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Choi, Bae, Kim, Chang, Cho, Kim, Ahn, Park, and Kim: Clinical Significance of MMP-2, MMP-9 and HIF-1α Expression in Thyroid Micropapillary Cancer
Original Article
Journal of the Korean Surgical Society

Journal of the Korean Surgical Society 2010; 78(3): 157-164.

Published online: 31 March 2010

DOI: https://doi.org/10.4174/jkss.2010.78.3.157

Clinical Significance of MMP-2, MMP-9 and HIF-1α Expression in Thyroid Micropapillary Cancer

Jae Young Choi, M.D., Ja Seong Bae, M.D., Young Ae Kim, M.S.1, Eun Deok Chang, M.D.2, Hang Joo Cho, M.D., Ki Hwan Kim, M.D., Chang Hyeok Ahn, M.D., Woo Chan Park, M.D., Jeong Soo Kim, M.D.

Department of Surgery, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu, Korea.

1Clinical Research Laboratory, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu, Korea.

2Department of Pathology, Uijeongbu St. Mary's Hospital, The Catholic University of Korea College of Medicine, Uijeongbu, Korea.

Corresponding author (drbreast@catholic.ac.kr)

Received 9 November 2009       Accepted 1 December 2009

Copyright © 2010 The Korean Surgical Society

Abstract

Purpose

Papillary Thyroid Microcarcinoma (PTMC) is rapidly increasing due to increased interests in the public health care system and improvements in ultrasonographic instruments and fine-needle-aspiration technique. The aim of this study is to investigate relationships between clinicopathologic features and molecular markers of PTMC and to help in developing therapeutic strategies in PTMC.

Methods

Tissue samples from patients with 38 PTMC and 21 benign thyroid tumors that were operated on from Jan. 2006 to Nov. 2008 were used to make microarrays and immunohistochemical staining for ER-α, E-CD, VEGF, MMP-2, MMP-9, and HIF-1α were performed. Clinicopathologic features of each immunohistochemical staining group were analyzed retrospectively.

Results

There is no immunohistochemistry staining in cases with benign thyroid lesions. The expression rate of ER-α, E-CD, VEGF, MMP-2, MMP-9, and HIF-1α in PTMC group was 66%, 58%, 82%, 66%, 71% and 63%, respectively. Bilateral tumor was statistically significant (48.0% vs 7.7%, P=0.015) related to MMP-2(+) PTMC group than in MMP-2(-) group. Bilateral tumor (44.4% vs 9.1%, P=0.060) and lymphovascular invasion (25.9% vs 0%, P=0.084) seemed to have greater relation to MMP-9(+) PTMC group than to MMP-9(-) group, but there is no statistically significant difference. Bilateral tumor (50.0% vs 7.1%, P=0.012), lymph node metastasis (45.8% vs 0%, P=0.003) and lymphovascular invasion (29.2% vs 0%, P=0.033) were significantly related to HIF-1α (+) PTMC group compared to HIF-1α(-) group.

Conclusion

Our findings suggest that MMP-2, MMP-9 and HIF-1α expression could be used as a prognostic marker in PTMC. Larger studies are needed to assess its prognostic value in PTMC.

Keywords: Thyroid carcinoma, Papillary microcarcinoma, MMP-2, MMP-9, HIF-1α

Figures and Tables

Fig. 1
Results of immunohistochemical staining of MMP-2, MMP-9 and HIF-1α (×200).
jkss-78-157-g001
Table 1
Clinicopathological characteristics of patients with PTMC or benign thyroid disease
jkss-78-157-i001

*PTMC = papillary thyroid microcarcinoma; †LN = lymph node.

Table 2
Results of Immunohistochemical scores for benign tumors and PTMC*
jkss-78-157-i002

*PTMC = papillary thyroid microcarcinoma; †ER-α = estrogen receptor-α; ‡E-CD = E-cadherin; §VEGF = vascular endothelial growth factor; ∥MMP-2 = matrix metalloproteinase-2; MMP-9 = matrix metalloproteinase-9; **HIF-1α = hypoxia inducible factor-1α.

Table 3
Summary of immunohistochemical staining results in PTMC* patients
jkss-78-157-i003

*PTMC = papillary thyroid microcarcinoma; †ER-α = estrogen receptor-α; ‡E-CD = E-cadherin; §VEGF = vascular endothelial growth factor; ∥MMP-2 = matrix metalloproteinase-2; MMP-9 = matrix metalloproteinase-9; **HIF-1α = hypoxia inducible factor-1α.

Table 4
Comparison of clinicopathologic characteristics according to results of immunohistochemical staining
jkss-78-157-i004

*ER-α = estrogen receptor-α; †E-CD = E-cadherin; ‡VEGF = vascular endothelial growth factor; §MMP-2 = matrix metalloproteinase-2; ∥MMP-9 = matrix metalloproteinase-9; HIF-1α = hypoxia inducible factor-1α.

References

1. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006. 295:2164–2167.
2. Ministry of Health and Welfare. Annual Report of the Korea Central Cancer Registry 2002. 2007.
3. Sherman SI. Thyroid carcinoma. Lancet. 2003. 361:501–511.
4. Hodgson NC, Button J, Solorzano CC. Thyroid cancer: is the incidence still increasing? Ann Surg Oncol. 2004. 11:1093–1097.
5. Choi YJ, Park YL, Koh JH. Prevalence of thyroid cancer at a medical screening center: pathological features of screen-detected thyroid carcinomas. Yonsei Med J. 2008. 49:748–756.
6. Beasley NJ, Lee J, Eski S, Walfish P, Witterick I, Freeman JL. Impact of nodal metastases on prognosis in patients with well-differentiated thyroid cancer. Arch Otolaryngol Head Neck Surg. 2002. 128:825–828.
7. Kilicarslan AB, Ogus M, Arici C, Pestereli HE, Cakir M, Karpuzoglu G. Clinical importance of vascular endothelial growth factor (VEGF) for papillary thyroid carcinomas. APMIS. 2003. 111:439–443.
8. Scarpino S, Cancellario d'Alena F, Di Napoli A, Pasquini A, Marzullo A, Ruco LP. Increased expression of Met protein is associated with up-regulation of hypoxia inducible factor-1 (HIF-1) in tumour cells in papillary carcinoma of the thyroid. J Pathol. 2004. 202:352–358.
9. von Wasielewski R, Rhein A, Werner M, Scheumann GF, Dralle H, Potter E, et al. Immunohistochemical detection of E-cadherin in differentiated thyroid carcinomas correlates with clinical outcome. Cancer Res. 1997. 57:2501–2507.
10. Klein M, Picard E, Vignaud JM, Marie B, Bresler L, Toussaint B, et al. Vascular endothelial growth factor gene and protein: strong expression in thyroiditis and thyroid carcinoma. J Endocrinol. 1999. 161:41–49.
11. Hay ID, Grant CS, van Heerden JA, Goellner JR, Ebersold JR, Bergstralh EJ. Papillary thyroid microcarcinoma: a study of 535 cases observed in a 50-year period. Surgery. 1992. 112:1139–1146. discussion 46-7.
12. Baudin E, Travagli JP, Ropers J, Mancusi F, Bruno-Bossio G, Caillou B, et al. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute experience. Cancer. 1998. 83:553–559.
13. Manole D, Schildknecht B, Gosnell B, Adams E, Derwahl M. Estrogen promotes growth of human thyroid tumor cells by different molecular mechanisms. J Clin Endocrinol Metab. 2001. 86:1072–1077.
14. Lee ML, Chen GG, Vlantis AC, Tse GM, Leung BC, van Hasselt CA. Induction of thyroid papillary carcinoma cell proliferation by estrogen is associated with an altered expression of Bcl-xL. Cancer J. 2005. 11:113–121.
15. Zeng Q, Chen GG, Vlantis AC, van Hasselt CA. Oestrogen mediates the growth of human thyroid carcinoma cells via an oestrogen receptor-ERK pathway. Cell Prolif. 2007. 40:921–935.
16. Cho MA, Lee MK, Nam KH, Chung WY, Park CS, Lee JH, et al. Expression and role of estrogen receptor alpha and beta in medullary thyroid carcinoma: different roles in cancer growth and apoptosis. J Endocrinol. 2007. 195:255–263.
17. Yane K, Kitahori Y, Konishi N, Okaichi K, Ohnishi T, Miyahara H, et al. Expression of the estrogen receptor in human thyroid neoplasms. Cancer Lett. 1994. 84:59–66.
18. Egawa C, Miyoshi Y, Iwao K, Shiba E, Noguchi S. Quantitative analysis of estrogen receptor-alpha and -beta messenger RNA expression in normal and malignant thyroid tissues by real-time polymerase chain reaction. Oncology. 2001. 61:293–298.
19. Hirohashi S, Kanai Y. Cell adhesion system and human cancer morphogenesis. Cancer Sci. 2003. 94:575–581.
20. Kapran Y, Ozbey N, Molvalilar S, Sencer E, Dizdaroglu F, Ozarmagan S. Immunohistochemical detection of E-cadherin, alpha- and beta-catenins in papillary thyroid carcinoma. J Endocrinol Invest. 2002. 25:578–585.
21. Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol. 2000. 10:415–433.
22. Duffy MJ, Maguire TM, Hill A, McDermott E, O'Higgins N. Metalloproteinases: role in breast carcinogenesis, invasion and metastasis. Breast Cancer Res. 2000. 2:252–257.
23. Nelson AR, Fingleton B, Rothenberg ML, Matrisian LM. Matrix metalloproteinases: biologic activity and clinical implications. J Clin Oncol. 2000. 18:1135–1149.
24. Yeh MW, Rougier JP, Park JW, Duh QY, Wong M, Werb Z, et al. Differentiated thyroid cancer cell invasion is regulated through epidermal growth factor receptor-dependent activation of matrix metalloproteinase (MMP)-2/gelatinase A. Endocr Relat Cancer. 2006. 13:1173–1183.
25. Tian X, Cong M, Zhou W, Zhu J, Liu Q. Relationship between protein expression of VEGF-C, MMP-2 and lymph node metastasis in papillary thyroid cancer. J Int Med Res. 2008. 36:699–703.
26. Jiang JB, Li XM, Zhang WD, Zhu M, Shou NH. Relationship of vascular endothelial growth factor-C and lymphangiogenesis with the development and prognosis of colon cancer. Zhonghua Wei Chang Wai Ke Za Zhi. 2005. 8:516–519.
27. Linderholm BK, Lindahl T, Holmberg L, Klaar S, Lennerstrand J, Henriksson R, et al. The expression of vascular endothelial growth factor correlates with mutant p53 and poor prognosis in human breast cancer. Cancer Res. 2001. 61:2256–2260.
28. Lennard CM, Patel A, Wilson J, Reinhardt B, Tuman C, Fenton C, et al. Intensity of vascular endothelial growth factor expression is associated with increased risk of recurrence and decreased disease-free survival in papillary thyroid cancer. Surgery. 2001. 129:552–558.
29. Sherman SI, Wirth LJ, Droz JP, Hofmann M, Bastholt L, Martins RG, et al. Motesanib diphosphate in progressive differentiated thyroid cancer. N Engl J Med. 2008. 359:31–42.
30. Semenza GL. HIF-1 and tumor progression: pathophysiology and therapeutics. Trends Mol Med. 2002. 8:S62–S67.
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