Expression and clinical significance of annexin A2 and human epididymis protein 4 in endometrial carcinoma

Journal of Experimental & Clinical Cancer Research

Bei Lin¹  Yingying Hao¹  Shuice Liu¹  Mingzi Tan¹  Huiyu Zhuang⁴  Huimin Wang¹  Mingbo Cai³  Xiao Li¹  Yiping Gao²  Lu Deng¹ 

[1] Department of Gynaecology and Obstetrics, Shengjing Hospital affiliated to China Medical University, No. 36 Sanhao Street, Heping District, Shenyang 110004, Liaoning, China;Tianjin Central Hospital of Gynaecology and Obstetrics, Tianjin, China;Department of Obstetrics and Gynecology, Hospital of Zhengzhou University, Zhengzhou, Henan, China;Department of Gynecology and Obstetrics, Beijing chaoyang Hospital, Capital Medical University, Beijing, China

关键词: Prognosis;    Immunohistochemistry;    Endometrial carcinoma;    Human epididymis protein 4;    Annexin A2;   

Others  :  1226260
DOI  :  10.1186/s13046-015-0208-8

 received in 2015-06-22, accepted in 2015-08-19,  发布年份 2015

【 摘 要 】

Background

It is well-known that the treatment and monitoring methods are limited for advanced stage of endometrial carcinoma. Biological molecules with expression changes during tumor progression become potential therapeutic targets for advanced stage endometrial carcinoma. Annexin A2 (ANXA2) has been reported to be overexpressed in recurrent endometrial carcinoma, and the expression of human epididymis protein 4 (HE4) is upregulated in endometrial carcinoma. What’s more, ANXA2 and HE4 interacted in ovarian cancer and promoted the malignant biological behavior. We speculated that their interaction may exist in endometrial carcinoma as well. We evaluated the expression and the correlation relationship of ANXA2 and HE4 in endometrial carcinoma.

Methods

The expression of ANXA2 and HE4 protein in 84 endometrial carcinoma, 30 endometrial atypical hyperplasia, and 18 normal endometrial tissue samples were then measured using an immunohistochemical assay in paraffin embedded endometrial tissues. The structural relationship between ANXA2 and HE4 was explored by immunoprecipitation and double immunofluorescent staining.

Results

ANXA2 and HE4 co-localized in both endometrial tissues and endometrial carcinoma cells. ANXA2 and HE4 were expressed in 95.2 % and 85.7 % of the the endometrial carcinoma, respectively, which were significantly higher than normal endometrium (55.6 % and 16.7 %, both p < 0.05). The expression of ANXA2 and HE4 was significantly correlated with FIGO stage, degree of differentiation, myometrial invasion, and lymph node metastasis. ANXA2 was an independent risk factor for the prognosis of endometrial carcinoma (p < 0.05, hazard ratio [HR] = 8.004). The expression of ANXA2 and HE4 was positively correlated (Spearman correlation coefficient = 0.228, p < 0.05). HE4 was an independent factor for ANXA2 in multivariate linear regression model (p < 0.05).

Conclusion

We revealed the co-localization of ANXA2 and HE4 in endometrial carcinoma. Expression levels of ANXA2 and HE4 were closely related to the malignant biological behavior of endometrial carcinoma, and ANXA2 was an independent risk factor for poor prognosis. The expression of ANXA2 and HE4 can affect each other.

【 授权许可】

   
2015 Deng et al.

【 图 表 】

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【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D: Global cancer statistics. CA Cancer J Clin 2011, 61:69-90.
• [2]Hill EK, Dizon DS: Medical therapy of endometrial cancer: current status and promising novel treatments. Drugs 2012, 72:705-713.
• [3]Shao R, Li X, Feng Y, Lin J-F, Billig H: Direct effects of metformin in the endometrium: a hypothetical mechanism for the treatment of women with PCOS and endometrial carcinoma. J Exp Clin Cancer Res 2014, 33:41. BioMed Central Full Text
• [4]Saso S, Chatterjee J, Georgiou E, Ditri AM, Smith JR, Ghaem-Maghami S: Endometrial cancer. BMJ 2011, 343:d3954.
• [5]Di Cristofano A, Ellenson LH: Endometrial carcinoma. Annu Rev Pathol 2007, 2:57-85.
• [6]Bokhman JV: Two pathogenetic types of endometrial carcinoma. Gynecol Oncol 1983, 15:10-17.
• [7]Ishikawa M, Nakayama K, Rahman MT, Rahman M, Katagiri A, Iida K, et al.: Functional and clinicopathological analysis of loss of MKK4 expression in endometrial cancer. Oncology 2010, 79:238-246.
• [8]Voss MA, Gordon N, Maloney S, Ganesan R, Ludeman L, McCarthy K, et al.: Tetraspanin CD151 is a novel prognostic marker in poor outcome endometrial cancer. Br J Cancer 2011, 104:1611-1618.
• [9]Bignotti E, Ragnoli M, Zanotti L, Calza S, Falchetti M, Lonardi S, et al.: Diagnostic and prognostic impact of serum HE4 detection in endometrial carcinoma patients. Br J Cancer 2011, 104:1418-1425.
• [10]Werner HMJ, Salvesen HB: Current status of molecular biomarkers in endometrial cancer. Current Oncology Reports 2014, 16:403.
• [11]Ma X, Zhao Y, Li Y, Lu H, He Y: Relevance of Bcl-x expression in different types of endometrial tissues. J Exp Clin Cancer Res 2010, 29:14. BioMed Central Full Text
• [12]Miszczak-Zaborska E, Kubiak R, Bienkiewicz A, Bartkowiak J: The cytosol activity of thymidine phosphorylase in endometrial cancer. J Exp Clin Cancer Res 2008, 27:64. BioMed Central Full Text
• [13]Peng Q, Mo C, Qin A, Lao X, Chen Z, Sui J, et al.: MDM2 SNP309 polymorphism contributes to endometrial cancer susceptibility: evidence from a meta-analysis. J Exp Clin Cancer Res 2013, 32:85. BioMed Central Full Text
• [14]Huebner K, Cannizzaro LA, Frey AZ, Hecht BK, Hecht F, Croce CM, et al.: Chromosomal localization of the human genes for lipocortin I and lipocortin II. Oncogene Res 1988, 2:299-310.
• [15]Waisman DM: Annexin II, tetramer: structure and function. Mol Cell Biochem 1995, 149–150:301-322.
• [16]Wang C-Y, Lin C-F: Annexin A2: Its Molecular Regulation and Cellular Expression in Cancer Development. Disease Markers. 2014.
• [17]Banerjee AG, Liu J, Yuan Y, Gopalakrishnan VK, Johansson SL, Dinda AK, et al.: Expression of biomarkers modulating prostate cancer angiogenesis: differential expression of annexin II in prostate carcinomas from India and USA. Mol Cancer 2003, 2:34. BioMed Central Full Text
• [18]Lokman NA, Ween MP, Oehler MK, Ricciardelli C: The role of annexin A2 in tumorigenesis and cancer progression. Cancer Microenviron 2011, 4:199-208.
• [19]Kirchhoff C: Molecular characterization of epididymal proteins. Rev Reprod 1998, 3:86-95.
• [20]Drapkin R, von Horsten HH, Lin YF, Mok SC, Crum CP, Welch WR, et al.: Human epididymis protein 4 (HE4) is a secreted glycoprotein that is overexpressed by serous and endometriold ovarian carcinomas. Cancer Res 2005, 65:2162-2169.
• [21]Yu S, Yang H-j, Xie S-q, Bao Y-X: Diagnostic value of HE4 for ovarian cancer: a meta-analysis. Clin Chem Lab Med 2012, 50:1439-1446.
• [22]Galgano MT, Hampton GM, Frierson HF: Comprehensive analysis of HE4 expression in normal and malignant human tissues. Mod Pathol 2006, 19:847-853.
• [23]Karlsen NS, Karlsen MA, Hogdall CK, Hogdall EV: HE4 tissue expression and serum HE4 levels in healthy individuals and patients with benign or malignant tumors: a systematic review. Cancer Epidemiol Biomark Prev 2014, 23:2285-2295.
• [24]Zhuang H, Tan M, Liu J, Hu Z, Liu D, Gao J, et al.: Human epididymis protein 4 in association with Annexin II promotes invasion and metastasis of ovarian cancer cells. Mol Cancer 2014, 13:243. BioMed Central Full Text
• [25]Zhuang H, Tan M, Liu J, Li X, Gao J, Hu Z, et al.: The expression of annexin II and Lewis y antigen in ovarian epithelial tumors and the correlation between them. Tumour Biol 2014, 36(4):2343-9.
• [26]Alonso-Alconada L, Santacana M, Garcia-Sanz P, Muinelo-Romay L, Colas E, Mirantes C, et al.: Annexin-A2 as predictor biomarker of recurrent disease in endometrial cancer. Int J Cancer J Int Du Cancer 2014, 136(8):1863-73.
• [27]Brennan DJ, Hackethal A, Metcalf AM, Coward J, Ferguson K, Oehler MK, et al.: Serum HE4 as a prognostic marker in endometrial cancer--a population based study. Gynecol Oncol 2014, 132:159-165.
• [28]Zhang F, Zhang H, Wang Z, Yu M, Tian R, Ji W, et al.: P-glycoprotein associates with Anxa2 and promotes invasion in multidrug resistant breast cancer cells. Biochem Pharmacol 2014, 87:292-302.
• [29]Zhao P, Zhang W, Wang SJ, Yu XL, Tang J, Huang W, et al.: HAb18G/CD147 promotes cell motility by regulating annexin II-activated RhoA and Rac1 signaling pathways in hepatocellular carcinoma cells. Hepatology 2011, 54:2012-2024.
• [30]Yang T, Peng H, Wang J, Yang J, Nice EC, Xie K, et al.: Prognostic and diagnostic significance of annexin A2 in colorectal cancer. Color Dis 2013, 15:E373-E381.
• [31]Kapoor M, Zhou Q, Otero F, Myers CA, Bates A, Belani R, et al.: Evidence for annexin II-S100A10 complex and plasmin in mobilization of cytokine activity of human TrpRS. J Biol Chem 2008, 283:2070-2077.
• [32]Huang T, Jiang SW, Qin L, Senkowski C, Lyle C, Terry K, et al.: Expression and diagnostic value of HE4 in pancreatic adenocarcinoma. Int J Mol Sci 2015, 16:2956-2970.
• [33]Guo YD, Wang JH, Lu H, Li XN, Song WW, Zhang XD, et al.: The human epididymis protein 4 acts as a prognostic factor and promotes progression of gastric cancer. Tumour Biol 2014, 36(4):2457-64.
• [34]Fowler PA, Tattum J, Bhattacharya S, Klonisch T, Hombach-Klonisch S, Gazvani R, et al.: An investigation of the effects of endometriosis on the proteome of human eutopic endometrium: a heterogeneous tissue with a complex disease. Proteomics 2007, 7:130-142.
• [35]Zhou S, Yi T, Liu R, Bian C, Qi X, He X, et al.: Proteomics identification of annexin A2 as a key mediator in the metastasis and proangiogenesis of endometrial cells in human adenomyosis. Mol Cell Proteomics 2012, 11:M112.017988.
• [36]Dominguez F, Garrido-Gomez T, Lopez JA, Camafeita E, Quinonero A, Pellicer A, et al.: Proteomic analysis of the human receptive versus non-receptive endometrium using differential in-gel electrophoresis and MALDI-MS unveils stathmin 1 and annexin A2 as differentially regulated. Hum Reprod 2009, 24:2607-2617.
• [37]Garrido-Gomez T, Dominguez F, Quinonero A, Estella C, Vilella F, Pellicer A, et al.: Annexin A2 is critical for embryo adhesiveness to the human endometrium by RhoA activation through F-actin regulation. Faseb j 2012, 26:3715-3727.