Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
BMC Cancer
Published in: BMC Cancer 1/2018

Open Access 01-12-2018 | Research article

The role of matrix metalloproteinase-9 as a prognostic biomarker in papillary thyroid cancer

Authors: Maryam Zarkesh, Azita Zadeh-Vakili, Mahdi Akbarzadeh, S. Ahmad Fanaei, Mehdi Hedayati, Fereidoun Azizi

Published in: BMC Cancer | Issue 1/2018

Login to get access

Abstract

Background

The aim of the present study was to investigate the association between matrix metalloproteinase-9 (MMP-9) expression with BRAF V600E mutation and clinicopathological features, in Iranian papillary thyroid cancer (PTC) patients.

Methods

In total, 90 participants including 60 PTC patients (15 males and 45 females) and 30 individuals with benign multinodular goiter (MNG) (5 males and 25 females) which were confirmed by surgical pathology, were investigated. MMP-9 was evaluated at both mRNA and protein levels, using SYBR-Green Real-Time PCR and enzyme-linked immune sorbent assay (ELISA), respectively. BRAF V600E mutation was detected by sequencing.

Results

Mean age of PTC and MNG patients was 37.6 ± 12.6 and 48.1 ± 13.3 years, respectively (P = 0.001). BRAF V600E mutation was found in 24 of the 60 (40%) PTC cases, with mean tumor size of 1.59 ± 1.20 cm. MMP-9 mRNA levels were elevated in tumoral compared to the adjacent non-tumoral tissues (P = 0.039); moreover, this rise was also observed in PTC patients compared to MNG patients (P = 0.001). The mRNA levels of MMP-9 increased in patients aged≥45 years (P = 0.015), those with lymphovascular invasion (P = 0.003), and higher tumor stages (III and IV) (P = 0.011). The protein level of MMP-9 increased in tumoral compared to adjacent non-tumoral tissues (P < 0.001); this increase was also found in PTC patients compared to MNG participants (P = 0.004). MMP-9 protein level was higher in patients aged≥45 years (P = 0.001), those with lymphovascular invasion (P = 0.036) and higher TNM stages (III and IV) (P = 0.001). Area under the ROC curve (AUC) was 0.70 (95%CI: 0.57–0.83, P = 0.003), with 91.4% sensitivity and 51.9% specificity at the cutoff value of 0.50.

Conclusion

The mRNA and protein levels of MMP-9 had no association with BRAF V600E mutation in Iranian PTC patients. These levels were associated with age, TNM stages, and lymphovascular invasion, being defined as malignant factors. Thus, elevated levels of MMP-9 in PTC patients compared to MNG participants illustrated that it can be used as a potential biomarker to differentiate PTC patients from those with MNG.
Literature
1.
Katoh H, Yamashita K, Enomoto T, Watanabe M. Classification and general considerations of thyroid cancer. Ann Clin Pathol. 2015;3(1):1045.
2.
3.
Giordano TJ, Kuick R, Thomas DG, Misek DE, Vinco M, Sanders D, Zhu Z, Ciampi R, Roh M, Shedden K. Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene. 2005;24(44):6646.CrossRefPubMed
4.
5.
Fugazzola L, Puxeddu E, Avenia N, Romei C, Cirello V, Cavaliere A, Faviana P, Mannavola D, Moretti S, Rossi S. Correlation between B-RAFV600E mutation and clinico–pathologic parameters in papillary thyroid carcinoma: data from a multicentric Italian study and review of the literature. Endocr Relat Cancer. 2006;13(2):455–64.CrossRefPubMed
6.
Zarkesh M, Zadeh-Vakili A, Azizi F, Seyed Fanaei A, Foroughi F, Hedayati M. 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; In press.
7.
Nikiforova MN, Kimura ET, Gandhi M, Biddinger PW, Knauf JA, Basolo F, Zhu Z, Giannini R, Salvatore G, Fusco A, 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.CrossRefPubMed
8.
Lee JH, Lee ES, Kim YS. Clinicopathologic significance of BRAF V600E mutation in papillary carcinomas of the thyroid. Cancer. 2007;110(1):38–46.CrossRefPubMed
9.
Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, Carson KA, Vasko V, Larin A, Tallini G, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005;90(12):6373–9.CrossRefPubMed
10.
Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, Lee S, Kim SY, Kim SC, Hong SJ. The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin Endocrinol (Oxf). 2006;65(3):364–8.CrossRef
11.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161.CrossRefPubMed
12.
López-Otín C, Overall CM. Protease degradomics: a new challenge for proteomics. Nat Rev Mol Cell Biol. 2002;3(7):509.CrossRefPubMed
13.
Maeta H, Ohgi S, Terada T. Protein expression of matrix metalloproteinases 2 and 9 and tissue inhibitors of metalloproteinase 1 and 2 in papillary thyroid carcinomas. Virchows Arch. 2001;438(2):121–8.CrossRefPubMed
14.
Mesa C, Mirza M, Mitsutake N, Sartor M, Medvedovic M, Tomlinson C, Knauf JA, Weber GF, Fagin JA. Conditional activation of RET/PTC3 and BRAFV600E in thyroid cells is associated with gene expression profiles that predict a preferential role of BRAF in extracellular matrix remodeling. Cancer Res. 2006;66(13):6521–9.CrossRefPubMed
15.
Frasca F, Nucera C, Pellegriti G, Gangemi P, Attard M, Stella M, Loda M, Vella V, Giordano C, Trimarchi F. BRAF (V600E) mutation and the biology of papillary thyroid cancer. Endocr Relat Cancer. 2008;15(1):191–205.CrossRefPubMed
16.
Edge S. American Cancer Society. AJCC cancer staging handbook: from the AJCC cancer staging manual. New York: Springer; 2010.
17.
Livak K, Schmittgen T. Analysis of relative gene expression data using real-time quantitative PCR and the 2− ΔΔCT method. Methods. 2001;25(4):402–8 External Resources Pubmed/Medline (NLM) CrossRef (DOI) 2001.CrossRefPubMed
18.
Buergy D, Weber T, Maurer GD, Mudduluru G, Medved F, Leupold JH, Brauckhoff M, Post S, Dralle H, Allgayer H. Urokinase receptor, MMP-1 and MMP-9 are markers to differentiate prognosis, adenoma and carcinoma in thyroid malignancies. Int J Cancer. 2009;125(4):894–901.CrossRefPubMed
19.
Carissimi E, Bommarito A, Pizzolanti G, Zito G, Richiusa P, Russo L, Coppola A, Smeraldi L, Galluzzo A, Giordano C. No association between BRAFV600E and metalloproteinase activity in anaplastic thyroid cell lines. Endocr Abstr. 2008;16:P822.
20.
Arndt A, Kraft K, Wardelmann E, Steinestel K. Lack of association between membrane-type 1 matrix metalloproteinase expression and clinically relevant molecular or morphologic tumor characteristics at the leading edge of invasive colorectal carcinoma. Biomed Res Int. 2015;2015:7. Published online 2015 May 27. https://​doi.​org/​10.​1155/​2015/​185404.CrossRef
21.
Fanjul-Fernández M, Folgueras AR, Cabrera S, López-Otín C. Matrix metalloproteinases: evolution, gene regulation and functional analysis in mouse models. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 2010;1803(1):3–19.CrossRef
22.
HUANG P, Li D-M, Huang Q-W, Song Y-M, Xia P. Expression of HMGB1, MMP-9 and VEGF-C in papillary thyroid carcinoma. J Endocrine Surg. 2013;7(4):265–8.
23.
Marečko I, Cvejić D, Šelemetjev S, Paskaš S, Tatić S, Paunović I, Savin S. Enhanced activation of matrix metalloproteinase-9 correlates with the degree of papillary thyroid carcinoma infiltration. Croat Med J. 2014;55(2):128–37.CrossRefPubMedPubMedCentral
24.
Kumar VH, Hasan OB. Clinical relevance of MMP-9 in terms of neoplasm growth, invasion and metastasis in thyroid, breast and colorectal cancer. Int Surg J. 2017;4(12):4049–53.CrossRef
25.
He J, Liu G, Shao K, Shen X, Chen L. Serum contents of matrix metalloproteinase-2 and 9 are correlated with the prognosis of papillary thyroid carcinoma after ultrasound-guided radiofrequency ablation. Biomed Res. 2017;28(15):6711–6.
26.
Zhang Y, Luo Y-K, Zhang M-B, Li J, Li C-T, Tang J, Li J-L. Values of ultrasound features and MMP-9 of papillary thyroid carcinoma in predicting cervical lymph node metastases. Sci Rep. 2017;7(1):6670.CrossRefPubMedPubMedCentral
27.
Vinodhkumar R, Song Y-S, Ravikumar V, Ramakrishnan G, Devaki T. Depsipeptide a histone deacetlyase inhibitor down regulates levels of matrix metalloproteinases 2 and 9 mRNA and protein expressions in lung cancer cells (A549). Chem Biol Interact. 2007;165(3):220–9.CrossRefPubMed
28.
Deryugina EI, Quigley JP. Matrix metalloproteinases and tumor metastasis. Cancer Metastasis Rev. 2006;25(1):9–34.CrossRefPubMed
29.
Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metalloproteinases in cancer progression and their pharmacological targeting. FEBS J. 2011;278(1):16–27.CrossRefPubMed
30.
Baldini E, Toller M, Graziano F, Russo F, Pepe M, Biordi L, Marchioni E, Curcio F, Ulisse S, Ambesi-Impiombato F. Expression of matrix metalloproteinases and their specific inhibitors in normal and different human thyroid tumor cell lines. Thyroid. 2004;14(11):881–8.CrossRefPubMed
31.
Komorowski J, Pasieka Z, Jankiewicz-Wika J, Stepień H. Matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases and angiogenic cytokines in peripheral blood of patients with thyroid cancer. Thyroid. 2002;12(8):655–62.CrossRefPubMed
32.
33.
Hofmann A, Laue S, Rost A-K, Scherbaum W, Aust G. mRNA levels of membrane-type 1 matrix metalloproteinase (MT1-MMP), MMP-2, and MMP-9 and of their inhibitors TIMP-2 and TIMP-3 in normal thyrocytes and thyroid carcinoma cell lines. Thyroid. 1998;8(3):203–14.CrossRefPubMed
34.
Campo E, Merino MJ, Liotta L, Neumann R, Stetler-Stevenson W. Distribution of the 72-kd type IV collagenase in nonneoplastic and neoplastic thyroid tissue. Hum Pathol. 1992;23(12):1395–401.CrossRefPubMed
Metadata
Title
The role of matrix metalloproteinase-9 as a prognostic biomarker in papillary thyroid cancer
Authors
Maryam Zarkesh
Azita Zadeh-Vakili
Mahdi Akbarzadeh
S. Ahmad Fanaei
Mehdi Hedayati
Fereidoun Azizi
Publication date
01-12-2018
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2018
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-018-5112-0

Other articles of this Issue 1/2018

BMC Cancer 1/2018 Go to the issue

Review

Fertility preservation healthcare circuit and networks in cancer patients worldwide: what are the issues?

Research article

Using Resistin, glucose, age and BMI to predict the presence of breast cancer

Research article

The exploration of contrasting pathways in Triple Negative Breast Cancer (TNBC)

Research article

Clinical significance of FBXO17 gene expression in high-grade glioma

Research article

Access to innovative drugs for metastatic lung cancer treatment in a French nationwide cohort: the TERRITOIRE study

Case report

Diffuse parenchymal pulmonary amyloidosis associated with multiple myeloma: a case report and systematic review of the literature
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits