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Archives of Gynecology and Obstetrics

, Volume 292, Issue 4, pp 899–904 | Cite as

Notch1 ligand signaling pathway activated in cervical cancer: poor prognosis with high-level JAG1/Notch1

  • Nasser Ghaly Yousif
  • Alaa Muhammad Sadiq
  • Maitham G. Yousif
  • Rihab H. Al-Mudhafar
  • Jinan J. Al-Baghdadi
  • Najah Hadi
Gynecologic Oncology

Abstract

Objective

Notch signalings are regulated multiple cellular processes during cancer progression. We aimed to investigate the significance and prognostic value of expression of Notch1 and JAG1 in cervical cancer to determine whether they could serve as prognostic predictors.

Methods/materials

The expression of Notch1/JAGD1 was investigated by real-time PCR, western blot assay and its association with overall survival of patients was analyzed by statistical analysis.

Results

Notch1 and JAGD1 expression level were significantly elevated in cervical cancer in comparison to normal specimens and other types of Notch receptors and ligands. It is also proved that Notch1 and JAGD1 expression were to be associated with cervical cancer invasion, lymph node metastasis, and FIGO system. In addition, survival analysis proved that elevated Notch1 and JAGD1 expression were associated with poor overall survival of patients (P = 0.01, P = 0.02 log-rank test), respectively.

Conclusions

The present data proved the over-expression of Notch1/JAGD1 and its association with tumor progression in human cervical cancer, which might be a potential valuable biomarker for cervical cancer and further studies need.

Keywords

Cervical cancer Notch1 JAG1 Survival rate 

Notes

Conflict of interest

The authors declare that they have no competing interests.

References

  1. 1.
    American Cancer Society (2012) Cancer facts and figures 2012. American Cancer Society, AtlantaGoogle Scholar
  2. 2.
    Köse FM, Naki MM (2014) Cervical premalignant lesions and their management. J Turk Ger Gynecol Assoc 15(2):109–121PubMedCentralCrossRefPubMedGoogle Scholar
  3. 3.
    Doshi WB, Thury PG, Chen R, Fishbein JA, Foley MK (2014) Synergistic interaction between AKT and Notch-1 signaling in cervical cancer: a critical role in tumor cell migration and invasion. Am J Biomed 2(2):200–211Google Scholar
  4. 4.
    Yousif NG, Al-Matwari M (2012) Overexpression of Notch-1 induced tamoxifen resistance through down regulation of ESR1 in positive estrogen receptor breast cancer. J Clin Oncol 30(15)Google Scholar
  5. 5.
    Ryu HS, Chun M, Chang KH, Chang HJ, Lee JP (2005) Postoperative adjuvant concurrent chemoradiotherapy improves survival rates for high-risk, early stage cervical cancer patients. Gynecol Oncol 96(2):490–495CrossRefPubMedGoogle Scholar
  6. 6.
    Varghese SS, Ram TS, Pavamani SP, Thomas EM, Jeyaseelan V, Viswanathan PN (2014) Concurrent chemo-irradiation with weekly cisplatin and paclitaxel in the treatment of locally advanced squamous cell carcinoma of cervix: a phase II study. J Cancer Res Ther 10(2):330–336CrossRefPubMedGoogle Scholar
  7. 7.
    Polgár C, Fodor J, Orosz Z, Major T, Takácsi-Nagy Z, Mangel LC (2002) Electron and high-dose-rate brachytherapy boost in the conservative treatment of stage I–II breast cancer first results of the randomized Budapest boost trial. Strahlenther Onkol. 178(11):615–623CrossRefPubMedGoogle Scholar
  8. 8.
    Brockbank E, Kokka F, Bryant A, Pomel C, Reynolds K (2013) Pre-treatment surgical para-aortic lymph node assessment in locally advanced cervical cancer. Cochrane Database Syst Rev 3:CD008217PubMedGoogle Scholar
  9. 9.
    Ebisawa K, Takano M, Fukuda M, Fujiwara K, Hada T, Ota Y, Kurotsuchi S, Kanao H, Andou M (2013) Obstetric outcomes of patients undergoing total laparoscopic radical trachelectomy for early stage cervical cancer. Gynecol Oncol 131(1):83–86CrossRefPubMedGoogle Scholar
  10. 10.
    Yu Q, Liu SL, Wang H, Shi G, Yang P, Chen XL (2013) miR-126 suppresses the proliferation of cervical cancer cells and alters cell sensitivity to the chemotherapeutic drug bleomycin. Asian Pac J Cancer Prev 14(11):6569–6572CrossRefGoogle Scholar
  11. 11.
    MacKenzie F, Duriez P, Wong F et al (2004) Notch4 inhibits endothelial apoptosis via RBP-Jkappa-dependent and -independent pathways. J Biol Chem 279:11657–11663CrossRefPubMedGoogle Scholar
  12. 12.
    Erard CM, Santos CB, Tracey SG (2013) Notch signaling in pathogenesis of diseases. Am J Biomed 1(2):19–22CrossRefGoogle Scholar
  13. 13.
    Nair P, Somasundaram K, Krishna S (2003) Activated Notch-1 inhibits p53-induced apoptosis and sustains transformation by human papillomavirus type 16 E6 and E7 oncogenes through a PI3K-PKB/Akt-dependent pathway. J Virol 77:7106–7112PubMedCentralCrossRefPubMedGoogle Scholar
  14. 14.
    Oswald F, Liptay S, Adler G et al (1998) NFkappa B2 is a putative target gene of activated Notch-1 via RBP-Jkappa. Mol Cell Biol 18:2077–2088PubMedCentralPubMedGoogle Scholar
  15. 15.
    Han J, Dong RG, Harris MJ, Scholand SF, Miller PW et al (2014) Potential effects of TPX2 in clinicopathologic features, prognosis and metastasis of gastric cancer patients. Am J Biomed 2(1):124–131Google Scholar
  16. 16.
    Rizzo P, Osipo C, Foreman K et al (2008) Rational targeting of Notch signaling in cancer. Oncogene 27:5124–5131CrossRefPubMedGoogle Scholar
  17. 17.
    Bray SJ (2006) Notch signalling: a simple pathway becomes complex. Nat Rev Mol Cell Biol 7:678CrossRefPubMedGoogle Scholar
  18. 18.
    Radtke F, Raj K (2003) The role of Notch in tumorigenesis: oncogene or tumour suppressor? Nat Rev Cancer 3:756–767CrossRefPubMedGoogle Scholar
  19. 19.
    Ellisen LW, Bird J, West DC et al (1991) TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms. Cell 66:649–661CrossRefPubMedGoogle Scholar
  20. 20.
    Zagouras P, Stifani S, Blaumueller CM et al (1995) Alterations in Notch signaling in neoplastic lesions of the human cervix. Proc Natl Acad Sci USA 92:6414–6418PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Gray GE, Mann RS, Mitsiadis E et al (1999) Human ligands of the Notch receptor. Am J Pathol 154:785–794PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Talora C, Sgroi D, Crum C et al (2002) Specific down-modulation of Notch-1 signaling in cervical cancer cells is required for sustained HPV-E6/E7 expression and late steps of malignant transformation. Genes Dev 16:2252–2263PubMedCentralCrossRefPubMedGoogle Scholar
  23. 23.
    Reedijk M, Odorcic S, Chang L et al (2005) High-level coexpression of JAG1 and NOTCH-1 is observed in human breast cancer and is associated with poor overall survival. Cancer Res 18:8530–8537CrossRefGoogle Scholar
  24. 24.
    Miele L, Golde T, Osborne B (2006) Notch signaling in cancer. Curr Mol Med 6:905–918CrossRefPubMedGoogle Scholar
  25. 25.
    Singer BS, Fishbein JA, Blino SK (2014) Critical role of E6 oncoprotein in cervical cancer: involved in cell proliferation, angiogenesis and apoptosis. Pathophysiol Cell Inj J 2(2):31–41Google Scholar
  26. 26.
    Artavanis-Tsakonas S, Rand MD, Lake RJ (1999) Notch signaling: cell fate control and signal integration in development. Science 284:770–776CrossRefPubMedGoogle Scholar
  27. 27.
    Wang J, Fu L, Gu F, Ma Y (2011) Notch1 is involved in migration and invasion of human breast cancer cells. Oncol Rep 26:1295–1303PubMedGoogle Scholar
  28. 28.
    Gao J, Song Z, Chen Y, Xia L, Wang J et al (2008) Deregulated expression of Notch receptors in human hepatocellular carcinoma. Dig Liver Dis 40:114–121CrossRefPubMedGoogle Scholar
  29. 29.
    Yeh TS, Wu CW, Hsu KW et al (2009) The activated Notch-1 signal pathway is associated with gastric cancer progression through cyclooxygenase-2. Cancer Res 69:5039–5048CrossRefPubMedGoogle Scholar
  30. 30.
    Reedijk M, Odorcic S, Zhang H et al (2008) Activation of Notch signaling in human colon adenocarcinoma. Int J Oncol 33:1223–1229PubMedCentralPubMedGoogle Scholar
  31. 31.
    Nicolas M, Wolfer A, Raj K et al (2003) Notch-1 functions as a tumor suppressor in mouse skin. Nat Genet 33:416–421CrossRefPubMedGoogle Scholar
  32. 32.
    Wang DG, Yousif NG, Sadiq AM, Schilling MM, Danielson XJ (2014) Critical role of SEMA5A expression in invasion and metastasis of ovarian cancer cell. Am J Biomed 2(3):292–305Google Scholar
  33. 33.
    Tanaka M, Setoguchi T, Hirotsu M et al (2009) Inhibition of Notch pathway prevents osteosarcoma growth by cell cycle regulation. Br J Cancer 100:1957–1965PubMedCentralCrossRefPubMedGoogle Scholar
  34. 34.
    Yousif NG, Al-Amran FG, Hadi N, Lee J, Adrienne J (2013) Expression of IL-32 modulates NF-κB and p38 MAP kinase pathways in human esophageal cancer. Cytokine 61(1):223–227CrossRefPubMedGoogle Scholar
  35. 35.
    Somasundaram K, Reddy SP, Vinnakota K et al (2005) Upregulation of ASCL1 and inhibition of Notch signaling pathway characterize progressive astrocytoma. Oncogene 47:7073–7083CrossRefGoogle Scholar
  36. 36.
    Jang MS, Zlobin A, Kast WM, Miele L (2000) Notch signaling as a target in multimodality cancer therapy. Curr Opin Mol Ther 2:55–65PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Nasser Ghaly Yousif
    • 1
  • Alaa Muhammad Sadiq
    • 2
  • Maitham G. Yousif
    • 3
  • Rihab H. Al-Mudhafar
    • 2
  • Jinan J. Al-Baghdadi
    • 2
  • Najah Hadi
    • 2
  1. 1.Department of Medicine and SurgeryUniversity of Colorado DenverDenverUSA
  2. 2.Gynaecology and Obstetrics Department, College of MedicineKufa UniversityNajafIraq
  3. 3.Department of BiologyAlqadysia UniversityDiwaniyaIraq

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