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European Archives of Oto-Rhino-Laryngology

, Volume 276, Issue 1, pp 93–100 | Cite as

Molecular interactions in juvenile nasopharyngeal angiofibroma: preliminary signature and relevant review

  • Anupam MishraEmail author
  • Riddhi Jaiswal
  • Pandey Amita
  • S. C. Mishra
Rhinology
  • 49 Downloads

Abstract

Background

The molecular profile of juvenile nasopharyngeal angiofibroma (JNA) is extremely variable. In absence of established molecular signature the molecular targeting seems difficult for this heterogeneous disease. To establish a basic molecular signature, this paper analyses the interaction of 7 markers according to their ranks as per the decreasing scale of molecular expression.

Materials and methods

Fourteen samples of JNA were obtained following surgical excision and mRNA expressions were established through real-time polymerase chain reaction (RT-PCR) for vasculoendothelial growth factor (VEGF), fibroblastic growth factor (FGF), c-Kit, c-myc, Ras, platelet-derived growth factor (PDGF) and tumor suppressor gene p53. Nasal polyp was taken as control. The quantitative expressions for every marker were ranked on a decreasing scale and were compared by Spearman’s rank correlation test to define the statistically significant interaction. An attempt was also made to overview the basic clinical parameters (age, duration of symptoms, radiological staging, intraoperative haemorrhage and tumor-volume/weight) associated with enhanced molecular expressions for every marker. Results: Five significant molecular interactions were identified on the basis of rank-correlation: (1) FGF/VEGF (p < 0.01); (2) Ras/FGF (p < 0.01); (3) Ras/VEGF (p < 0.001), (4) FGF/c-Kit (p < 0.05); (5) c-Myc/p53 (p < 0.05). These basic ‘molecular signatures’ suggested a preliminary ‘molecular classification’. The implication of the interactions between FGF, VEGF and Ras were the most outstanding observation that not only revealed a direct relationship but were also consistent with the clinical behaviour. In addition, a non-significant interaction was identified with c-Myc/PDGF and also an inverse relationship between FGF/c-Kit.

Conclusions

FGF, VEGF, and Ras being significantly interrelated seemed to be the ‘most soft’ molecular targets for JNA. The other targets observed included FGF/c-Kit and c-Myc/p53 interactions that seemed equally important but only after VEGF/FGF/Ras complex per se. These preliminary signatures are likely to provide a background for further expansion of the molecular classification of JNA.

Keywords

Juvenile nasopharyngeal angiofibroma Molecular interactions VEGF FGF C-Kit c-Myc Ras PDGF P53 

Notes

Acknowledgements

The principal author would like to acknowledge Dr. Girija Kant Shukla Professor of Statistics at Indian Institute of Management, Lucknow and Professor Vinod Jain for their important inputs.

Funding

None.

Compliance with ethical standards

Conflict of interest

All authors declared that they have no conflict of interest.

References

  1. 1.
    Mishra A, Mishra SC (2016) Changing trends in the incidence of juvenile nasopharyngeal angiofibroma: seven decades of experience at King George’s Medical University, Lucknow, India. J Laryngol Otol.  https://doi.org/10.1017/S0022215116000268 Google Scholar
  2. 2.
    Mishra A, Mishra SC, Pandey A (2017) Variations in molecular expressions of juvenile nasopharyngeal angiofibroma. J Laryngol Otol 131(9):752–759CrossRefGoogle Scholar
  3. 3.
    Mishra A, Mishra SC, Verma V, Singh HP, Kumar S, Tripathi AM, Patel B, Singh V (2016) In defence of transpalatal, transpalatal-circumaxillary (transpterygopalatine) and transpalatal-circumaxillary-sublabial approaches to lateral extensions of juvenile nasopharyngeal angiofibroma. J Laryngol Otol 130(5):462–473.  https://doi.org/10.1017/S0022215116000773 CrossRefGoogle Scholar
  4. 4.
    Pandey P, Mishra A, Tripathi AM, Verma V, Trivedi R, Singh HP, Kumar S, Patel B, Singh V, Pandey S, Pandey A, Mishra SC (2016) Current molecular profile of juvenile nasopharyngeal angiofibroma: first comprehensive study from India. Laryngoscope.  https://doi.org/10.1002/lary.26250 Google Scholar
  5. 5.
    Mishra A, Sachadeva M, Jain A, Mishra Shukla N, Pandey A (2016) Human Papilloma virus in Juvenile Nasopharyngeal Angiofibroma: possible recent trend. Am J Otolaryngol Head Neck Med Surg 37:317–322Google Scholar
  6. 6.
    Mishra A, Mishra SC, Tripathi AM, Verma V, Pandey A (2018) Clinical Correlation of Molecular (VEGF, FGF, PDGF, c-Myc, c-Kit, Ras, p53) Expression in Juvenile Nasopharyngeal Angiofibroma. Eur Arch Otorhinolaryngol.  https://doi.org/10.1007/s00405-018-5110-5 Google Scholar
  7. 7.
    Schuon R, Brieger J, Heinrich UR, Roth Y, Szyfter W, Mann WJ (2007) Immunohistochemical analysis of growth mechanisms in juvenile angiofibroma. Eur Arch Otorhinolaryngol 264:389–394CrossRefGoogle Scholar
  8. 8.
    Xiao L, Du Y, Shen Y, He Y, Zhao H, Li Z (2012) TGF-beta 1 induced fibroblast proliferation is mediated by the FGF-2/ERK pathway. Front Biosci (Landmark Ed) 17:2667–2674CrossRefGoogle Scholar
  9. 9.
    Thomas KA, Rios-Candelore M, Gimenez-Gallego G, DiSalvo J, Bennett C, Rodkey J, Fitzpatrick S (1985) Pure brain-derived acidic Fibroblast Growth Factor is a potent angiogenic vascular endothelial cell mitogen with sequence homology to interleukin 1. Proc Natl Acad Sci USA 82:6409–6413CrossRefGoogle Scholar
  10. 10.
    Schiff M, Gonzalez A, Ong M, Baird A (1992) Juvenile nasopharyngeal angiofibroma contain an angiogenic growth factor: basic FGF. Laryngoscope 102:940–945CrossRefGoogle Scholar
  11. 11.
    Narasimhan P (2009) VEGF stimulates the ERK 1/2 signalling pathway and apoptosis in cerebral endothelial cells after ischemic conditions. Stroke 40:1467–1473CrossRefGoogle Scholar
  12. 12.
    Abid MR, Guo S, Minami T, Spokes KC, Ueki K, Skurk C, Walsh K, Aird WC (2004) Vascular endothelial growth factor activates PI3K/Akt/forkhead signaling in endothelial cells. Arterioscler Thromb Vasc Biol 24(2):294–300 (Epub 2003 Dec 1) CrossRefGoogle Scholar
  13. 13.
    Shiojima I, Walsh K (2002) Role of Akt signalling in vascular homeostasis and angiogenesis. Circ Res 90(12):1243–1250CrossRefGoogle Scholar
  14. 14.
    Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M (2005) Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev 16:159–178CrossRefGoogle Scholar
  15. 15.
    Pepper MS, Ferrara N, Orci L, Montesano R (1992) Potent synergism between vascular endothelial growth factor and basic fibroblast growth factor in the induction of angiogenesis in vitro. Biochem Biophys Res Commun 189:824–831CrossRefGoogle Scholar
  16. 16.
    Tille JC, Wood J, Mandriota SJ, Schnell C, Ferrari S, Mestan J, Zhu Z, Witte L, Pepper MS (2001) Vascular endothelial growth factor (VEGF) receptor-2 antagonists inhibit VEGF- and basic fibroblast growth factor-induced angiogenesis in vivo and in vitro. J Pharmacol Exp Ther 299:1073–1085Google Scholar
  17. 17.
    Giavazzi R, Sennino B, Coltrini D, Garofalo A, Dossi R, Ronca R, Tosatti MP, Presta M (2003) Distinct role of fibroblast growth factor-2 and vascular endothelial growth factor on tumor growth and angiogenesis. Am J Pathol 162:1913–1926CrossRefGoogle Scholar
  18. 18.
    Shi YH, Bingle L, Gong LH, Wang YX, Corke KP, Fang WG (2007) Basic FGF augments hypoxia induced HIF-1-alpha expression and VEGF release in T47D breast cancer cells. Pathology 39:396–400CrossRefGoogle Scholar
  19. 19.
    Seghezzi G, Patel S, Ren CJ, Gualandris A, Pintucci G, Robbins ES, Shapiro RL, Galloway AC, Rifkin DB, Mignatti P (1998) Fibroblast growth factor-2 (FGF-2) induces vascular endothelial growth factor (VEGF) expression in the endothelial cells of forming capillaries: an autocrine mechanism contributing to angiogenesis. J Cell Biol 141(7):1659–1673CrossRefGoogle Scholar
  20. 20.
    Okumura N, Yoshida H, Kitagishi Y, Murakami M, Nishimura Y, Matsuda S (2012) PI3K/AKT/PTEN signaling as a molecular target in leukemia angiogenesis. Adv Hematol 2012:843085.  https://doi.org/10.1155/2012/843085 CrossRefGoogle Scholar
  21. 21.
    Downward J (2003) Targeting RAS signalling pathways in cancer therapy. Nat Rev Cancer 3:11–22CrossRefGoogle Scholar
  22. 22.
    Meadows KN, Bryant P, Vincent PA, Pumiglia KM (2004) Activated ras induces a proangiogenic phenotype in primary endothelial cells. Oncogene 23:192–200.  https://doi.org/10.1038/sj.onc.1206921 CrossRefGoogle Scholar
  23. 23.
    Coutinho CM, Bassini AS, Gutie´rrez LG et al (1999) Genetic alterations in Ki-ras and Ha-ras genes in juvenile nasopharyngeal angiofibromas and head and neck cancer. Sao Paulo Med J 117:113–120CrossRefGoogle Scholar
  24. 24.
    Breieri G, Blumi S, Peli J, Grooti M, Wild C, Risau W, Richmann E (2002) Transforming growth factor-b and Ras regulate the VEGF/VRGF receptor system during tumour angiogenesis. Int J Cancer 97:142–148CrossRefGoogle Scholar
  25. 25.
    Jones MK, Itani RM, Wang H, Tomikawa M, Sarfeh IJ, Szabo S, Tarnawski AS (1999) Activation of VEGF and Ras genes in gastric mucosa during angiogenic response to ethanol injury. Am J Physiol 276(6 Pt 1):G1345–G1355Google Scholar
  26. 26.
    Meadows KN, Bryant P, Pumiglia K (2001) Vascular endothelial growth factor induction of the angiogenic phenotype requires Ras activation. J Biol Chem 276(52):49289–49298CrossRefGoogle Scholar
  27. 27.
    Yamada S, Yoshimura A (2002) Computer modeling of Ras-MAPK signal transduction pathway. Genome Inform 13:361–362Google Scholar
  28. 28.
    Klint P, Kanda S, Kloog Y, Claesson-Welsh L (1999) Contribution of Src and Ras pathways in FGF-2 induced endothelial cell differentiation. Oncogene 18:3354–3364CrossRefGoogle Scholar
  29. 29.
    Yan D, Ellman MB, Muddasani P, Cs-Szabo G, Im HJ (2012) FGF-2 promotes catabolism via FGFR1-Ras-Raf-MEK1/2-ERK1/2 axis and PKCd pathway in articular chondrocytes. Poster No. 1718 • ORS 2012 Annual MeetingGoogle Scholar
  30. 30.
    Nie Z, Hu G, Wei G, Cui K, Yamane A, Resch W, Wang R, Green DR, Tessarollo L, Casellas R, Zhao K, Levens D (2012) c-Myc is a universal amplifier of expressed genes in lymphocytes and embryonic stem cells. Cell 151(1):68–79.  https://doi.org/10.1016/j.cell.2012.08.033. (PMC 3471363.PMID 23021216) CrossRefGoogle Scholar
  31. 31.
    Levens D (2002) Disentangling the MYC web. Proc Natl Acad Sci USA 99:5757–5759CrossRefGoogle Scholar
  32. 32.
    Nagai MA, Butugan O, Logullo A, Brentani MM (1996) Expression of growth factors, protooncogenes and p53 in nasopharyngeal angiofibromas. Laryngoscope 106:190–195CrossRefGoogle Scholar
  33. 33.
    Schick B, Veldung B, Wemmert S, Jung V, Montenarh M, Meese E, Urbschat S (2005) p53 and Her-2/neu in juvenile angiofibromas. Oncol Rep 13:453–457Google Scholar
  34. 34.
    Ho JSL, Ma W, Mao DYL, Benchimol S (2005) p53-dependent transcriptional repression of c-myc is required for G1 cell cycle arrest. Mol Cell Biol 25(17):7423–7431CrossRefGoogle Scholar
  35. 35.
    Symonds HL. Krall L, Remington M, Saenz-Robles S, Lowe T, Jacks, Van Dyke T (1994) p53-dependent apoptosis suppresses tumor growth and progression in vivo. Cell 78:703–711CrossRefGoogle Scholar
  36. 36.
    Hundley JE, Koester SK, Troyer DA, Hilsenbeck SG, Subler MA, Windle JJ (1997) Increased tumor proliferation and genomic instability without decreased apoptosis in MMTV-ras mice deficient in p53. Mol Cell Biol 17:723–731CrossRefGoogle Scholar
  37. 37.
    Eischen CM, Weber JD, Roussel MF, Sherr CJ, Cleveland JL (1999) Disruption of the ARFMdm2-p53 tumor suppressor pathway in Myc-induced lymphomagenesis. Genes Dev 13:2658–2669CrossRefGoogle Scholar
  38. 38.
    Phesse TJ, Myant KB, Cole AM, Ridgway RA, Pearson H, Muncan V, van den Brink GR, Vousden KH, Sears R, Vassilev LT, Clarke AR, Sansom OJ (2014) Endogenous c-Myc is essential for p53-induced apoptosis in response to DNA damage in vivo. Cell Death Differ 21:956–966.  https://doi.org/10.1038/cdd.2014.15 CrossRefGoogle Scholar
  39. 39.
    Sachdeva M, Zhua S, Wua F, Wua H, Waliab V, Kumarb S, Elbleb R, Watabea K, Moa YY (2009) p53 represses c-Myc through induction of the tumor suppressor miR-145. Proc Natl Acad Sci USA 106(9):3207–3212.  https://doi.org/10.1073/pnas.0808042106 CrossRefGoogle Scholar
  40. 40.
    Zhang PJ, Weber R, Liang H, Pasha TL, LiVolsi VA (2003) Growth factors and receptors in juvenile nasopharyngeal angiofibroma and nasal polyps. Arch Pathol Lab Med 127:1480–1484Google Scholar
  41. 41.
    Pauli J, Gundelach R, Vanelli-Rees A, Rees G, Campbell C, Dubey S, Perry C (2008) Juvenile nasopharyngeal angiofibroma: an immunohistochemical characterisation of the stromal cell. Pathology 40(4):396–400.  https://doi.org/10.1080/00313020802035857 CrossRefGoogle Scholar
  42. 42.
    Koritschoner NP, Bartunek P, Knespel S, Blendinger G, Zenke M (1999) The Fibroblast growth factor receptor FGFR-4 acts as a ligand dependent modulator of erythroid cell proliferation. Oncogene 18:5904–5914CrossRefGoogle Scholar
  43. 43.
    Burger PE, Lukey PT, Coetzee S, Wilson EL (2002) Basic fibroblast growth factor modulates the expression of glycophorin A and c-kit and inhibits erythroid differentiation in K562 Cells. J Cell Physiol 190:83–91CrossRefGoogle Scholar
  44. 44.
    Singla D, Wang J (2016) Fibroblast growth factor-9 Activates c-Kit progenitor cells and enhances angiogenesis in the infarcted diabetic heart. Oxidative Med Cell Longev (Hindawi Publishing Corporation).  https://doi.org/10.1155/2016/5810908 (Article ID 5810908) Google Scholar
  45. 45.
    Bardeesy N, Bastian BC, Hezel A, Pinkel D, DePinho RA, Chin L (2001) Dual inactivation of RB and p53 pathways in RAS-induced melanomas. Mol Cell Biol 21:2144–2153CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of OtorhinolaryngologyKing George’s Medical UniversityLucknowIndia
  2. 2.Department of PathologyKing George’s Medical UniversityLucknowIndia
  3. 3.OBGYN/Medical GeneticsKing George’s Medical UniversityLucknowIndia
  4. 4.Department of OtorhinolaryngologyNepalgunj Medical CollegeNepalgunjNepal

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