Document Type : Original Article


1 Department of Pathology, Faculty of Medicine, Zagazig University, Zagazig, Egypt

2 Department of Clinical Oncology, Faculty of Medicine, Zagazig University, Zagazig, Egypt


Background: Endometrial cancer (EC) is a common gynecological cancer ranks as fifth cancer worldwide and the tenth common cancer in Egypt. Termed DEL-1 (EGF like repeats and discoid domains 3), is an embryonic endothelial cell protein. EDIL3 was associated with regulation of angiogenesis. SOX (sex-determining region Y-related high-mobility-group box transcription factor). SOX4 expression was altered in many human cancers. This research aimed to study the expression of EDIL3, SOX4 in EC in atrial to explore their relationship with clinicopathological parameters prognostic and treatment outcome.
Method: This retrospective study included 50 paraffin blocks of cases of endometrial adenocarcinoma (endometroid type) with different grades which were selected from the archives of the Pathology Department, Zagazig University, Egypt during a period from January 2015 to last of December 2019. The expression of EDIL3, SOX4 was evaluated using immunohistochemistry.
Results: 56% of the studied patients were >45 years old. 54% had well-differentiated adenocarcinoma, and 56% absent lymph node metastasis. EDIL3 and SOX4 expression is found in 70% and 84% of the studied patients. A statistically significant relation was detected between EDIL 3 and tumor grade, stage, lympho-vascular invasion (LVI), and lymph node metastasis (P value was 0.001, <0.001, 0.002, and 0.005, respectively). SOX4 was significantly correlated with tumor grade, stage, lymph node metastasis, and LVI (P value was 0.039, 0.002, 0.006, and 0.015, respectively).
Conclusion: expressions are associated with advanced clinicopathological parameters, unfavorable prognosis, and poor treatment response.


How to cite this article:

Atwa HA, Elwan A, Abouhashem NS. Clinicopathological features, prognostic impact and treatment outcome of EDIL3 and SOX4 expressions in endometrial adenocarcinoma. Middle East J Cancer. 2023;14(1):82-91. doi: 10.30476/mejc.2022.91144.1611.

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61(2):69-90. doi: 10.3322/caac.20107. Erratum in: CA Cancer J Clin. 2011;61(2):134.
  2. Murali R, Soslow RA, Weigelt B. Classification of endometrial carcinoma: more than two types. Lancet Oncol. 2014;15(7):e268-78. doi: 10.1016/S1470- 2045(13)70591-6.
  3. Jiang SH, Wang Y, Yang JY, Li J, Feng MX, Wang YH, et al. Overexpressed EDIL3 predicts poor prognosis and promotes anchorage-independent tumor growth in human pancreatic cancer. Oncotarget. 2016;7(4):4226-40. doi: 10.18632/oncotarget.6772.
  4. Aoka Y, Johnson FL, Penta K, Hirata Ki K, Hidai C, Schatzman R, et al. The embryonic angiogenic factor Del1 accelerates tumor growth by enhancing vascular formation. Microvasc Res. 2002;64(1):148-61. doi: 10.1006/mvre.2002.2414.
  5. Zhong J, Eliceiri B, Stupack D, Penta K, Sakamoto G, Quertermous T, et al. Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1. J Clin Invest. 2003;112(1):30-41. doi: 10.1172/JCI17034.
  6. Ho HK, Jang JJ, Kaji S, Spektor G, Fong A, Yang P, et al. Developmental endothelial locus-1 (Del-1), a novel angiogenic protein: its role in ischemia. Circulation. 2004;109(10):1314-9. doi: 10.1161/01.CIR.0000118465.36018.2D.
  7. Choi EY, Chavakis E, Czabanka MA, Langer HF, Fraemohs L, Economopoulou M, et al. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science. 2008;322(5904):1101-4. doi: 10.1126/science.1165218. Erratum in: Science. 2009;325(5943):946.
  8. Bowles J, Schepers G, Koopman P. Phylogeny of the SOX family of developmental transcription factors based on sequence and structural indicators. Dev Biol. 2000;227(2):239-55. doi: 10.1006/dbio.2000.9883.
  9. Huang YW, Liu JC, Deatherage DE, Luo J, Mutch DG, Goodfellow PJ, et al. Epigenetic repression of microRNA-129-2 leads to overexpression of SOX4 oncogene in endometrial cancer. Cancer Res. 2009;69(23):9038-46. doi: 10.1158/0008-5472.CAN- 09-1499.
  10. Wang L, Zhang J, Yang X, Chang YW, Qi M, Zhou Z, et al. SOX4 is associated with poor prognosis in prostate cancer and promotes epithelial-mesenchymal transition in vitro. Prostate Cancer Prostatic Dis. 2013;16(4):301-7. doi: 10.1038/pcan.2013.25.
  11. Bilir B, Osunkoya AO, Wiles WG 4th, Sannigrahi S, Lefebvre V, Metzger D, et al. SOX4 is essential for prostate tumorigenesis initiated by PTEN ablation. Cancer Res. 2016;76(5):1112-21. doi: 10.1158/0008- 5472.CAN-15-1868.
  12. Galaal K, Al Moundhri M, Bryant A, Lopes AD, Lawrie TA. Adjuvant chemotherapy for advanced endometrial cancer. Cochrane Database Syst Rev. 2014;2014(5):CD010681. doi: 10.1002/14651858. CD010681.pub2.
  13. Kurra V, Krajewski KM, Jagannathan J, Giardino A, Berlin S, Ramaiya N. Typical and atypical metastatic sites of recurrent endometrial carcinoma. Cancer Imaging. 2013;13(1):113-22. doi: 10.1102/1470- 7330.2013.0011.
  14. Colombo N, Preti E, Landoni F, Carinelli S, Colombo A, Marini C, et al. Endometrial cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and followup. Ann Oncol. 2013;24 Suppl 6:vi33-8. doi: 10.1093/annonc/mdt353.
  15. Feng Y, Minca EC, Lanigan C, Liu A, Zhang W, Yin L, et al. High MET receptor expression but not gene amplification in ALK 2p23 rearrangement positive non-small-cell lung cancer. J Thorac Oncol. 2014;9(5):646-53. doi: 10.1097/JTO.0000000000 000145.
  16. Jafarnejad SM, Wani AA, Martinka M, Li G. Prognostic significance of SOX4 expression in human cutaneous melanoma and its role in cell migration and invasion. Am J Pathol. 2010; 177:2741-52. doi: 10.2353/ajpath. 2010.100377.
  17. Opławski M, Michalski M, Witek A, Michalski B, Zmarzły N, Jęda-Golonka A, et al. Identification of a gene expression profile associated with the regulation of angiogenesis in endometrial cancer. Mol Med Rep. 2017;16(3):2547-55. doi: 10.3892/mmr.2017.6868.
  18. Lopes-Bastos BM, Jiang WG, Cai J. Tumourendothelial cell communications: Important and indispensable mediators of tumour angiogenesis. Anticancer Res. 2016;36(3):1119-26.
  19. Xia H, Chen J, Shi M, Gao H, Sekar K, Seshachalam VP, et al. EDIL3 is a novel regulator of epithelialmesenchymal transition controlling early recurrence of hepatocellular carcinoma. J Hepatol. 2015;63(4):863-73. doi: 10.1016/j.jhep.2015.05.005.
  20. Kalluri R, Weinberg RA. The basics of epithelialmesenchymal transition. J Clin Invest. 2009;119(6): 1420-8. doi: 10.1172/JCI39104. Erratum in: J Clin Invest. 2010;120(5):1786.
  21. Zheng JH, Jian ZX, Jin HS, Chen SC, Wang GY. Expression of SOX4 gene and early recurrence of hepatocellular carcinoma: their relationship and the clinical significance. [Article in Chinese] Nan Fang Yi Ke Da Xue Xue Bao. 2010;30(4):818-9.
  22. Niu JX, Zhang WJ, Ye LY, Wu LQ, Zhu GJ, Yang ZH, et al The role of adhesion molecules, alpha v beta 3, alpha v beta 5 and their ligands in the tumor cell and endothelial cell adhesion. Eur J Cancer Prev. 2007;16(6):517-27. doi: 10.1097/CEJ.0b013e3280 145c00.
  23. Lee JE, Moon PG, Cho YE, Kim YB, Kim IS, Park H, et al. Identification of EDIL3 on extracellular vesicles involved in breast cancer cell invasion. J Proteomics. 2016; 131:17-28. doi: 10.1016/j.jprot. 2015.10.005.
  24. Lee SH, Kim DY, Jing F, Kim H, Yun CO, Han DJ, et al. Del-1 overexpression potentiates lung cancer cell proliferation and invasion. Biochem Biophys Res Commun. 2015;468(1-2):92-8. doi: 10.1016/j.bbrc. 2015.10.159.
  25. Jeong D, Ban S, Oh S, Jin Lee S, Yong Park S, Koh YW. Prognostic significance of EDIL3 expression and correlation with mesenchymal phenotype and microvessel density in lung adenocarcinoma. Sci Rep. 2017;7(1):8649. doi: 10.1038/s41598-017-08851-9.
  26. Liao H, Lin P. Expression of SOX4 in endometrial cancer and its relationship with clinicopathological characteristic in endometrial cancer patients. Journal of Clinical and Nursing Research (JCNR). 2020;4(4): 45-9. doi: 10.26689/ jcnrv4i4.1338.
  27. Huang YW, Kuo CT, Chen JH, Goodfellow PJ, Huang TH, Rader JS, et al. Hypermethylation of miR-203 in endometrial carcinomas. Gynecol Oncol. 2014;133(2): 340-5. doi: 10.1016/j.ygyno.2014.02.009.
  28. Wang C, Zhao H, Lu J, Yin J, Zang L, Song N, et al. Clinicopathological significance of SOX4 expression in primary gallbladder carcinoma. Diagn Pathol. 2012; 7:41. doi: 10.1186/1746-1596-7-41.
  29. Andersen CL, Christensen LL, Thorsen K, Schepeler T, Sørensen FB, Verspaget HW, et al. Dysregulation of the transcription factors SOX4, CBFB and SMARCC1 correlates with outcome of colorectal cancer. Br J Cancer. 2009;100(3):511-23. doi: 10.1038/sj.bjc.6604884.
  30. Koumangoye RB, Andl T, Taubenslag KJ, Zilberman ST, Taylor CJ, Loomans HA, et al. SOX4 interacts with EZH2 and HDAC3 to suppress microRNA-31 in invasive esophageal cancer cells. Mol Cancer. 2015; 14:24. doi: 10.1186/s12943-014-0284-y.
  31. Vervoort SJ, de Jong OG, Roukens MG, Frederiks CL, Vermeulen JF, Lourenço AR, et al. Global transcriptional analysis identifies a novel role for SOX4 in tumor-induced angiogenesis. Elife. 2018;7: e27706. doi: 10.7554/eLife.27706.