J Gynecol Oncol.  2011 Jun;22(2):89-96. 10.3802/jgo.2011.22.2.89.

Expression of matrix metalloproteinase-2 and survivin in endometrioid and nonendometrioid endometrial cancers and clinicopathologic significance

• Yilmaz E
• Koyuncuoglu M
• Gorken IB
• Okyay E
• Saatli B
• Ulukus EC
• Saygili U

• KMID: 2288572
• DOI: http://doi.org/10.3802/jgo.2011.22.2.89

Abstract

OBJECTIVE
To determine matrix metalloproteinase-2 and survivin expressions in endometrial cancers, their relation to clinical and histologic parameters and to investigate any difference in the expression of these markers between endometrioid and nonendometrioid cancers.
METHODS
Ninety-five patients with endometrial cancer, were included. Matrix metalloproteinase-2 and survivin expressions were analyzed immunohistochemically from paraffin-embedded tissues by using specific monoclonal antibodies.
RESULTS
Survivin nuclear expression was higher in endometrioid cancer as compared to nonendometrioid cancer (p=0.040), but there was no difference for cytoplasmic survivin and matrix metalloproteinase-2 expressions between type I and type II carcinomas. Survivin cytoplasmic staining was significantly lower in patients with deep myometrial invasion (p=0.038). Nuclear expression of survivin is decreased in histologic grade 3 tumors compared to grade 1 and 2 tumors (p=0.013), but there is no difference between grade 1 and 2. We did not find any statistically significant difference between survivin or matrix metalloproteinase-2 expressions and survival.
CONCLUSION
Survivin and matrix metalloproteinase-2 are present in endometrioid and nonendometrioid cancers. Grade 1 and 2 tumors and carcinomas having myometrial invasion less than 50% have higher survivin expression. These results supports that, survivin may play an important role in early stage tumors and early phases of tumor development. We did not find any association between matrix metalloproteinase-2 expression and classical prognostic factors in endometrial cancer and both proteins were not associated with survival.

Keyword

Endometrial cancer; Matrix metalloproteinases; Survivin; Prognosis; Survival

MeSH Terms

Cytoplasm
Endometrial Neoplasms
Female
Humans
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Prognosis
Proteins
Matrix Metalloproteinase 2
Matrix Metalloproteinases
Proteins

Figure

• 

  Fig. 1 Survivin cytoplasmic (A) and nuclear (B) immunohistochemical staining in pT3a endometrioid endometrial adenocarcinoma (×400).

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  Fig. 2 Matrix metalloproteinase-2 positivity in pT1b endometrioid endometrial adenocarcinoma (×100).

Reference

1. Prat J. Prognostic parameters of endometrial carcinoma. Hum Pathol. 2004. 35:649–662.

2. Sorosky JI. Endometrial cancer. Obstet Gynecol. 2008. 111:436–447.

3. Bokhman JV. Two pathogenetic types of endometrial carcinoma. Gynecol Oncol. 1983. 15:10–17.

4. Matias-Guiu X, Catasus L, Bussaglia E, Lagarda H, Garcia A, Pons C, et al. Molecular pathology of endometrial hyperplasia and carcinoma. Hum Pathol. 2001. 32:569–577.

5. Sun H, Enomoto T, Fujita M, Wada H, Yoshino K, Ozaki K, et al. Mutational analysis of the PTEN gene in endometrial carcinoma and hyperplasia. Am J Clin Pathol. 2001. 115:32–38.

6. Tashiro H, Isacson C, Levine R, Kurman RJ, Cho KR, Hedrick L. p53 gene mutations are common in uterine serous carcinoma and occur early in their pathogenesis. Am J Pathol. 1997. 150:177–185.

7. Tritz D, Pieretti M, Turner S, Powell D. Loss of heterozygosity in usual and special variant carcinomas of the endometrium. Hum Pathol. 1997. 28:607–612.

8. Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA. Molecular aspects of tumor cell invasion and metastasis. Cancer. 1993. 71:1368–1383.

9. Chang C, Werb Z. The many faces of metalloproteases: cell growth, invasion, angiogenesis and metastasis. Trends Cell Biol. 2001. 11:S37–S43.

10. Parks WC. Matrix metalloproteinases in repair. Wound Repair Regen. 1999. 7:423–432.

11. Rodgers WH, Osteen KG, Matrisian LM, Navre M, Giudice LC, Gorstein F. Expression and localization of matrilysin, a matrix metalloproteinase, in human endometrium during the reproductive cycle. Am J Obstet Gynecol. 1993. 168:253–260.

12. Monaghan H, MacWhinnie N, Williams AR. The role of matrix metalloproteinases-2, -7 and -9 and beta-catenin in high grade endometrial carcinoma. Histopathology. 2007. 50:348–357.

13. Graesslin O, Cortez A, Uzan C, Birembaut P, Quereux C, Darai E. Endometrial tumor invasiveness is related to metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expressions. Int J Gynecol Cancer. 2006. 16:1911–1917.

14. Ambrosini G, Adida C, Altieri DC. A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med. 1997. 3:917–921.

15. Altieri DC. Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene. 2003. 22:8581–8589.

16. Altieri DC, Marchisio PC. Survivin apoptosis: an interloper between cell death and cell proliferation in cancer. Lab Invest. 1999. 79:1327–1333.

17. Erkanli S, Kayaselcuk F, Kuscu E, Bagis T, Bolat F, Haberal A, et al. Expression of survivin, PTEN and p27 in normal, hyperplastic, and carcinomatous endometrium. Int J Gynecol Cancer. 2006. 16:1412–1418.

18. Takai N, Miyazaki T, Nishida M, Nasu K, Miyakawa I. Survivin expression correlates with clinical stage, histological grade, invasive behavior and survival rate in endometrial carcinoma. Cancer Lett. 2002. 184:105–116.

19. Lambropoulou M, Papadopoulos N, Tripsianis G, Alexiadis G, Pagonopoulou O, Kiziridou A, et al. Co-expression of survivin, c-erbB2, and cyclooxygenase-2 (COX-2): prognostic value and survival of endometrial cancer patients. J Cancer Res Clin Oncol. 2010. 136:427–435.

20. Lee KR, Tavassoli FA, Prat J. Tavassoli FA, Devilee P, editors. Surface epithelial-stromal tumours. World Health Organization classification of tumours. Pathology and genetics of the breast and female genital organs. 2003. Lyon: IARC Press;117–145.

21. Benedet JL, Bender H, Jones H 3rd, Ngan HY, Pecorelli S. FIGO staging classifications and clinical practice guidelines in the management of gynecologic cancers: FIGO Committee on Gynecologic Oncology. Int J Gynaecol Obstet. 2000. 70:209–262.

22. Gilcrease MZ, Truong L, Brown RW. Correlation of very late activation integrin and CD44 expression with extrarenal invasion and metastasis of renal cell carcinomas. Hum Pathol. 1996. 27:1355–1360.

23. Shaco-Levy R, Sharabi S, Piura B, Sion-Vardy N. MMP-2, TIMP-1, E-cadherin, and beta-catenin expression in endometrial serous carcinoma compared with low-grade endometrial endometrioid carcinoma and proliferative endometrium. Acta Obstet Gynecol Scand. 2008. 87:868–874.

24. Moser PL, Hefler L, Tempfer C, Neunteufel W, Kieback DG, Gitsch G. Immunohistochemical detection of matrix metalloproteinases (MMP) 1 and 2, and tissue inhibitor of metalloproteinase 2 (TIMP 2) in stage I and II endometrial cancer. Anticancer Res. 1999. 19(3B):2365–2367.

25. Aglund K, Rauvala M, Puistola U, Angstrom T, Turpeenniemi-Hujanen T, Zackrisson B, et al. Gelatinases A and B (MMP-2 and MMP-9) in endometrial cancer-MMP-9 correlates to the grade and the stage. Gynecol Oncol. 2004. 94:699–704.

26. Di Nezza LA, Misajon A, Zhang J, Jobling T, Quinn MA, Ostor AG, et al. Presence of active gelatinases in endometrial carcinoma and correlation of matrix metalloproteinase expression with increasing tumor grade and invasion. Cancer. 2002. 94:1466–1475.

27. Lopata A, Agresta F, Quinn MA, Smith C, Ostor AG, Salamonsen LA. Detection of endometrial cancer by determination of matrix metalloproteinases in the uterine cavity. Gynecol Oncol. 2003. 90:318–324.

28. Honkavuori M, Talvensaari-Mattila A, Soini Y, Turpeenniemi-Hujanen T, Santala M. MMP-2 expression associates with CA 125 and clinical course in endometrial carcinoma. Gynecol Oncol. 2007. 104:217–221.

29. Shaco-Levy R, Sharabi S, Benharroch D, Piura B, Sion-Vardy N. Matrix metalloproteinases 2 and 9, E-cadherin, and beta-catenin expression in endometriosis, low-grade endometrial carcinoma and non-neoplastic eutopic endometrium. Eur J Obstet Gynecol Reprod Biol. 2008. 139:226–232.

30. Iurlaro M, Loverro G, Vacca A, Cormio G, Ribatti D, Minischetti M, et al. Angiogenesis extent and expression of matrix metalloproteinase-2 and -9 correlate with upgrading and myometrial invasion in endometrial carcinoma. Eur J Clin Invest. 1999. 29:793–801.

31. Tamm I, Wang Y, Sausville E, Scudiero DA, Vigna N, Oltersdorf T, et al. IAP-family protein survivin inhibits caspase activity and apoptosis induced by Fas (CD95), Bax, caspases, and anticancer drugs. Cancer Res. 1998. 58:5315–5320.

32. Ai Z, Yin L, Zhou X, Zhu Y, Zhu D, Yu Y, et al. Inhibition of survivin reduces cell proliferation and induces apoptosis in human endometrial cancer. Cancer. 2006. 107:746–756.

33. Pallares J, Martinez-Guitarte JL, Dolcet X, Llobet D, Rue M, Palacios J, et al. Survivin expression in endometrial carcinoma: a tissue microarray study with correlation with PTEN and STAT-3. Int J Gynecol Pathol. 2005. 24:247–253.

34. Saitoh Y, Yaginuma Y, Ishikawa M. Analysis of Bcl-2, Bax and Survivin genes in uterine cancer. Int J Oncol. 1999. 15:137–141.

35. Lehner R, Enomoto T, McGregor JA, Shroyer L, Haugen BR, Pugazhenthi U, et al. Correlation of survivin mRNA detection with histologic diagnosis in normal endometrium and endometrial carcinoma. Acta Obstet Gynecol Scand. 2002. 81:162–167.