Biological Trace Element Research

, Volume 183, Issue 1, pp 32–39 | Cite as

sEcad and EGF Levels Increased in Urine of Non-ferrous Metal Workers and Medium of Uroepithelial Cell Line Treated by Arsenic

  • Jieyu Liu
  • Peiyu Jin
  • Shengnan Liu
  • Fei Wang
  • Xiaoyan Wang
  • Li Yang
  • Shuhua Xi


Inorganic arsenic (iAs) is a carcinogen and could increase the risks of bladder, lung, and skin cancer. Mining and smelting of non-ferrous metals are common occupational arsenic exposures. In this study, 125 individuals working in non-ferrous metal smelting plants were separated into two groups according to urinary total arsenic (TAs) levels: group 1, TAs < 100 μg/g Cr; group 2, TAs ≥ 100 μg/g Cr. Demographic characteristics of participants were obtained by questionnaire interview. Levels of E-cadherin soluble ectodomain fragment (sEcad) and epidermal growth factor (EGF) in workers urine were determined by ELISA test. We found that concentrations of sEcad and EGF present in urine were significantly elevated in the high urinary arsenic group 2 compared with the low urinary arsenic group 1. Urinary levels of the shedding of E-cadherin soluble ectodomain fragment (sEcad) and epidermal growth factor (EGF) were positively related to the concentrations of iAs in urine after adjusting for the confounding effects. A positive correlation between sEcad and EGF concentrations in urine was also observed. In order to verify the effects of iAs on sEcad and EGF, the human uroepithelial cell line (SV-HUC-1) was treated with NaAsO2 for 24 h in vitro. sEcad and EGF levels in the 4 μM NaAsO2-treated SV-HUC-1 cell medium significantly increased compared to the control group. In conclusion, urinary levels of sEcad and EGF increased in higher urinary arsenic workers of non-ferrous metal plants and are closely associated with urinary iAs concentration. The results suggested that sEcad and EGF may potentially be preclinical prognostic factors of bladder injury and early detection in arsenic exposure individuals.


Arsenic Non-ferrous metals sEcad EGF Uroepithelial cells 



This work was supported by the National Natural Science Foundation of China (NSFC) (81373023 and 81673207) and the Program for Liaoning Innovative Research Team in University (LT2015028).

Compliance with Ethical Standards

All participants provided informed consents before the questionnaire interview and then donated urine. The study was approved by the China Medical University Ethics Committee.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Charles E, Thomas DS, Dewey D, Davey M, Ngallaba SE, Konje E (2013) A cross-sectional survey on knowledge and perceptions of health risks associated with arsenic and mercury contamination from artisanal gold mining in Tanzania. BMC Public Health 13:74CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Wang QQ, Thomas DJ, Naranmandura H (2015) Importance of being thiomethylated: formation, fate, and effects of methylated thioarsenicals. Chem Res Toxicol 28:281–289CrossRefPubMedGoogle Scholar
  3. 3.
    Mohammed Abdul KS, Jayasinghe SS, Chandana EP, Chandana EP, Jayasumana C, De Silva PM (2015) Arsenic and human health effects: a review. Environ Toxicol Pharmacol 40:828–846CrossRefGoogle Scholar
  4. 4.
    Marchiset-Ferlay N, Savanovitch C, Sauvant-Rochat MP (2012) What is the best biomarker to assess arsenic exposure via drinking water? Environ Int 39:150–171CrossRefPubMedGoogle Scholar
  5. 5.
    IARC (International Agency for Research on Cancer) (2012) A review of human carcinogens: arsenic, metals, fibres, and dusts. Vol. 100c,Google Scholar
  6. 6.
    Chiou HY, Chiou ST, Hsu YH, Chou YL, Tseng CH, Wei ML, Chen CJ (2001) Incidence of transitional cell carcinoma and arsenic in drinking water: a follow-up study of 8,102 residents in an arseniasis-endemic area in northeastern Taiwan. Am J Epidemiol 153:411–418CrossRefPubMedGoogle Scholar
  7. 7.
    Smith AH, Goycolea M, Haque R, Biggs ML (1998) Marked increase in bladder and lung cancer mortality in a region of Northern Chile due to arsenic in drinking water. Am J Epidemiol 147:660–669CrossRefPubMedGoogle Scholar
  8. 8.
    Steinmaus C, Ferreccio C, Acevedo J, Yuan Y, Liaw J, Durán V et al (2014) Increased lung and bladder cancer incidence in adults after in utero and early-life arsenic exposure. Cancer Epidemiol Biomark Prev 23:1529–1538CrossRefGoogle Scholar
  9. 9.
    Steinmaus CM, Ferreccio C, Romo JA, Yuan Y, Cortes S, Marshall G et al (2013) Drinking water arsenic in northern Chile: high cancer risks 40 years after exposure cessation. Cancer Epidemiol Biomark Prev 22:623–630CrossRefGoogle Scholar
  10. 10.
    Semb H, Christofori G (1998) The tumor-suppressor function of E-cadherin. Am J Hum Genet 63:1588–1593CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Maretzky T, Reiss K, Ludwig A, Buchholz J, Scholz F, Proksch E et al (2005) ADAM10 mediates E-cadherin shedding and regulates epithelial cell–cell adhesion, migration, and beta-catenin translocation. Proc Natl Acad Sci U S A 102:9182–9187CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Brouxhon SM, Kyrkanides S, Teng X, Athar M, Ghazizadeh S, Simon M et al (2014) Soluble E-cadherin: a critical oncogene modulating receptor tyrosine kinases, MAPK and PI3K/Akt/mTOR signaling. Oncogene 33:225–235CrossRefPubMedGoogle Scholar
  13. 13.
    Charalabopoulos K, Gogali A, Dalavaga Y, Daskalopoulos G, Vassiliou M, Bablekos G et al (2006) The clinical significance of soluble E-cadherin in nonsmall cell lung cancer. Exp Oncol 28:83–85PubMedGoogle Scholar
  14. 14.
    Salama RH, Selem TH, El-Gammal M, Elhagagy AE, Bakar SM (2013) Urinary tumor markers could predict survival in bladder carcinoma. Indian J Clin Biochem 28:265–271CrossRefPubMedGoogle Scholar
  15. 15.
    Shi B, Laudon V, Yu S, Dong D, Zhu Y, Xu Z (2008) E-cadherin tissue expression and urinary soluble forms of E-cadherin in patients with bladder transitional cell carcinoma. Urol Int 81:320–324CrossRefPubMedGoogle Scholar
  16. 16.
    Brouxhon SM, Kyrkanides S, Teng X, O’Banion MK, Clarke R, Byers S et al (2014) Soluble-E-cadherin activates HER and IAP family members in HER2+ and TNBC human breast cancers. Mol Carcinog 53:893–906CrossRefPubMedGoogle Scholar
  17. 17.
    Najy AJ, Day KC, Day ML (2008) The ectodomain shedding of E-cadherin by ADAM15 supports ErbB receptor activation. J Biol Chem 283:18393–18401CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Inge LJ, Barwe SP, D’Ambrosio J, Gopal J, Lu K, Ryazantsev S et al (2011) Soluble E-cadherin promotes cell survival by activating epidermal growth factor receptor. Exp Cell Res 317:838–848CrossRefPubMedGoogle Scholar
  19. 19.
    Kari C, Chan TO, Rocha de Quadros M, Rodeck U (2003) Targeting the epidermal growth factor receptor in cancer: apoptosis takes center stage. Cancer Res 63:1–5PubMedGoogle Scholar
  20. 20.
    Eblin KE, Bredfeldt TG, Buffington S, Gandolfi AJ (2007) Mitogenic signal transduction caused by monomethylarsonous acid in human bladder cells: role in arsenic-induced carcinogenesis. Toxicol Sci 95:321–330CrossRefPubMedGoogle Scholar
  21. 21.
    Simeonova PP, Wang S, Hulderman T, Luster MI (2002) c-Src dependent activation of the epidermal growth factor receptor and mitogenactivated protein kinase pathway by arsenic. Role in carcinogenesis. J Biol Chem 277:2945–2950CrossRefPubMedGoogle Scholar
  22. 22.
    Grivas PD, Day M, Hussain M (2011) Urothelial carcinomas: a focus on human epidermal receptors signaling. Am J Transl Res 3:362–373PubMedPubMedCentralGoogle Scholar
  23. 23.
    Cheng JC, Klausen C, Leung PC (2010) Hydrogen peroxide mediates EGF-induced down-regulation of E-cadherin expression via p38 MAPK and snail in human ovarian cancer cells. Mol Endocrinol 24:1569–1580CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Cheng JC, Qiu X, Chang HM, Leung PC (2013) HER2 mediates epidermal growth factor-induced down-regulation of E-cadherin in human ovarian cancer cells. Biochem Biophys Res Commun 434:81–86CrossRefPubMedGoogle Scholar
  25. 25.
    Hu QP, Kuang JY, Yang QK, Bian XW, Yu SC (2016) Beyond a tumor suppressor: soluble E-cadherin promotes the progression of cancer. Int J Cancer 138:2804–2812CrossRefPubMedGoogle Scholar
  26. 26.
    Brouxhon SM, Kyrkanides S, Raja V, Silberfeld A, Teng X, Trochesset D et al (2014) Ectodomain-specific E-cadherin antibody suppresses skin SCC growth and reduces tumor grade: a multitargeted therapy modulating RTKs and the PTEN–p53–MDM2 Axis. Mol Cancer Ther 13:1791–1802CrossRefPubMedGoogle Scholar
  27. 27.
    De Wever O, Derycke L, Hendrix A, De Meerleer G, Godeau F, Depypere H et al (2007) Soluble cadherins as cancer biomarkers. Clin Exp Metastasis 24:685–697CrossRefPubMedGoogle Scholar
  28. 28.
    Sewpaul A, French JJ, Khoo TK, Kernohan M, Kirby JA, Charnley RM (2009) Soluble E-cadherin: an early marker of severity in acute pancreatitis. HPB Surg 397375Google Scholar
  29. 29.
    Liu S, Sun Q, Wang F, Zhang L, Song Y, Xi S et al (2014) Arsenic induced overexpression of inflammatory cytokines based on the human urothelial cell model in vitro and urinary secretion of individuals chronically exposed to arsenic. Chem Res Toxicol 27:1934–1942CrossRefPubMedGoogle Scholar
  30. 30.
    Sun G, Xu Y, Li X, Jin Y, Li B, Sun X (2007) Urinary arsenic metabolites in children and adults exposed to arsenic in drinking water in Inner Mongolia, China. Environ Health Perspect 115:648–652CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Hayashido Y, Hamana T, Yoshioka Y, Kitano H, Koizumi K, Okamoto T (2005) Plasminogen activator/plasmin system suppresses cell-cell adhesion of oral squamous cell carcinoma cells via proteolysis of E-cadherin. Int J Oncol 27:693–698PubMedGoogle Scholar
  32. 32.
    Shariat SF, Matsumoto K, Casella R, Jian W, Lerner SP (2005) Urinary levels of soluble E-cadherin in the detection of transitional cell carcinoma of the urinary bladder. Eur Urol 48:69–76CrossRefPubMedGoogle Scholar
  33. 33.
    Symowicz J, Adley BP, Gleason KJ, Johnson JJ, Ghosh S, Fishman DA et al (2007) Engagement of collagen-binding integrins promotes matrix metalloproteinase-9-dependent E-cadherin ectodomain shedding in ovarian carcinoma cells. Cancer Res 67:2030–2039CrossRefPubMedGoogle Scholar
  34. 34.
    Achanzar WE, Moyer CF, Marthaler LT, Gullo R, Chen SJ, French MH et al (2007) Urine acidification has no effect on peroxisome proliferator-activated receptor (PPAR) signaling or epidermal growth factor (EGF) expression in rat urinary bladder urothelium. Toxicol Appl Pharmacol 223:246–256CrossRefPubMedGoogle Scholar
  35. 35.
    Izumi K, Zheng Y, Li Y, Zaengle J, Miyamoto H (2012) Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor. Int J Oncol 41:1587–1592CrossRefPubMedPubMedCentralGoogle Scholar
  36. 36.
    Grabowska MM, Sandhu B, Day ML (2012) EGF promotes the shedding of soluble E-cadherin in an ADAM10-dependent manner in prostate epithelial cells. Cell Signal 24:532–538CrossRefPubMedGoogle Scholar
  37. 37.
    Melak D, Ferreccio C, Kalman D, Parra R, Acevedo J, Pérez L et al (2014) Arsenic methylation and lung and bladder cancer in a case control study in northern Chile. Toxicol Appl Pharmacol 274:225–231CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  1. 1.Department of Environmental and Occupational Health, Liaoning Provincial Key Laboratory of Arsenic Biological Effect and Poisoning, School of Public HealthChina Medical UniversityShenyangPeople’s Republic of China

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