Prognostic significance of annexin II, human epididymis protein (HE-4) and claudin in endometrial carcinoma

Abstract

Introduction: Endometrial cancer (EC) is one of the most prevalent malignant tumors of the female reproductive system worldwide. Annexins are membrane binding proteins with important role in tumor development and progression. Human Epididymis Protein (HE-4) is a novel marker for gynecolgical tumors. Claudins are proteins of tight junction category playing an important role in cell adhesion and tumor spread. Material and methods: Seventy blocks of paraffin-embedded tissues of endometrial carcinoma cases. Immunohistochemical evaluation of Annexin II, HE- 4 and Claudin-7 staining was performed. Clinical follow-up to all cases was done every three months. Results: Positive Annexin II,HE-4 expression were observed in 88.6% and 77.1% of EC respectively. Significant correlation was found between expression of both Annexin II and HE-4 and FIGO stage, decreased both overall and disease free survival rates. Positive Claudin-7 expression was observed in 40% of EC, with significant correlation with high grade only, however, no correlation with other clinical parameters or survival analysis was detected. Conclusion: Annexin II, HE-4 and Claudin-7 are prognostic factors for endometrial carcinoma and could be used in molecular targeted therapy.

Keywords

Endometrial carcinoma / AnnexinII / HE-4 / Claudin-7 / IHC / Prognosis

Conflicts of Interest Disclosure

The authors declare no conflict of interest.

References

[1] Siegel RL, Miller KD, Jemal A. Cancer statistics. 2019: CA Cancer J Clin. 2016; 66: 7-30. PMid:26742998. https://doi.org/10.3 322/caac. 21332

[2] Zola P, Macchi C, Cibula D, et al. Follow-up in gynecological malignancies: a state of art. Int J Gynecol Cancer. 2015; 25(7): 1151-1164. PMid:26207784. https://doi.org/10.1097/IGC. 0000000000 000498

[3] Dong C, Liu P, Li C. Value of HE 4 combined with cancer Antigen 125 in the diagnosis of Endometrial Cancer. Pak J Med Sci. 2017; 33(4): 1013-1017. https://doi.org/10.12669/pjms.334.12755

[4] Singh N, Hirschowitz L, Zaino R, et al. Pathologic Prognostic Factors in Endometrial Carcinoma (Other Than Tumor Type and Grade. International Journal of Gynecological Pathology. 2019; 38: S93-S113. PMid:30550486. https://doi.org/10.1097/PGP. 0000000000 000524

[5] Yeramian A, Moreno-Bueno G, Dolcet X, et al. Endometrial carcinoma: molecular alterations involved in tumor development and progression. Oncogene. 2013; 32: 403-413. PMid:22430211. https: //doi.org/10.1038/onc.2012.76

[6] Bharadwaj A, Bydoun M, Holloway R, et al. Annexin A 2 heterotetramer: structure and function. Int J Mol Sci. 2013; 14: 62596305. PMid:23519104. https://doi.org/10.3390/ijms14036259

[7] Lokman NA, Ween MP, Oehler MK, et al. The role of annexin A2 in tumorigenesis and cancer progression. Cancer Microenviron. 2011; 4: 199-208. PMid:21909879. https://doi.org/10.1007/s123 07-011-0064-9

[8] Waisman DM. Annexin A 2 is a novel cellular redox regulatory protein involved in tumorigenesis. Oncotarget. 2011, 2: 1075-1093. PMid:22185818. https://doi.org/10.18632/oncotarget. 37 5

[9] Sharma M. Annexin A 2 (ANX A2): An emerging biomarker and potential therapeutic target for aggressive cancers. Int J Cancer. 2019; 144: 2074-2081. PMid:30125343. https://doi.org/10.1002/ ijc. 31817

[10] Li J, Dowdy S, Tipton T, et al. HE 4 as a biomarker for ovarian and endometrial cancer management. Expert Rev Mol Diagn. 2009; 9(6): 555-566. PMid:19732003. https://doi.org/10.1586/erm. 09. 39

[11] Karlsen NS, Karlsen MA, Hogdall CK, et al. HE 4 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: 2285-95. PMid:25169975. https://doi.org/10.1158/1055-9965.EPI-14-0447

[12] Yilmaz SA, Altinkaya SO, Kerimoglu OS, et al. The role of human epididymis secretory protein E 4 in patients with endometrial cancer and premalignant endometrial lesions. J Obstet Gynaecol. 2017; 37(1): 58-63. PMid:28006994. https://doi.org/10.3109/01 443615.2016.1174199

[13] Bian J, Sun X, Li B, et al. Clinical significance of serum HE4, CA125, CA724, and CA19-9 in patients with endometrial cancer. Technol Cancer Res Treat. 2017; 16(4): 435-439. PMid:27562869. https://doi.org/10.1177/1533034616666644

[14] Bie Y, Zhang Z. Diagnostic value of serum HE4 in endometrial cancer: a meta-analysis. World J Surg Oncol. 2014; 12: 169. PMid:24885319. https://doi.org/10.1186/1477-781 9-12-169

[15] González-Mariscal L, Betanzos A, Nava P et al. Tight junction proteins. Prog Biophys Mol Biol. 2003; 81: 1-44.

[16] Gunzel D, Yu AS. Claudins and the modulation of tight junction permeability. Physiol Rev. 2013; 93(2): 525-569. PMid:23589827. https://doi.org/10.1152/physrev.00019.2012

[17] Kapral M, Strzalka-Mrozik B, Kowalczyk M, et al. Transcriptional activities of histone H3, cyclinD1 and claudin-7 encoding genes in laryngeal cancer. Eur Arch Otorhinolaryngol. 2011; 268(5): 709714. PMid:21193919. https://doi.org/10.1007/s00405-010 -1471-0

[18] Bornholdt J, Friis S, Godiksen S, et al. The level of claudin-7 is reduced as an early event in colorectal carcinogenesis. BMC Cancer. 2011; 11(1): 1-9. PMid:21310043. https://doi.org/10.1186/ 1471-2407-11-65

[19] Dahiya N, Becker KG, Wood WH, et al. Claudin-7 is frequently overexpressed in ovarian cancer and promotes invasion. PLoS One. 2011; 6(7): e22119. PMid:21789222. https://doi.org/10. 137 1/journal.pone. 0022119

[20] Lu Z, Ding L, Hong H, et al. Claudin-7 inhibits human lung cancer cell migration and invasion through ERK/MAPK signaling pathway. Exp Cell Res. 2011; 317: 1935-1946. PMid:21641901. https://doi.org/10.1016/j.yexcr.2011.05.019

[21] Hsu SM, Raine L, Fanger H. Use of Avidin Biotin peroxidase complex (ABC) in immunoperoxidase techniques: acomparison between ABC and unlabeled antibody (PAP) procedures. J Histochem Cytochem. 1981; 29: 577-580. PMid:6166661. https: //doi.org/10.1177/29.4.6166661

[22] Deng L, Gao Y, Li X, et al. Expression and clinical significance of Annexin A2 and human epididymis protein 4 in endometrial carcinoma. J Exp Clin Cancer. 2015; 34: 96. PMid:26362938. https://doi.org/10.1186/s13046-015-0208-8

[23] Li X, Li Y, Qiu H, et al. Downregulation of claudin 7 potentiates cellular proliferation and invasion in endometrial cancer. Oncology letters. 2013; 101-105. PMid:23946785. https://doi.org/10.3 892/ol.2013.1330

[24] Deng L, Gao Y, Li X, et al. Expression and clinical significance of annexin A2 and human epididymis protein 4 in endometrial carcinoma. J Exp Clin Cancer Res. 2015; 34: 96. PMid:26362938. https://doi.org/10.1186/s13046-015-0208-8

[25] Alonso-Alconada L, Santacana M, Garcia-Sanz P, et al. Annexin-A 2 as predictor biomarker of recurrent disease in endometrial cancer. Int J Cancer J Int Du Cancer. 2014; 136(8): 1863-73. PMid:25219463. https://doi.org/10.1002/ijc. 29213

[26] Stiekema A, Lok C, Korse CM, et al. Serum HE 4 is correlated to prognostic factors and survival in patients with endometrial cancer. Virchows Arch. 2017; 470: 655-664. PMid:28401338. https : //doi.org/10.1007/s00428-017-2115-1

[27] Angioli R, Capriglione S, Scaletta G, et al. The role of HE4 in endometrial cancer recurrence: how to choose the optimal follow-up program. Tumour Biol. 2016; 37(4): 4973-4978. PMid:26531723. https://doi.org/10.1007/s13277-015-4324-z

[28] Brennan DJ, Hackethal A, Mann KP, et al. Serum HE 4 detects recurrent endometrial cancer in patients undergoing routine clinical surveillance. BMC Cancer. 2015; 15: 33. PMid:25655024. https://doi.org/10.1186/s12885-015-1028-0

[29] Capriglione S, Plotti F, Miranda A, et al. Further insight into prognostic factors in endometrial cancer: the new serum biomarker HE4. Expert Rev Anticancer Ther. 2017; 17: 9-18. PMid:27892774. https://doi.org/10.1080/14737140.2017.1266263

[30] Lu Z, Kim DH, Fan J, et al. A non-tight junction function of claudin 7 - interaction with integrin signaling in suppressing lung cancer cell proliferation and detachment. Mol Cancer. 2015; 14(1): 120135. PMid:26081244. https://doi.org/10.1186/s12943-015 -0387-0

[31] Flores AR, Rêma A, Carvalho F, et al. Clinicopathological significance of immunoexpression of claudin-1 and claudin-7 in feline mammary carcinomas. J Comp Pathol. 2014; 151(4): 339-346. PMid:25246182. https://doi.org/10.1016/j.gdata.2016.0 5.010

[32] Alikanoglu AS, Gunduz S, Demirpence O, et al. Expression pattern and prognostic significance of claudin 1, 4 and 7 in pancreatic cancer. Asian Pac J Cancer Prev. 2015; 16(10): 4387-4392. PMid:26028104. https://doi.org/10.7314/APJCP.2015.16.10.4387

[33] Xu C, Wang X, Li W, et al. Expression and Clinical Significance of Claudin-7 in Patients With Colorectal. Cancer Technology in Cancer Research & Treatment. 2018, 17: 1-10. https://doi.org/10. 1 177/1533033818817774