Low Expression of Occludin in the Melanoma Patient

Document Type: Original Research

Authors

1 Department of Biology, Parand Branch, Islamic Azad University, Parand, Iran

2 Department of Pathology, Tehran University of Medical Sciences, Tehran, Iran

10.30699/ijp.2019.85213.1801

Abstract

Background & Objective: Malignant melanoma is the fatal cutaneous neoplasm which is curable by the early diagnosis. The expression of occludin protein which is an integral membrane protein is altered in an epithelial-to-mesenchymal transition. Although, recent studies provide sufficient evidence supporting the functional importance of occludin in cancer, the prognostic significance of occludin expression levels in melanoma remains obscure. The aim of this study was to determine occludin expression level and itscorrelation with clinicopathological features of the patients with melanoma. 
Methods: The occludin mRNA level was compared between paraffin-embedded tissues of 40 patients with melanoma and 10 subjects with normal skin. The quality and quantity of the RNA was determined and occludin expression level was measured using Real-time PCR and ∆∆CT computational technique.
Results: Theoccludin mRNA level reduced five-fold in the melanoma patients compared to the control group (P=0.000). No significant difference was observed between male and female cases (P=0.533). No significant correlation was observed between occludin mRNA level, mitotic count (P=0.252), and Breslow levels (P=0.171)
Conclusion: We can conclude that down-regulation of occludin expression in the patients with melanoma is a hallmark of cancer progression and it might be used as a prognostic factor. No significant correlation was found between occludin gene expression and clinicopathological characteristics including Clark level, Breslow staging, mitotic count, age and gender (P<0.05).

Keywords

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Introduction

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  1. McCoy ML, Mueller CR, Roskelley CD. The role of the breast cancer susceptibility gene 1 (BRCA1) in sporadic epithelial ovarian cancer. Reprod Biol Endocrinol. 2003;1:72. [DOI:10.1186/1477-7827-1-72] [PMID] [PMCID]
  2. Feng S, Huang Y, Chen Z. Does VEGF secreted by leukemic cells increase the permeability of blood-brain barrier by disrupting tight-junction protein since central nervous system leukemia? Med Hypotheses. 2011;76(5):618-621. [DOI:10.1016/j.mehy.2010.12.001] [PMID]
  3. Thompson JF, Scolyer RA, Kefford RF. Cutaneous melanoma in the era of molecular profiling. Lancet. 2009; 374(9687):362-65. [DOI:10.1016/S0140-6736(09)61397-0]
  4. Curtin JA, Busam K, Pinkel D, Bastian BC. Somatic activation of KIT in distinct subtypes of melanoma. J Clin Oncol. 2006; 24(26):4340-46. [DOI:10.1200/JCO.2006.06.2984] [PMID]
  5. Broekaert SM, Roy R, Okamoto I, Van Den Oord J, Bauer J, Garbe C, et al. Genetic and morphologic features for melanoma classification. Pigment cell & melanoma research. 2010 Dec;23(6):763-70. [DOI:10.1111/j.1755-148X.2010.00778.x] [PMID] [PMCID]
  6. Jayagopal A, Yang JL, Haselton FR, and Chang MS. Tight junction-associated signaling pathways modulate cell proliferation in uveal melanoma. Invest Ophthalmol Vis Sci. 2011;52 (1):588-93. [DOI:10.1167/iovs.10-5746] [PMID] [PMCID]
  7. Flaherty KT, Hodi FS, Fisher DE. From genes to drugs: targeted strategies for melanoma. Nat Rev Cancer. 2012;12(5):349-61. [DOI:10.1038/nrc3218] [PMID]
  8. Donizy P, Kaczorowski M, Halon A, Leskiewicz M, Kozyra C, Matkowski R. Paucity of tumor-infiltrating lymphocytes is an unfavorable prognosticator and predicts lymph node metastases in cutaneous melanoma patients. Anticancer Res. 2015;35(1):351-58. [DOI:10.1155/2015/975436] [PMID] [PMCID]
  9. Bhat AA, Uppada S, Achkar IW, Hashem S, Yadav SK, Shanmugakonar M, et al. Tight junction proteins and signaling pathways in cancer and inflammation: A functional crosstalk. Front Physiol. 2019;9:1942. [DOI:10.3389/fphys.2018.01942] [PMID] [PMCID]
  10. Coradini D, Casarsa C, Oriana S. Epithelial cell polarity and tumorigenesis: new perspectives for cancer detection and treatment. Acta Pharmacol Sin. 2011;32(5):552-64. [DOI:10.1038/aps.2011.20] [PMID] [PMCID]
  11. Paschoud S, Bongiovanni M, Pache JC, Citi S. Claudin-1 and claudin-5 expression patterns differentiate lung squamous cell carcinomas from adenocarcinomas. Mod Pathol. 2007; 20(9):947-54. [DOI:10.1038/modpathol.3800835] [PMID]
  12. Al-Sadi R, Khatib K, Guo S, Ye D, Youssef M, Ma T. Occludin regulates macromolecule flux across the intestinal epithelial tight junction barrier. Am J Physiol Gastrointest Liver Physiol. 2011;300(6):G1054-64. [DOI:10.1152/ajpgi.00055.2011] [PMID] [PMCID]
  13. Buschmann MM, Shen L, Rajapakse H, Raleigh DR, Wang Y, Wang Y, et al. Occludin OCELdomain interactions are required for maintenance and regulation ofthe tightjunction barrier to macromolecular flux. Mol Biol Cell. 2013;24(19):3056-68. [DOI:10.1091/mbc.e12-09-0688] [PMID] [PMCID]
  14. De Benedetto A, Rafaels NM, McGirt LY, Ivanov AI, Georas SN, Cheadle C, et al. Tight junction defects in patients with atopic dermatitis. J Allergy Clin Immunol. 2011;127(3):773-786 e771-7. [DOI:10.1016/j.jaci.2010.10.018] [PMID] [PMCID]
  15. Du D, Xu F, Yu L, Zhang C, Lu X, Yuan H, et al. The tight junction protein, occludin, regulates the directional migration of epithelial cells. Dev cell. 2010;18(1):52-63. [DOI:10.1016/j.devcel.2009.12.008] [PMID]
  16. Furuse M, Moriwaki K. The role of claudin-based tight junctions in morphogenesis. Ann N Y Acad Sci. 2009;1165:58-61. [DOI:10.1111/j.1749-6632.2009.04441.x] [PMID]
  17. Turksen K, Troy TC. Junctions gone bad: Claudins and loss of the barrier in cancer. Biochim Biophys Acta. 2011;1816(1):73-79. [DOI:10.1016/j.bbcan.2011.04.001] [PMID]
  18. Martin TA, Mansel RE, Jiang WG. Loss of occludin leads to the progression of human breast cancer. Int J Mol Med. 2010;26(5):723-34. [DOI:10.3892/ijmm_00000519] [PMID]
  19. Kominsky SL, Argani P, Korz D, Evron E, Raman V, Garrett E, et al. Loss of the tight junction protein claudin-7 correlates with histological grade in both ductal carcinoma in situ and invasive ductal carcinoma of the breast. Oncogene. 2003;22:2021-33. [DOI:10.1038/sj.onc.1206199] [PMID]
  20. Sehrawat A, Singh SV. Benzyl isothiocyanate inhibits epithelial-mesenchymal transition in cultured and xenografted human breast cancer cells. Cancer Prev Res. (Phila) 2011;4(7):1107-17. [DOI:10.1158/1940-6207.CAPR-10-0306] [PMID] [PMCID]
  21. Qin Z, Fang D, Fang Y. Low expression of occludin: a predictor of poor prognosis in esophageal squamous cell carcinoma. Int J Clin Exp Pathol. 2017;10(7):7451-59.
  22. Vollmer RT. A Probabilistic Analysis of Mitotic Counts in Melanoma. Am J Clin Pathol. 2014;141(2):213-18. [DOI:10.1309/AJCPFOV67CLZVPZZ] [PMID]
  23. Mahdavi T, Tafvizi F, Keyri Manjili HR. Increased MicroRNA-362 level in malignant skin melanoma. WCRJ. 2018;5(4):e1170.
  24. Ahmadi M, Tafvizi F, Moslemi E. Comparison of c-Myc expression in benign prostatic hyperplasia and adenocarcinoma and its correlation with clinicopathological characteristics. International Journal of Medical Laboratory. 2018;5(2):103-12.
  25. Garbe C, Leiter U. Melanoma epidemiology and trends. Clin Dermatol 2009; 27(1): 3-9. [DOI:10.1016/j.clindermatol .2008.09.001] [PMID]
  26. Wood C. Travel health: sun protection and skin cancer prevention for travellers. Br J Nurs. 2011;20(15):909-13. [DOI:10.12968/bjon.2011.20.15.909] [PMID]
  27. Brusselbach S, Mohle-Steinlein U, Wang ZQ, Schreiber M, Lucibello FC, et al. Cell proliferation and cell cycle progression are not impaired in fibroblasts and ES cells lacking c-Fos. Oncogene. 1995;10(1):79-86.
  28. Rachow SM, Zorn-Kruppa U, Ohnemus N, Kirschner S, Vidal-y-Sy P, von den Driesch C, et al. Occludin is involved in adhesion, apoptosis, differentiation and Ca 2+-homeostasis of human keratinocytes: implications for tumorigenesis. PLoS ONE. 2013;8(2):e55116. [DOI:10.1371/journal.pone.0055116] [PMID] [PMCID]
  29. Guillemot L, Citi S. Cingulin regulates claudin-2 expression and cell proliferation through the small GTPase RhoA. Mol Biol Cell. 2006;17(8):3569-77. [DOI:10.1091/mbc.e06-02-0122] [PMID] [PMCID]
  30. Gupta I, Ryan A. Claudins: unlocking the code to tight junction function during embryogenesis and in disease. Clin Genet. 2010;77(4):314-25. [DOI:10.1111/j.1399-0004.2010.01397.x] [PMID]
  31. Brandner JM, Zorn-Kruppa M, Yoshida T, Moll I, Beck LA, De Benedetto A. Epidermal tight junctions in health and disease. Tissue Barriers. 2015;3(1-2):e974451. [DOI:10.4161/21688370.2014.974451] [PMID] [PMCID]
  32. Fazakas C, Wilhelm I, Nagyoszi P, Farkas AE, Haskó J, Molnár J, et al. Transmigration of melanoma cells through the blood-brain barrier: role of endothelial tight junctions and melanoma-released serine proteases. PLoS ONE. 2011;6 (6):e20758. [DOI:10.1371/journal.pone.0020758] [PMID] [PMCID]
  33. Fasano A. Zonulin and its regulation of intestinal barrier function: the biological door to in flammation, autoimmunity, and cancer. Physiol Rev. 2011;91(1):151-75 [DOI:10.1152/physrev.00003.2008] [PMID]
  34. Martin TA, Mason MD and Jiang WG. Tight junctions in cancer metastasis. Front Biosci (Landmark Ed). 2011;16:898-36. [DOI:10.2741/3726]
  35. Tsukita S, Yamazaki Y, Katsuno T and Tamura A. Tight junction-based epithelial microenvironment and cell proliferation. Oncogene. 2008; 27(55):6930-38. [DOI:10.1038/onc.2008.344] [PMID]
  36. Martin TA, Jordan N, Davies EL and Jiang WG. Metastasis to bone in human cancer is associated with loss of occludin expression. Anticancer Res. 2016;36 (3):1287-93. [DOI:10.3892/or.2016.4773] [PMID] [PMCID]
  37. Xiong L, Wen Y, Miao X and Yang Z. Expressions of cell junction regulatory proteins and their association with clinicopathologic parameters in benign and malignant gallbladder lesions. Am J Med Sci. 2011;342 (5):388-94. [DOI:10.1097/MAJ.0b013e31821e12af] [PMID]
  38. Chen H, Zhang S, Zhen K and Wang XF. [Relationship between the expression of occluding and tumor genesis and development in the gastric carcinoma]. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi. 2010;26 (10):1008-11.
  39. Ohtani S, Terashima M, Satoh J, Soeta N, Saze Z, Kashimura S, et al. Expression of tight-junctionassociated proteins in human gastric cancer: downregulation of claudin-4 correlates with tumor aggressiveness and survival. Gastric Cancer. 2009;12 (1):43-51. [DOI:10.1007/s10120-008-0497-0] [PMID]
  40. Nemeth Z, Szasz AM, Somoracz A, Tatrai P, Nemeth J, Gyorffy H, et al. Zonula occludens-1, occludin, and E-cadherin protein expression in biliary tract cancers. Pathol Oncol Res. 2009;15 (3):533-39. [DOI:10.1007/s12253-009-9150-4] [PMID]
  41. Najafi M, Alizadeh SA, Azad M, Naserpour Farivar T, Rajaei F, Hotam Sorouri K, et al. Effect of calprotectin subunit S100A9 on the expression and methylation of OCLN in humanmelanoma cell line A-375. Turk J Biol. 2017;41(6):849-56. [DOI:10.3906/biy-1704-14] [PMID] [PMCID]
  42. Beeman N, Webb PG, Baumgartner HK. Occludin is required for apoptosis when claudin claudin interactions are disrupted. Cell Death Dis. 2012; 3:e273. [DOI:10.1038/cddis.2012.14] [PMID] [PMCID]