Remodeling Factors, Transcription Factors and Angiogenetic Factors in Cholesteatoma in Ontogenetic Aspect

Document Type : Original

Authors

1 Department of Otorhinolaryngology, Riga Stradins University, 16 Dzirciema Street, LV-1007, Riga, Latvia.

2 Institute of Anatomy and Anthropology, Riga Stradins University, Kronvalda Boulevard 9, LV–1010 Riga, Latvia.

Abstract

Introduction:
The main goal of our study was to describe the transcription factor (NF-κβ), angiogenetic factor (VEGF), and remodeling markers (MMP-9 and TIMP-4) of the cholesteatoma tissue compared to control skin tissue. There are still uncertainties how transcription, angiogenetic and remodeling factors affect the cholesteatoma course.
 
Materials and Methods:
Eight cholesteatoma tissue specimens were retrieved from children, seven – from adults, seven skin controls – from cadavers. Obtained material immunohistochemically were stained for NF-κβ, MMP-9, TIMP-4, VEGF. Non-para­metric statistic methods were used.
 
Results:
A statistically significant higher numbers of NF-κβ and TIMP-4 immunoreactive cells in the cholesteatoma compared to control group. A very strong positive correlation between MMP-9 and TIMP-4 was seen in the patient group. A strong positive correlation - between MMP-9 in matrix and MMP-9, VEGF in perimatrix, between TIMP-4 in matrix and TIMP-4 in perimatrix, NF-κβ in the matrix and VEGF; between TIMP-4 in perimatrix and NF-κβ in the matrix.
 
Conclusions:
Correlation between MMP-9 and TIMP-4 suggests that TIMP-4 in cholesteatoma tissue intercorrelates to MMP-9. TIMP-4 likely regulates the development of cholesteatoma. Disbalance between MMPs and TIMPs affects NF-κβ and causes uncontrolled cell proliferation and immune response in this tumor. There is a lack of VEGF strong expression in cholesteatoma perimatrix.
 

Keywords


  1. Laeeq S, Faust R. Modeling the cholesteatoma microenvironment: coculture of HaCaT keratinocytes with WS1 Fibroblasts induces MMP- 2 activation, invasive phenotype, and proteolysis of the extracellular matrix. Laryngoscope 2007;117(2):313-8 doi: 10. 1097/ 01.mlg.0000251164.26405.1a.
  2. Wang S, Liu Z, Wang L, Zhang X. NF-kappaB signaling pathway, inflammation and colorectal cancer. Cell Mol Immunol 2009; 6(5): 327-334 doi:10.1038/cmi.2009.43
  3. Zielinski MR, Krueger JM. Inflammation and sleep. In Barkoukis TJ, Matheson JK, Ferber R, Doghramji K. Therapy in sleep medicine Philadelphia, PA: Elsevier, 2012;607-616
  4. Courtois G. Tumor suppressor CYLD: negative regulation of NF-κB signaling and more. Cellular and Molecular Life Sciences 2008; 65(7-8):1123-32 doi: 10.1007/s00018-007-7465-4.
  5. Zhang QA, Hamajima Y, Zhang Q, Lin J. Identification of Id1 in acquired middle ear cholesteatoma. Arch Otolaryngol Head Neck Surg 2008;134(3):306-310 doi:10.1001/ archotol.134.3.306
  6. Li N, Qin ZB. Inflammation-induced miR-802 promotes cell proliferation in Biotechnol Lett 2014; 36(9): 1753-1759 doi: 10.1007/ s10529-014-1545-y y
  7. Byun JY, Yune TY, Lee JY, et al. Expression of CYLD and NF-κB inhuman Cholesteatoma Epithelium. Mediators Inflamm 2010; 2010:796315 doi:10.1155/2010/796315
  8. Hamajima Y, Komori M, Preciado DA, et al. The role of inhibitor of DNA-binding (Id1) in hyperproliferation of keratinocytes: the pathological basis for middle ear cholesteatoma from chronic otitis media. Cell Prolif 2010;43(5):457-463 doi:10.1111/j. 1365-2184.2010.00695.x
  9. Sunderkötter C, Steinbrink K, Goebeler M, Bhardwaj R, Sorg C. Macrophages and angiogenesis. J Leukoc Biol 1994;55(3):410-422 doi:10.1002/jlb.55.3.410
  10. Frank S, Hübner G, Breier G, Longaker MT, Greenhalgh DG, Werner S. Regulation of vascular endothelial growth factor expression in cultured keratinocytes. Implications for normal and impaired wound healing. J Biol Chem 1995;270(21):12607-12613 doi:10.1074/jbc.270.21.12607
  11. Itakura J, Ishiwata T, Shen B, Kornmann M, Korc M. Concomitant over-expression of vascular endothelial growth factor and its receptors in pancreatic cancer. Int J Cancer 2000;85(1):27-34 doi:10.1002/(sici)1097-0215(20000101)85:1<27::aid-ijc5>3.0.co;2-8
  12. Bujía J, Holly A, Stammberger M, Sudhoff H. Angiogénesis en el colesteatoma de oído medio [Angiogenesis in cholesteatoma of the middle ear]. Acta Otorrinolaringol Esp 1996;47(3):187-192
  13. Olszewska E, Chodynicki S, Chyczewski L. Znaczenie angiogenezy w patogenezie perlaka ucha środkowego u dorosłych [Role of angiogenesis in the pathogenesis of cholesteatoma in adults]. Otolaryngol Pol 2004;58(3):559-563
  14. Ferrara N, Davis-Smyth T. The biology of vascular endothelial growth factor. Endocr Rev 1997; 18(1): 4-25 doi:10.1210/edrv.18.1.0287
  15. Sudhoff H, Dazert S, Gonzales AM, et al. Angiogenesis and angiogenic growth factors in middle ear cholesteatoma. Am J Otol 2000; 21(6): 793-798
  16. Juhn SK, Jung MK, Hoffman MD, et al. The role of inflammatory mediators in the pathogenesis of otitis media and sequelae. Clin Exp Otorhinolaryngol 2008;1(3):117-138 doi:10.3342/ceo.2008.1.3.117
  17. Kakiuchi M, Tsujigiwa H, Orita Y, et al. Cyclooxygenase 2 expression in otitis media with effusion. Am J Otolaryngol 2006;27(2):81-85 doi: 10. 1016/j.amjoto.2005.07.009
  18. Bancroft CC, Chen Z, Dong G, et al. Coexpression of proangiogenic factors IL-8 and VEGF by human head and neck squamous cell carcinoma involves coactivation by MEK-MAPK and IKK-NF-kappaB signal pathways. Clin Cancer Res 2001;7(2):435-442
  19. Fukudome S, Wang C, Hamajima Y, et al. Regulation of the angiogenesis of acquired middle ear cholesteatomas by inhibitor of DNA binding transcription factor. JAMA Otolaryngol Head Neck Surg 2013;139(3):273-278 doi: 10. 1001/ jamaoto. 2013.1750
  20. Shibosawa E, Tsutsumi K, Takakuwa T, Takahashi S. Stromal expression of matrix metalloprotease-9 in middle ear cholesteatomas. Am J Otol 2000;21(5):621-624
  21. Schmidt M, Grünsfelder P, Hoppe F. Up-regulation of matrix metalloprotease-9 in middle ear cholesteatoma--correlations with growth factor expression in vivo?. Eur Arch Otorhinolaryngol 2001;258(9):472-476 doi:10.1007/s004050100359
  22. Suchozebrska-Jesionek D, Szymański M, Kurzepa J, Gołabek W, Stryjecka-Zimmer M. Gelatinolytic activity of matrix metalloproteinases 2 and 9 in middle ear cholesteatoma. J Otolaryngol Head Neck Surg 2008;37(5):628-632 doi: 10.2310/ 7070.2008.0079
  23. Schönermark M, Mester B, Kempf HG, Bläser J, Tschesche H, Lenarz T. Expression of matrix-metalloproteinases and their inhibitors in human cholesteatomas. Acta Otolaryngol 1996;116(3):451-456 doi:10.3109/00016489609137872
  24. Holt JJ. Cholesteatoma and otosclerosis: two slowly progressive causes of hearing loss treatable through corrective surgery. Clin Med Res 2003;1(2):151-154 doi:10.3121/cmr.1.2.151
  25. Banerjee AR, James R, Narula AA. Matrix metalloproteinase-2 and matrix metalloproteinase-9 in cholesteatoma and deep meatal skin. Clin Otolaryngol Allied Sci 1998;23(4):345-347 doi: 10.1046/j.1365-2273.1998.00159.x
  26. Rezende CE, Souto RP, Rapoport PB, Campos Ld, Generato MB. Cholesteatoma gene expression of matrix metalloproteinases and their inhibitors by RT-PCR. Braz J Otorhinolaryngol 2012;78(3):116-121
  27. Olszewska E, Matulka M, Mroczko B, et al. Diagnostic value of matrix metalloproteinase 9 and tissue inhibitor of matrix metalloproteinases 1 in cholesteatoma. Histol Histopathol 2016;31(3):307-315 doi:10.14670/HH-11-677
  28. Juhász A, Sziklai I, Rákosy Z, Ecsedi S, Adány R, Balázs M. Elevated level of tenascin and matrix metalloproteinase 9 correlates with the bone destruction capacity of cholesteatomas. Otol Neurotol 2009;30(4):559-565 doi:10. 1097/ MAO. 0b013e31819fe6ed
  29. Liu YE, Wang M, Greene J, et al. Preparation and characterization of recombinant tissue inhibitor of metalloproteinase 4 (TIMP-4). J Biol Chem 1997; 272(33):20479-20483 doi:10. 1074/jbc. 33.204 79
  30. Zhang J, Cao YJ, Zhao YG, Sang QX, Duan EK. Expression of matrix metalloproteinase-26 and tissue inhibitor of metalloproteinase-4 in human normal cytotrophoblast cells and a choriocarcinoma cell line, JEG-3. Mol Hum Reprod 2002;8(7):659-666 doi:10.1093/molehr/8.7.659
  31. Troeberg L, Tanaka M, Wait R, Shi YE, Brew K, Nagase H. E. coli expression of TIMP-4 and comparative kinetic studies with TIMP-1 and TIMP-2: insights into the interactions of TIMPs and matrix metalloproteinase 2 (gelatinase A). Biochemistry 2002;41(50):15025-15035 doi:10.1021/bi026454l
  32. Melendez-Zajgla J, Del Pozo L, Ceballos G, Maldonado V. Tissue inhibitor of metalloproteinases-4. The road less traveled. Mol Cancer 2008;7:85 doi: 10.1186/1476-4598-7-85
  33. Shynlova O, Bortolini MA, Alarab M. Genes responsible for vaginal extracellular matrix metabolism are modulated by women's reproductive cycle and menopause. Int Braz J Urol 2013; 39(2): 257-267 doi:10.1590/S1677-5538.IBJU.2013.02.15
  34. Arpino V, Brock M, Gill SE. The role of TIMPs in regulation of extracellular matrix proteo- lysis. Matrix Biol 2015;44-46:247-254 doi:10. 1016/ j.matbio.2015.03.005
  35. Pilmane M, Rumba I, Sundler F, Luts A. Patterns of distribution and occurrence of neuroendocrine elements in lungs of humans with chronic lung disease. Proc. Latv. Acad. Sci 1998; 52:144–152
  36. Jackson HW, Defamie V, Waterhouse P, Khokha R. TIMPs: versatile extracellular regulators in cancer. Nat Rev Cancer 2017;17(1):38-53 doi:10. 1038/nrc.2016.115
  37. Bister V, Skoog T, Virolainen S, Kiviluoto T, Puolakkainen P, Saarialho-Kere U. Increased expression of matrix metalloproteinases-21 and -26 and TIMP-4 in pancreatic adenocarcinoma. Mod Pathol 2007; 20(11):1128-1140 doi:10.1038/ modpathol.3800956
  38. Lizarraga F, Espinosa M, Maldonado V, Melendez-Zajgla J. Tissue inhibitor of metalloproteinases-4 is expressed in cervical cancer patients. Anticancer Res 2005;25(1B):623-627
  39. Lizarraga F, Espinosa M, Ceballos-Cancino G, Vazquez-Santillan K, Bahena-Ocampo I, Schwarz-Cruz y Celis A et al. Tissue inhibitor of metalloproteinases-4 (TIMP-4) regulates stemness in cervical cancer cells. Molecular Carcinogenesis 2016;55(12):1952-1961 https://doi.org/ 1002/ mc. 22442
  40. Navratilova Z, Zatloukal J, Kriegova E, Kolek V, Petrek M. Simultaneous up-regulation of matrix metalloproteinases 1, 2, 3, 7, 8, 9 and tissue inhibitors of metalloproteinases 1, 4 in serum of patients with chronic obstructive pulmonary disease. Respirology 2012; 17(6):1006-1012 doi:10.1111/j.1440-1843. 2012. 02197.x
  41. Huber MA, Beug H, Wirth T. Epithelial-mesenchymal transition: NF-kappaB takes center stage. Cell Cycle. 2004;3(12):1477-1480. doi:10. 4161/cc.3.12.1280
  42. Abu El-Asrar AM, Ahmad A, Bittoun E, et al. Differential expression and localization of human tissue inhibitors of metalloproteinases in proliferative diabetic retinopathy. Acta Ophthalmol 2018; 96(1): e27-e37. doi:10.1111/aos.13451