Generic placeholder image

Current Pharmaceutical Biotechnology


ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Evaluation of Changes in the Expression Pattern of EDIL3 in Different Grades of Endometrial Cancer

Author(s): Marcin Oplawski*, Konrad Dziobek, Nikola Zmarzły, Beniamin Grabarek, Barbara Tomala, Ewa Leśniak, Iwona Adwent, Piotr Januszyk, Dariusz Dąbruś and Dariusz Boroń

Volume 20, Issue 6, 2019

Page: [483 - 488] Pages: 6

DOI: 10.2174/1389201020666190408112822

open access plus


Background: EDIL3 is an extracellular matrix protein that plays a key role in angiogenesis. Changes in the pattern of its expression also affect cellular processes and the tumor microenvironment. Elevated level of EDIL3 is considered an unfavorable prognostic marker of survival.

Objective: The aim of this study was to evaluate the changes in EDIL3 expression in endometrial cancer at various degrees of its differentiation (G1-G3) and to discuss its potential role as a molecular diagnostic marker and therapeutic target.

Methods: The study group consisted of 45 patients with endometrial cancer: G1, 17; G2, 15; G3, 13. The control group (C) included 15 patients without neoplastic changes. The expression of EDIL3 was assessed using immunohistochemistry. Statistical analysis was performed using the Statistica 12 PL software (p<0.05).

Results: Analysis of EDIL3 expression showed that the average optical density of the reaction product in G1 reached 130% of the control, while the values in G2 and G3 were 153% and 158%, respectively. Regardless of the endometrial cancer grade, an increase in EDIL3 level was observed compared to the control.

Conclusion: In our study, we demonstrated overexpression of EDIL3 protein in endometrial cancer. Differences in expression between degrees of tumor differentiation suggest the potential of using changes in EDIL3 level as a new complementary diagnostic marker and target for anti-angiogenic therapy.

Keywords: EDIL3, endometrial cancer, complementary diagnostic marker, immunohistochemistry, personalized medicine, epithelial-mesenchymal transition, TGFβs.

Graphical Abstract
Hynes, R.O. The extracellular matrix, not just pretty fibrils. Science, 2009, 326(5957), 1216-1219.
Ma, M.Z.; Zhuang, C.; Yang, X.M.; Zhang, Z.Z.; Ma, H.; Zhang, W.M.; You, H.; Qin, W.; Gu, J.; Yang, S.; Cao, H.; Zhang, Z.G. CTHRC acts as a prognostic factor and promotes invasiveness of gastrointestinal stromal tumors by activating Wnt/PCP-Rho signaling. Neoplasia, 2014, 16(3), 265-278.
Ye, Q.H.; Qin, L.X.; Forgues, M.; He, P.; Kim, J.W.; Peng, A.C.; Simon, R.; Li, Y.; Robles, A.I.; Chen, Y.; Ma, Z.C.; Wu, Z.Q.; Ye, S.L.; Liu, Y.K.; Tang, Z.Y.; Wang, X.W. Predicting hepatitis B virus-positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning. Nat. Med., 2003, 9(4), 416-423.
Bergamini, C.; Sgarra, C.; Trerotoli, P.; Lupo, L.; Azzariti, A.; Antonaci, S.; Giannelli, G. Laminin-5 stimulates hepatocellular carcinoma growth through a different function of alpha6beta4 and alpha3beta1 integrins. Hepatology, 2007, 46(6), 1801-1809.
Li, H.; Ge, C.; Zhao, F.; Yan, M.; Hu, C.; Jia, D.; Tian, H.; Zhu, M.; Chen, T.; Jiang, G.; Xie, H.; Cui, Y.; Gu, J.; Tu, H.; He, X.; Yao, M.; Liu, Y.; Li, J. Hypoxia-inducible factor 1 alpha-activated angiopoietin-like protein 4 contributes to tumor metastasis via vascular cell adhesion molecule-1/integrin β1 signaling in human hepatocellular carcinoma. Hepatology, 2011, 54(3), 910-919.
Muir, A.; Danai, L.V.; Vander Heiden, M.G. Microenvironmental regulation of cancer cell metabolism, implications for experimental design and translational studies. Dis. Model Mech., 2018, 11(8) , pii, dmm035758.
Camussi, G.; Deregibus, M.C.; Bruno, S.; Cantaluppi, V.; Biancone, L. Exosomes/microvesicles as a mechanism of cell-to-cell communication. Kidney Int., 2010, 78(9), 838-848.
Hidai, C.; Zupancic, T.; Penta, K.; Mikhail, A.; Kawana, M.; Quertermous, E.E.; Aoka, Y.; Fukagawa, M.; Matsui, Y.; Platika, D.; Auerbach, R.; Hogan, B.L.; Snodgrass, R.; Quertermous, T. Cloning and characterization of developmental endothelial locus-1, an embryonic endothelial cell protein that binds the alphavbeta3 integrin receptor. Genes Dev., 1998, 12(1), 21-33.
Zhong, J.; Eliceiri, B.; Stupack, D.; Penta, K.; Sakamoto, G.; Quertermous, T.; Coleman, M.; Boudreau, N.; Varner, J.A. Neovascularization of ischemic tissues by gene delivery of the extracellular matrix protein Del-1. J. Clin. Invest., 2003, 112(1), 30-41.
Ho, H.K.; Jang, J.J.; Kaji, S.; Spektor, G.; Fong, A.; Yang, P.; Hu, B.S.; Schatzman, R.; Quertermous, T.; Cooke, J.P. Developmental endothelial locus-1 (Del-1), a novel angiogenic protein, its role in ischemia. Circulation, 2004, 109(10), 1314-1319.
Choi, E.Y.; Chavakis, E.; Czabanka, M.A.; Langer, H.F.; Fraemohs, L.; Economopoulou, M.; Kundu, R.K.; Orlandi, A.; Zheng, Y.Y.; Prieto, D.A.; Ballantyne, C.M.; Constant, S.L.; Aird, W.C.; Papayannopoulou, T.; Gahmberg, C.G.; Udey, M.C.; Vajkoczy, P.; Quertermous, T.; Dimmeler, S.; Weber, C.; Chavakis, T. Del-1, an endogenous leukocyte-endothelial adhesion inhibitor, limits inflammatory cell recruitment. Science, 2008, 322(5904), 1101-1104.
Sun, J.C.; Liang, X.T.; Pan, K.; Wang, H.; Zhao, J.J.; Li, J.J.; Ma, H.Q.; Chen, Y.B.; Xia, J.C. High expression level of EDIL3 in HCC predicts poor prognosis of HCC patients. World J. Gastroenterol., 2010, 16(36), 4611-4615.
Luo, J.H.; Ren, B.; Keryanov, S.; Tseng, G.C.; Rao, U.N.; Monga, S.P.; Strom, S.; Demetris, A.J.; Nalesnik, M.; Yu, Y.P. Ranganathan, S.; Michalopoulos, G.K. Transcriptomic and genomic analysis of human hepatocellular carcinomas and hepatoblastomas. Hepatology, 2006, 44(4), 1012-1024.
Damhofer, H.; Medema, J.P.; Veenstra, V.L.; Badea, L.; Popescu, I.; Roelink, H.; Bijlsma, M.F. Assessment of the stromal contribution to Sonic Hedgehog-dependent pancreatic adenocarcinoma. Mol. Oncol., 2013, 7(6), 1031-1042.
Watanabe, T.; Kobunai, T.; Yamamoto, Y.; Ikeuchi, H.; Matsuda, K.; Ishihara, S.; Nozawa, K.; Iinuma, H.; Kanazawa, T.; Tanaka, T.; Yokoyama, T.; Konishi, T.; Eshima, K.; Ajioka, Y.; Hibi, T.; Watanabe, M.; Muto, T.; Nagawa, H. Predicting ulcerative colitis-associated colorectal cancer using reverse-transcription polymerase chain reaction analysis. Clin. Colorectal Cancer, 2011, 10(2), 134-141.
Beckham, C.J.; Olsen, J.; Yin, P.N.; Wu, C.H.; Ting, H.J.; Hagen, F.K.; Scosyrev, E.; Messing, E.M.; Lee, Y.F. Bladder cancer exosomes contain EDIL-3/Del1 and facilitate cancer progression. J. Urol., 2014, 192(2), 583-592.
Lee, J.E.; Moon, P.G.; Cho, Y.E.; Kim, Y.B.; Kim, I.S.; Park, H.; Baek, M.C. Identification of EDIL3 on extracellular vesicles involved in breast cancer cell invasion. J. Proteomics, 2016, 131, 17-28.
Jeong, D.; Ban, S.; Oh, S.; Jin Lee, S. Yong Park, S.; Koh, Y.W. Prognostic significance of EDIL3 expression and correlation with mesenchymal phenotype and microvessel density in lung adenocarcinoma. Sci. Rep., 2017, 7(1), 8649.
Yang, Z.F.; Poon, R.T. Vascular changes in hepatocellular carcinoma. Anat. Rec. (Hoboken), 2008, 291(6), 721-734.
Pang, R.; Poon, R.T. Angiogenesis and antiangiogenic therapy in hepatocellular carcinoma. Cancer Lett., 2006, 242(2), 151-167.
Niu, J.X.; Zhang, W.J.; Ye, L.Y.; Wu, L.Q.; Zhu, G.J.; Yang, Z.H.; Grau, G.E.; Lou, J.N. 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), 517-527.
Wang, Z.; Longaker, M.T.; Yang, G.P. Anti-apoptotic effects of the angiogenic factor Del1 on endothelial cells. J. Surg. Res., 2006, 130, 237.
Helpman, L.; Kupets, R.; Covens, A.; Saad, R.S.; Khalifa, M.A.; Ismiil, N.; Ghorab, Z.; Dubé, V.; Nofech-Mozes, S. Assessment of endometrial sampling as a predictor of final surgical pathology in endometrial cancer. Br. J. Cancer, 2014, 110(3), 609-615.
Greenwald, Z.R.; El-Zein, M.; Bouten, S.; Ensha, H.; Vazquez, F.L.; Franco, E.L. Mobile screening units for the early detection of cancer, a systematic review. Cancer Epidemiol. Biomarkers Prev., 2017, 26(12), 1679-1694.
Heitzer, E.; Perakis, S.; Geigl, J.B.; Speicher, M.R. The potential of liquid biopsies for the early detection of cancer. NPJ Precis. Oncol., 2017, 1(1), 36.
Wulfkuhle, J.D.; Liotta, L.A.; Petricoin, E.F. Proteomic applications for the early detection of cancer. Nat. Rev. Cancer, 2003, 3(4), 267-275.
Coultas, L.; Chawengsaksophak, K.; Rossant, J. Endothelial cells and VEGF in vascular development. Nature, 2005, 438(7070), 937-945.
Opławski, M.; Michalski, M.; Witek, A.; Michalski, B.; Zmarzły, N.; Jęda-Golonka, A.; Styblińska, M.; Gola, J.; Kasprzyk-Żyszczyńska, M.; Mazurek, U.; Plewka, A. Identification of a gene expression profile associated with the regulation of angiogenesis in endometrial cancer. Mol. Med. Rep., 2017, 16(3), 2547-2555.
Xia, H.; Jianxiang, C.; Shi, M.; Gao, H.; Karthik, S.; Pratap, S.V.; Ooi, L.L.; Hui, K.M. EDIL3 is a novel regulator of epithelial mesenchymal transition controlling early recurrence of hepatocellular carcinoma. J. Hepatol., 2015, 63(4), 863-873.
Grenda, A.; Budzyński, M.; Filip, A. Biogeneza cząsteczek mikrona oraz ich znaczenie w powstawaniu i przebiegu wybranych zaburzeń hematologicznych. Postepy Hig. Med. Dosw.(online)., 2013, 67, 174-185.
Betel, D.; Wilson, M.; Gabow, A.; Marks, D.S.; Sander, C. The resource, targets and expression. Nucleic Acids Res., 2008, 36(Database issue), D149-D153.
Cobb, L.P.; Siamakpour-Reihani, S.; Zhang, D.; Owzar, K.; Berchuck, A.; Bae-Jump, V.L.; Secord, A.A. Obesity is associated with altered angiogenic gene expression in endometrioid endometrial cancer. Gynecol. Oncol., 2018, 149(1), 177-178.
Szymkowiak, J. Otyłość jako rodzaj przewlekłego zapalenia. Wszechświat, 2011, 112(10), 264-272.
Lopes-Bastos, B.M.; Jiang, W.G.; Cai, J. Tumour-endothelial cell communications, important and indispensable mediators of tumour angiogenesis. Anticancer Res., 2016, 36(3), 1119-1126.
Zhang, R. Wei; Y.H., Zhao, C.Y.; Song, H.Y.; Shen, N.; Cui, X.; Gao, X.; Qi, Z.T.; Zhong, M.; Shen, W. EDIL3 depletion suppress epithelial-mesenchymal transition of lens epithelial cells via transforming growth factor β pathway. Int. J. Ophthalmol., 2018, 11(1), 18-24.
Vouk, K.; Smuc, T.; Guggenberger, C.; Ribič-Pucelj, M.; Sinkovec, J.; Husen, B.; Thole, H.; Houba, P.; Thaete, C.; Adamski, J.; Rižner, T.L. Novel estrogen-related genes and potential biomarkers of ovarian endometriosis identified by differential expression analysis. J. Steroid Biochem. Mol. Biol., 2011, 125(3-5), 231-224.
Jiang, S.H.; Wang, Y.; Yang, J.Y.; Li, J.; Feng, M.X.; Wang, Y.H.; Yang, X.M.; He, P.; Tian, G.A.; Zhang, X.X.; Li, Q.; Cao, X.Y.; Huo, Y.M.; Yang, M.W.; Fu, X.L.; Li, J.; Liu, D.J.; Dai, M.; Wen, S.Y.; Gu, J.R.; Hong, J.; Hua, R.; Zhang, Z.G. Sun. Y.W. Overexpressed EDIL3 predicts poor prognosis and promotes anchorage-independent tumor growth in human pancreatic cancer. Oncotarget, 2016, 7(4), 4226-4240.
Jones, G.N.; Rooney, C.; Griffin, N.; Roudier, M.; Young, L.A.; Garcia-Trinidad, A.; Hughes, G.D.; Whiteaker, J.R.; Wilson, Z.; Odedra, R.; Zhao, L.; Ivey, R.G.; Howat, W.J.; Harrington, E.A.; Barrett, J.C.; Ramos-Montoya, A.; Lau, A.; Paulovich, A.G.; Cadogan, E.B.; Pierce, A.J. pRAD50, a novel and clinically applicable pharmacodynamic biomarker of both ATM and ATR inhibition identified using mass spectrometry and immunohistochemistry. Br. J. Cancer, 2018, 119(10), 1233-1243.
Seuma, J.; Bunch, J.; Cox, A.; McLeod, C.; Bell, J.; Murray, C. Combination of immunohistochemistry and laser ablation ICP mass spectrometry for imaging of cancer biomarkers. Proteomics, 2008, 8(18), 3775-3784.
Schwamborn, K.; Caprioli, R.M. Molecular imaging by mass spectrometry-looking beyond classical histology. Nat. Rev. Cancer, 2010, 10(9), 639-646.
Kaweewong, K.; Garnjanagoonchorn, W.; Jirapakkul, W.; Roytrakul, S. Solubilization and identification of hen eggshell membrane proteins during different times of chicken embryo development using the proteomic approach. Protein J., 2013, 32(4), 297-308.
Stamer, W.D.; Hoffman, E.A. Luthe,r J.M.; Hache,y D.L.; Schey, K.L. Protein profile of exosomes from trabecular meshwork cells. J. Proteomics, 2011, 74(6), 796-804.
Netea, M.G.; Balkwill, F.; Chonchol, M.; Cominelli, F.; Donath, M.Y.; Giamarellos-Bourboulis, E.J.; Golenbock, D.; Gresnigt, M.S.; Heneka, M.T.; Hoffman, H.M.; Hotchkiss, R.; Joosten, L.A.B.; Kastner, D.L.; Korte, M.; Latz, E.; Libby, P.; Mandrup-Poulsen, T.; Mantovani, A.; Mills, K.H.G.; Nowak, K.L.; O’Neill, L.A.; Pickkers, P.; van der Poll, T.; Ridker, P.M.; Schalkwijk, J.; Schwartz, D.A.; Siegmund, B.; Steer, C.J.; Tilg, H.; van der Meer, J.W.M.; van de Veerdonk, F.L.; Dinarello, C.A. A guiding map for inflammation. Nat. Immunol., 2017, 18(8), 826-831.
Yin, X.H.; Shi, M.; Wu, H.; Zhou, L.; Xu, B. Role of HAND2 gene and protein expression in endometrial carcinoma. Eur. J. Gynaecol. Oncol., 2017, 38(1), 95-101.
Opławski, M.; Dziobek, K.; Adwent, I.; Dąbruś, D.; Grabarek, B.; Zmarzły, N.; Plewka, A.; Boroń, D. Expression profile of endoglin in different grades of endometrial cancer. Curr. Pharm. Biotechnol., 2018, 19(12), 990-995.
Opławski, M.; Dziobek, K.; Grabarek, B.; Zmarzły, N.; Dąbruś, D.; Januszyk, P.; Brus, R.; Tomala, B.; Boroń, D. Expression of NRP-1 and NRP-2 in Endometrial Cancer. Curr. Pharm. Biotechnol., 2018, 20, 1-7.

© 2022 Bentham Science Publishers | Privacy Policy