of quantitative real-time PCR experiments. Clinical chemistry 55: 611–622, 2009.

    Article  CAS  PubMed  Google Scholar 

  27. Bustin SA, Benes V, Nolan T, Pfaffl MW Quantitative real-time RT-PCR--a perspective. J Mol Endocrinol 34: 597–601, 2005.

    Article  CAS  PubMed  Google Scholar 

  28. Bustin SA Absolute quantification of mRNA using real-time reverse transcription polymerase chain reaction assays. J Mol Endocrinol 25: 169–193, 2000.

    Article  CAS  PubMed  Google Scholar 

  29. Melino G p63 is a suppressor of tumorigenesis and metastasis interacting with mutant p53. Cell Death Differ 18: 1487–1499, 2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Das RK, Pal M, Barui A, et al. Assessment of malignant potential of oral submucous fibrosis through evaluation of p63, E-cadherin and CD105 expression. J Clin Pathol 63: 894–899, 2010.

    Article  PubMed  Google Scholar 

  31. Di Como CJ, Urist MJ, Babayan I, et al. p63 expression profiles in human normal and tumor tissues. Clin Cancer Res 8: 494–501, 2002.

    CAS  PubMed  Google Scholar 

  32. Barbieri CE, Pietenpol JA p63 and epithelial biology. Exp Cell Res 312: 695–706, 2006.

    Article  CAS  PubMed  Google Scholar 

  33. Amin R, Morita-Fujimura Y, Tawarayama H, et al. DeltaNp63alpha induces quiescence and downregulates the BRCA1 pathway in estrogen receptor-positive luminal breast cancer cell line MCF7 but not in other breast cancer cell lines. Mol Oncol 10: 575–593, 2016.

    Article  CAS  PubMed  Google Scholar 

  34. Barbieri CE, Tang LJ, Brown KA, Pietenpol JA Loss of p63 leads to increased cell migration and up-regulation of genes involved in invasion and metastasis. Cancer Res 66: 7589–7597, 2006.

    Article  CAS  PubMed  Google Scholar 

  35. Lo Muzio L, Santarelli A, Caltabiano R, et al. p63 overexpression associates with poor prognosis in head and neck squamous cell carcinoma. Hum Pathol 36: 187–194, 2005.

    Article  CAS  PubMed  Google Scholar 

  36. Sniezek JC, Matheny KE, Westfall MD, Pietenpol JA Dominant negative p63 isoform expression in head and neck squamous cell carcinoma. Laryngoscope 114: 2063–2072, 2004.

    Article  CAS  PubMed  Google Scholar 

  37. Shimada Y, Ishii G, Nagai K.et al. Expression of podoplanin, CD44, and p63 in squamous cell carcinoma of the lung. Cancer Sci 100: 2054–2059, 2009.

    Article  CAS  PubMed  Google Scholar 

  38. Si H, Lu H, Yang X, et al. TNF-alpha modulates genome-wide redistribution of DeltaNp63alpha/TAp73 and NF-kappaB cREL interactive binding on TP53 and AP-1 motifs to promote an oncogenic gene program in squamous cancer. Oncogene, 2016.

  39. Bornachea O, Lopez-Calderon FF, Duenas M, et al. The downregulation of DeltaNp63 in p53-deficient mouse epidermal tumors favors metastatic behavior. Oncotarget 6: 24230–24245, 2015.

    Article  PubMed  PubMed Central  Google Scholar 

  40. Lo Iacono M, Monica V, Saviozzi S, et al. p63 and p73 isoform expression in non-small cell lung cancer and corresponding morphological normal lung tissue. Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer 6: 473–481, 2011.

    Article  Google Scholar 

  41. Su X, Chakravarti D, Flores ER p63 steps into the limelight: crucial roles in the suppression of tumorigenesis and metastasis. Nat Rev Cancer 13: 136–143, 2013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hadzhiyanev A, Ivanova R, Nachev E, et al. Evaluation of prognostic utility of MIB-1 and p53 expression in pituitary adenomas: correlations with clinical behaviour and follow-up results. Biotechnology, biotechnological equipment 28: 502–507, 2014.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Gejman R, Swearingen B, Hedley-Whyte ET Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum Pathol 39: 758–766, 2008.

    Article  CAS  PubMed  Google Scholar 

  44. Ma J, Meng Y, Kwiatkowski DJ, et al. Mammalian target of rapamycin regulates murine and human cell differentiation through STAT3/p63/Jagged/Notch cascade. J Clin Invest 120: 103–114, 2010.

    Article  CAS  PubMed  Google Scholar 

  45. Beckers A, Daly AF The clinical, pathological, and genetic features of familial isolated pituitary adenomas. Eur J Endocrinol 157: 371–382, 2007.

    Article  CAS  PubMed  Google Scholar 

  46. Mezzomo LC, Gonzales PH, Pesce FG, et al. Expression of cell growth negative regulators MEG3 and GADD45gamma is lost in most sporadic human pituitary adenomas. Pituitary 15: 420–427, 2012.

    Article  CAS  PubMed  Google Scholar 

  47. Stratakis CA, Tichomirowa MA, Boikos S, et al. The role of germline AIP, MEN1, PRKAR1A, CDKN1B and CDKN2C mutations in causing pituitary adenomas in a large cohort of children, adolescents, and patients with genetic syndromes. Clinical genetics 78: 457–463, 2010.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Aulinas A, Colom C, Ybarra J, et al. Immediate and delayed postoperative morbidity in functional and non-functioning pituitary adenomas. Pituitary 15: 380–385, 2012.

    PubMed  Google Scholar 

Download references

Acknowledgements

We wish to thank the Neuroendocrinology Center of Hospital São José, Irmandade Santa Casa de Misericórdia from Porto Alegre, Brazil, for providing the human pituitary tissues and the access to clinical data. We also thank especially M.D. Ligia Maria Barbosa Coutinho and M.S. Grasiela Agnes for the valuable contributions in this research. We are very grateful to many young scientists who were involved in the early stage of this study and Nupesc, UFCSPA, for helping with the statistical analysis. This work was supported by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), Ministry of Education—Brazil, and Post Graduation Program of Pathology—UFCSPA (Universidade Federal de Ciências da Saúde de Porto Alegre—Porto Alegre, Brazil).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Lisiane Cervieri Mezzomo.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mezzomo, L.C., Pesce, F.G., Marçal, J.M.B. et al. Decreased TAp63 and ΔNp63 mRNA Levels in Most Human Pituitary Adenomas Are Correlated with Notch3/Jagged1 Relative Expression. Endocr Pathol 28, 13–21 (2017). https://doi.org/10.1007/s12022-016-9463-2

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12022-016-9463-2

Keywords

Navigation