International Journal of Endocrinology and Metabolism

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The Association of BRAF V600E Mutation With Tissue Inhibitor of Metalloproteinase-3 Expression and Clinicopathological Features in Papillary Thyroid Cancer

Maryam Zarkesh 1 , Azita Zadeh-Vakili 1 , Fereidoun Azizi 2 , S Ahmad Fanaei 3 , Forough Foroughi 4 and Mehdi Hedayati 1 , *
Authors Information
1 Cellular and Molecular Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
2 Endocrine Research Center, Research Institute for Endocrine Sciences, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
3 Association Professor of General Surgery, Erfan Hospital, Tehran, IR Iran
4 Department of Pathology, Shahid Beheshti University of Medical Sciences, Tehran, IR Iran
Article information
  • International Journal of Endocrinology and Metabolism: April 2018, 16 (2); e56120
  • Published Online: February 10, 2018
  • Article Type: Research Article
  • Received: July 2, 2017
  • Revised: November 18, 2017
  • Accepted: January 7, 2018
  • DOI: 10.5812/ijem.56120

To Cite: Zarkesh M, Zadeh-Vakili A, Azizi F, Fanaei S A, Foroughi F, et al. The Association of BRAF V600E Mutation With Tissue Inhibitor of Metalloproteinase-3 Expression and Clinicopathological Features in Papillary Thyroid Cancer, Int J Endocrinol Metab. 2018 ; 16(2):e56120. doi: 10.5812/ijem.56120.

Copyright © 2018, International Journal of Endocrinology and Metabolism. This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License ( which permits copy and redistribute the material just in noncommercial usages, provided the original work is properly cited
1. Background
2. Materials and Methods
3. Results
4. Discussion
  • 1. Sipos JA, Mazzaferri EL. Thyroid cancer epidemiology and prognostic variables. Clin Oncol (R Coll Radiol). 2010;22(6):395-404. doi: 10.1016/j.clon.2010.05.004. [PubMed: 20627675].
  • 2. Kilfoy BA, Zheng T, Holford TR, Han X, Ward MH, Sjodin A, et al. International patterns and trends in thyroid cancer incidence, 1973-2002. Cancer Causes Control. 2009;20(5):525-31. doi: 10.1007/s10552-008-9260-4. [PubMed: 19016336].
  • 3. Hay ID, Bergstralh EJ, Goellner JR, Ebersold JR, Grant CS. Predicting outcome in papillary thyroid carcinoma: development of a reliable prognostic scoring system in a cohort of 1779 patients surgically treated at one institution during 1940 through 1989. Surgery. 1993;114(6):1050-7. discussion 1057-8. [PubMed: 8256208].
  • 4. Sherman SI, Brierley JD, Sperling M, Ain KB, Bigos ST, Cooper DS. Prospective multicenter study of thyroiscarcinoma treatment: initial analysis of staging and outcome. Nation Thyroid Canc Treat Cooperat Stud Regist Group. 1998;83(5):1012-21.
  • 5. Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005;12(2):245-62. doi: 10.1677/erc.1.0978. [PubMed: 15947100].
  • 6. Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, et al. BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas. J Clin Endocrinol Metab. 2003;88(11):5399-404. doi: 10.1210/jc.2003-030838. [PubMed: 14602780].
  • 7. Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005;90(12):6373-9. doi: 10.1210/jc.2005-0987. [PubMed: 16174717].
  • 8. Cohen Y, Xing M, Mambo E, Guo Z, Wu G, Trink B, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst. 2003;95(8):625-7. [PubMed: 12697856].
  • 9. Vasko V, Espinosa AV, Scouten W, He H, Auer H, Liyanarachchi S, et al. Gene expression and functional evidence of epithelial-to-mesenchymal transition in papillary thyroid carcinoma invasion. Proc Natl Acad Sci U S A. 2007;104(8):2803-8. doi: 10.1073/pnas.0610733104. [PubMed: 17296934].
  • 10. Hu S, Liu D, Tufano RP, Carson KA, Rosenbaum E, Cohen Y, et al. Association of aberrant methylation of tumor suppressor genes with tumor aggressiveness and BRAF mutation in papillary thyroid cancer. Int J Cancer. 2006;119(10):2322-9. doi: 10.1002/ijc.22110. [PubMed: 16858683].
  • 11. Apte SS, Mattei MG, Olsen BR. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Genomics. 1994;19(1):86-90. doi: 10.1006/geno.1994.1016. [PubMed: 8188246].
  • 12. Qi JH, Ebrahem Q, Moore N, Murphy G, Claesson-Welsh L, Bond M, et al. A novel function for tissue inhibitor of metalloproteinases-3 (TIMP3): inhibition of angiogenesis by blockage of VEGF binding to VEGF receptor-2. Nat Med. 2003;9(4):407-15. doi: 10.1038/nm846. [PubMed: 12652295].
  • 13. Lui E, Loo W, Zhu L, Cheung M, Chow L. DNA hypermethylation of TIMP3 gene in invasive breast ductal carcinoma. Biomed Pharmacotherap. 2005;59:S363-S5.
  • 14. Liu MC, Choong DY, Hooi CS, Williams LH, Campbell IG. Genetic and epigenetic analysis of the TIMP-3 gene in ovarian cancer. Cancer Lett. 2007;247(1):91-7. doi: 10.1016/j.canlet.2006.03.024. [PubMed: 16644110].
  • 15. Fendrich V, Slater EP, Heinmoller E, Ramaswamy A, Celik I, Nowak O, et al. Alterations of the tissue inhibitor of metalloproteinase-3 (TIMP3) gene in pancreatic adenocarcinomas. Pancreas. 2005;30(2):e40-5. [PubMed: 15714128].
  • 16. Das AM, Bolkestein M, van der Klok T, Oude Ophuis CM, Vermeulen CE, Rens JA, et al. Tissue inhibitor of metalloproteinase-3 (TIMP3) expression decreases during melanoma progression and inhibits melanoma cell migration. Eur J Cancer. 2016;66:34-46. doi: 10.1016/j.ejca.2016.06.020. [PubMed: 27522248].
  • 17. Pietruszewska W, Bojanowska-Pozniak K, Kobos J. Matrix metalloproteinases MMP1, MMP2, MMP9 and their tissue inhibitors TIMP1, TIMP2, TIMP3 in head and neck cancer: an immunohistochemical study. Otolaryngol Pol. 2016;70(3):32-43. doi: 10.5604/00306657.1202546. [PubMed: 27386931].
  • 18. Hoque MO, Rosenbaum E, Westra WH, Xing M, Ladenson P, Zeiger MA, et al. Quantitative assessment of promoter methylation profiles in thyroid neoplasms. J Clin Endocrinol Metab. 2005;90(7):4011-8. doi: 10.1210/jc.2005-0313. [PubMed: 15840741].
  • 19. Edge S. American Cancer Society. AJCC cancer staging handbook: from the AJCC cancer staging manual. New York: Springer; 2010.
  • 20. Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2 −ΔΔCT method. Method. 2001;25(4):402-8.
  • 21. Tang KT, Lee CH. BRAF mutation in papillary thyroid carcinoma: pathogenic role and clinical implications. J Chin Med Associat. 2010;73(3):113-28.
  • 22. Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12(1):9-18. doi: 10.1038/ [PubMed: 11942415].
  • 23. Pelizzo MR, Dobrinja C, Casal Ide E, Zane M, Lora O, Toniato A, et al. The role of BRAF(V600E) mutation as poor prognostic factor for the outcome of patients with intrathyroid papillary thyroid carcinoma. Biomed Pharmacother. 2014;68(4):413-7. doi: 10.1016/j.biopha.2014.03.008. [PubMed: 24721322].
  • 24. Anania MC, Sensi M, Radaelli E, Miranda C, Vizioli MG, Pagliardini S, et al. TIMP3 regulates migration, invasion and in vivo tumorigenicity of thyroid tumor cells. Oncogene. 2011;30(27):3011-23. doi: 10.1038/onc.2011.18. [PubMed: 21339735].
  • 25. Su CW, Huang YW, Chen MK, Su SC, Yang SF, Lin CW. Polymorphisms and Plasma Levels of Tissue Inhibitor of Metalloproteinase-3: Impact on Genetic Susceptibility and Clinical Outcome of Oral Cancer. Medicine (Baltimore). 2015;94(46). e2092. doi: 10.1097/MD.0000000000002092. [PubMed: 26579821].
  • 26. Guan Z, Zhang J, Song S, Dai D. Promoter methylation and expression of TIMP3 gene in gastric cancer. Diagn Pathol. 2013;8:110. doi: 10.1186/1746-1596-8-110. [PubMed: 23819566].
  • 27. Selaru FM, Olaru AV, Kan T, David S, Cheng Y, Mori Y, et al. MicroRNA-21 is overexpressed in human cholangiocarcinoma and regulates programmed cell death 4 and tissue inhibitor of metalloproteinase 3. Hepatology. 2009;49(5):1595-601. doi: 10.1002/hep.22838. [PubMed: 19296468].
  • 28. Leonardi GC, Candido S, Carbone M, Raiti F, Colaianni V, Garozzo S, et al. BRAF mutations in papillary thyroid carcinoma and emerging targeted therapies (review). Mol Med Rep. 2012;6(4):687-94. doi: 10.3892/mmr.2012.1016. [PubMed: 22858857].
  • 29. Liu RT, Chen YJ, Chou FF, Li CL, Wu WL, Tsai PC, et al. No correlation between BRAFV600E mutation and clinicopathological features of papillary thyroid carcinomas in Taiwan. Clin Endocrinol (Oxf). 2005;63(4):461-6. doi: 10.1111/j.1365-2265.2005.02367.x. [PubMed: 16181240].
  • 30. Yasuhiro I, Yoshida H, Maruo R, Morita S, Takano T, Hirokawa M. BRAF mutation in papillary thyroid carcinoma in a Japanese population: its lack of correlation with high-risk clinicopathological features and disease-free survival of patients. Endocrin J. 2009;56(1):89-97.
  • 31. Feng H, Cheung AN, Xue WC, Wang Y, Wang X, Fu S, et al. Down-regulation and promoter methylation of tissue inhibitor of metalloproteinase 3 in choriocarcinoma. Gynecol Oncol. 2004;94(2):375-82. doi: 10.1016/j.ygyno.2004.04.019. [PubMed: 15297175].
  • 32. Masson D, Rioux-Leclercq N, Fergelot P, Jouan F, Mottier S, Theoleyre S, et al. Loss of expression of TIMP3 in clear cell renal cell carcinoma. Eur J Cancer. 2010;46(8):1430-7. doi: 10.1016/j.ejca.2010.01.009. [PubMed: 20194016].
  • 33. Darnton SJ, Hardie LJ, Muc RS, Wild CP, Casson AG. Tissue inhibitor of metalloproteinase-3 (TIMP-3) gene is methylated in the development of esophageal adenocarcinoma: loss of expression correlates with poor prognosis. Int J Cancer. 2005;115(3):351-8. doi: 10.1002/ijc.20830. [PubMed: 15688381].
  • 34. Brait M, Loyo M, Rosenbaum E, Ostrow KL, Markova A, Papagerakis S, et al. Correlation between BRAF mutation and promoter methylation of TIMP3, RARbeta2 and RASSF1A in thyroid cancer. Epigenetics. 2012;7(7):710-9. doi: 10.4161/epi.20524. [PubMed: 22694820].
  • 35. Liu J, Debnath J. The Evolving, Multifaceted Roles of Autophagy in Cancer. Adv Cancer Res. 2016;130:1-53. doi: 10.1016/bs.acr.2016.01.005. [PubMed: 27037750].
  • 36. Terayama Y, Matsuura T, Ozaki K. Lack of Correlation between Aberrant p16, RAR-beta2, TIMP3, ERCC1, and BRCA1 Protein Expression and Promoter Methylation in Squamous Cell Carcinoma Accompanying Candida albicans-Induced Inflammation. PLoS One. 2016;11(7). e0159090. doi: 10.1371/journal.pone.0159090. [PubMed: 27410681].
  • 37. Bodnar M, Szylberg L, Kazmierczak W, Marszalek A. Tumor progression driven by pathways activating matrix metalloproteinases and their inhibitors. J Oral Pathol Med. 2015;44(6):437-43. doi: 10.1111/jop.12270. [PubMed: 25244188].
  • 38. Xing M. Molecular pathogenesis and mechanisms of thyroid cancer. Nat Rev Cancer. 2013;13(3):184-99. doi: 10.1038/nrc3431. [PubMed: 23429735].

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