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Characterization of Notch Signalling Pathway Members in Normal Prostate, Prostatic Intraepithelial Neoplasia (PIN) and Prostatic Adenocarcinoma

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Pathology & Oncology Research

Abstract

Prostate Cancer (PCa) holds the second place in terms of cancer-related mortality rate among men. The Notch signalling pathway regulates the proliferation and differentiation in embryonic and adult tissues and determines the cell fate. The body of knowledge in the present literature is currently controversial about the effect of the Notch pathway on prostatic cancer. Therefore, the present study aimed to examine the immunolocalization and expression levels of Notch1-4, Jagged1-2, Delta, HES1 and HES5 from among the members of the Notch signalling pathway in tissues of normal, prostatic intraepithelial neoplasia (PIN) and malignant prostate. The current study included a sample of 20 patients with localised prostatic adenocarcinoma, 18 patients with high grade PIN (H-PIN) and 18 normal prostatic tissue. Immunolocalisations of Notch1, 2, 3, 4, Jagged1, 2, Delta, HES1 and HES5 were identified through the immunohistochemical method. The findings of the present study showed that all in-scope members of the Notch signalling pathway were localised in PIN structures to a greater extent than in other tissues and from amongst these members, specifically Notch1, Notch4, Jagged1 and HES1 were at more significant levels. Consequently, the findings of the present study may indicate that the Notch signalling pathway can play a role especially in the formation of PIN structures.

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Abbreviations

ADAM17:

A disintegrin and metalloproteinase domain-containing protein 10 or 17

CSL:

CBF1, Su(H) and LAG-1

DAB:

Diaminobenzidine

DII1:

Delta like 1

HES:

Hairy/Enhancer-of-Split family

HEY:

Hairy/Enhancer-of-Split related with YRPW motif-like protein

NEC :

Notch extracellular domain

NIC :

Notch intracellular domain

N™:

Notch transmembrane domain

PCa:

Prostate cancer

PBS:

phosphate buffered saline

PIN:

Prostatic intraepithelial neoplasia

sc:

Santa Cruz Biotechnology

NB:

Novus Biologicals

BA:

Vector Laboratories

References

  1. Siegel R, Naishadham D, Jemal A (2012) Cancer statistics, 2012. CA Cancer J Clin 62(1):10–29. doi:10.3322/caac.20138

    Article  PubMed  Google Scholar 

  2. Jemal A, Murray T, Ward E, Samuels A, Tiwari RC, Ghafoor A, Feuer EJ, Thun MJ (2005) Cancer statistics, 2005. CA Cancer J Clin 55(1):10–30

    Article  PubMed  Google Scholar 

  3. Jemal A, Siegel R, Ward E, Hao Y, Xu J, Thun MJ (2009) Cancer statistics, 2009. CA Cancer J Clin 59(4):225–249. doi:10.3322/caac.20006

    Article  PubMed  Google Scholar 

  4. Ferlay J, Parkin DM, Steliarova-Foucher E (2010) Estimates of cancer incidence and mortality in europe in 2008. Eur J Cancer 46(4):765–781. doi:10.1016/j.ejca.2009.12.014

    Article  CAS  PubMed  Google Scholar 

  5. Baade PD, Coory MD, Aitken JF (2004) International trends in prostate-cancer mortality: the decrease is continuing and spreading. Cancer Causes Control : CCC 15(3):237–241. doi:10.1023/B:CACO.0000024212.66334.26

    Article  CAS  PubMed  Google Scholar 

  6. Gronberg H (2003) Prostate cancer epidemiology. Lancet 361(9360):859–864. doi:10.1016/S0140-6736(03)12713-4

    Article  PubMed  Google Scholar 

  7. Greene KL, Li L.C., Okino S.T., Carroll P.R. (2008) Molecular basis of prostate cancer. In: Mendelson J, Howley, P.M., Israel M.A., Gray, J.W., Thompson, C.B. (ed) The Molecular Basis of Cancer. Third edn., pp 431–441

    Google Scholar 

  8. Zhu H, Zhou X, Redfield S, Lewin J, Miele L (2013) Elevated jagged-1 and notch-1 expression in high grade and metastatic prostate cancers. Am J Transl Res 5(3):368–378

    PubMed Central  CAS  PubMed  Google Scholar 

  9. Danza G, Di Serio C, Rosati F, Lonetto G, Sturli N, Kacer D, Pennella A, Ventimiglia G, Barucci R, Piscazzi A, Prudovsky I, Landriscina M, Marchionni N, Tarantini F (2012) Notch signaling modulates hypoxia-induced neuroendocrine differentiation of human prostate cancer cells. Molecular Cancer Research : MCR 10(2):230–238. doi:10.1158/1541-7786.MCR-11-0296

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  10. Gridley T (2007) Notch signaling in vascular development and physiology. Development 134(15):2709–2718. doi:10.1242/dev.004184

    Article  CAS  PubMed  Google Scholar 

  11. Fortini ME (2009) Notch signaling: the core pathway and its posttranslational regulation. Dev Cell 16(5):633–647. doi:10.1016/j.devcel.2009.03.010

    Article  CAS  PubMed  Google Scholar 

  12. Blaumueller CM, Qi H, Zagouras P, Artavanis-Tsakonas S (1997) Intracellular cleavage of notch leads to a heterodimeric receptor on the plasma membrane. Cell 90(2):281–291

    Article  CAS  PubMed  Google Scholar 

  13. Miele L (2006) Notch signaling. Clin Cancer Res : Off J Am Assoc Cancer Res 12(4):1074–1079. doi:10.1158/1078-0432.CCR-05-2570

    Article  CAS  Google Scholar 

  14. Miele L, Miao H, Nickoloff BJ (2006) NOTCH signaling as a novel cancer therapeutic target. Curr Cancer Drug Targets 6(4):313–323

    Article  CAS  PubMed  Google Scholar 

  15. Dunwoodie SL, Henrique D, Harrison SM, Beddington RS (1997) Mouse Dll3: a novel divergent delta gene which may complement the function of other delta homologues during early pattern formation in the mouse embryo. Dev 124(16):3065–3076

    CAS  Google Scholar 

  16. Lindsell CE, Shawber CJ, Boulter J, Weinmaster G (1995) Jagged: a mammalian ligand that activates Notch1. Cell 80(6):909–917

    Article  CAS  PubMed  Google Scholar 

  17. Shawber C, Boulter J, Lindsell CE, Weinmaster G (1996) Jagged2: a serrate-like gene expressed during rat embryogenesis. Dev Biol 180(1):370–376. doi:10.1006/dbio.1996.0310

    Article  CAS  PubMed  Google Scholar 

  18. Maier MM, Gessler M (2000) Comparative analysis of the human and mouse Hey1 promoter: Hey genes are new notch target genes. Biochem Biophys Res Commun 275(2):652–660. doi:10.1006/bbrc.2000.3354

    Article  CAS  PubMed  Google Scholar 

  19. Grishina IB, Kim SY, Ferrara C, Makarenkova HP, Walden PD (2005) BMP7 inhibits branching morphogenesis in the prostate gland and interferes with notch signaling. Dev Biol 288(2):334–347. doi:10.1016/j.ydbio.2005.08.018

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Wang XD, Leow CC, Zha J, Tang Z, Modrusan Z, Radtke F, Aguet M, de Sauvage FJ, Gao WQ (2006) Notch signaling is required for normal prostatic epithelial cell proliferation and differentiation. Dev Biol 290(1):66–80. doi:10.1016/j.ydbio.2005.11.009

    Article  CAS  PubMed  Google Scholar 

  21. Shou J, Ross S, Koeppen H, de Sauvage FJ, Gao WQ (2001) Dynamics of notch expression during murine prostate development and tumorigenesis. Cancer Res 61(19):7291–7297

    CAS  PubMed  Google Scholar 

  22. Scorey N, Fraser SP, Patel P, Pridgeon C, Dallman MJ, Djamgoz MB (2006) Notch signalling and voltage-gated Na + channel activity in human prostate cancer cells: independent modulation of in vitro motility. Prostate Cancer Prostatic Dis 9(4):399–406. doi:10.1038/sj.pcan.4500894

    Article  CAS  PubMed  Google Scholar 

  23. Brown MD, Gilmore PE, Hart CA, Samuel JD, Ramani VA, George NJ, Clarke NW (2007) Characterization of benign and malignant prostate epithelial hoechst 33342 side populations. Prostate 67(13):1384–1396. doi:10.1002/pros.20620

    Article  PubMed  Google Scholar 

  24. Santagata S, Demichelis F, Riva A, Varambally S, Hofer MD, Kutok JL, Kim R, Tang J, Montie JE, Chinnaiyan AM, Rubin MA, Aster JC (2004) JAGGED1 expression is associated with prostate cancer metastasis and recurrence. Cancer Res 64(19):6854–6857. doi:10.1158/0008-5472.CAN-04-2500

    Article  CAS  PubMed  Google Scholar 

  25. Kopan R, Ilagan MX (2009) The canonical notch signaling pathway: unfolding the activation mechanism. Cell 137(2):216–233. doi:10.1016/j.cell.2009.03.045

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Yoon HA, Noh MH, Kim BG, Han JS, Jang JS, Choi SR, Jeong JS, Chun JH (2011) Clinicopathological significance of altered notch signaling in extrahepatic cholangiocarcinoma and gallbladder carcinoma. World J Gastroenterol : WJG 17(35):4023–4030. doi:10.3748/wjg.v17.i35.4023

    Article  PubMed Central  PubMed  Google Scholar 

  27. Callahan R, Raafat A (2001) Notch signaling in mammary gland tumorigenesis. J Mammary Gland Biol Neoplasia 6(1):23–36

    Article  CAS  PubMed  Google Scholar 

  28. Harrison H, Farnie G, Howell SJ, Rock RE, Stylianou S, Brennan KR, Bundred NJ, Clarke RB (2010) Regulation of breast cancer stem cell activity by signaling through the Notch4 receptor. Cancer Res 70(2):709–718. doi:10.1158/0008-5472.CAN-09-1681

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  29. Zayzafoon M, Abdulkadir SA, McDonald JM (2004) Notch signaling and ERK activation are important for the osteomimetic properties of prostate cancer bone metastatic cell lines. The J Biol Chem 279(5):3662–3670. doi:10.1074/jbc.M308158200

    Article  CAS  Google Scholar 

  30. Wang X, Fu Y, Chen X, Ye J, Lu B, Ye F, Lu W, Xie X (2010) The expressions of bHLH gene HES1 and HES5 in advanced ovarian serous adenocarcinomas and their prognostic significance: a retrospective clinical study. J Cancer Res Clin Oncol 136(7):989–996. doi:10.1007/s00432-009-0744-8

    Article  PubMed Central  CAS  PubMed  Google Scholar 

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Acknowledgments

We wish to thank Sibel Ozden Ozer for their technical assistance.

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The authors declare no conflict of interest.

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Correspondence to Ismail Ustunel.

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Soylu, H., Acar, N., Ozbey, O. et al. Characterization of Notch Signalling Pathway Members in Normal Prostate, Prostatic Intraepithelial Neoplasia (PIN) and Prostatic Adenocarcinoma. Pathol. Oncol. Res. 22, 87–94 (2016). https://doi.org/10.1007/s12253-015-9983-y

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  • DOI: https://doi.org/10.1007/s12253-015-9983-y

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