Skip to main content

Advertisement

SpringerLink
Log in

Copper and zinc levels in plasma and cancerous tissues and their relation with expression of VEGF and HIF-1 in the pathogenesis of muscle invasive urothelial bladder cancer: a case-controlled clinical study

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

To evaluate Cu and Zn levels in bladder cancer (BC) patients and their relationship with expression of vascular endothelial growth factor (VEGF) and hypoxia-inducible factor 1 (HIF-1). Plasma levels of Cu and Zn were determined in 66 transitional bladder cell carcinoma patients (BC group) and 60 matched controls. The concentration of Cu and Zn as well as the expressions of both VEGF and HIF-1 were also estimated in cancerous and non-cancerous bladder tissues in the BC group. The results showed that plasma Cu and Cu/Zn ratio were significantly higher in BC group when compared with the control group. In contrast, the plasma Zn in BC group was significantly lower than in the controls. Comparing levels of Cu and Zn in cancerous and non-cancerous bladder tissues among the BC group indicated a significantly higher Cu levels in the cancerous tissues, while Zn levels was significantly lower. There were higher expressions of both VEGF and HIF-1 in the cancerous samples. Moreover, the Cu concentration in cancerous tissues was significantly correlated with expressions of VEGF and HIF-1. Logistic regression analysis revealed that the increase in plasma Cu/Zn ratio and plasma Cu and the decrease in plasma Zn may be risk factors for development of bladder cancer. We concluded that alteration of plasma and bladder tissue levels of both Cu and Zn is correlated with pathogenesis of bladder cancer. The increase in Cu level in cancerous tissues of BC group has an important role in angiogenesis in bladder cancer cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  • Abnet CC et al (2005) Zinc concentration in esophageal biopsy specimens measured by x-ray fluorescence and esophageal cancer risk. J Natl Cancer Inst 97:301–306

    Article  CAS  Google Scholar 

  • Baldewijns M et al (2007) High-grade clear cell renal cell carcinoma has a higher angiogenic activity than low-grade renal cell carcinoma based on histomorphological quantification and qRT–PCR mRNA expression profile. Br J Cancer 96:1888

    Article  CAS  Google Scholar 

  • Boehm T, O'Reilly MS, Keough K, Shiloach J, Shapiro R, Folkman J (1998) Zinc-binding of endostatin is essential for its antiangiogenic activity. Biochem Biophys Res Commun 252:190–194

    Article  CAS  Google Scholar 

  • Cervantes-Cervantes MP, Calderón-Salinas JV, Albores A, Muñoz-Sánchez JL (2005) Copper increases the damage to DNA and proteins caused by reactive oxygen species. Biol Trace Elem Res 103:229–248

    Article  CAS  Google Scholar 

  • Denoyer D, Masaldan S, La Fontaine S, Cater MA (2015) Targeting copper in cancer therapy:‘Copper That Cancer’. Metallomics 7:1459–1476

    Article  CAS  Google Scholar 

  • Dhawan D, Chadha VD (2010) Zinc: a promising agent in dietary chemoprevention of cancer. Indian J Med Res 132:676

    CAS  Google Scholar 

  • Fatfat M et al (2014) Copper chelation selectively kills colon cancer cells through redox cycling and generation of reactive oxygen species. BMC Cancer 14:527

    Article  Google Scholar 

  • Fedewa SA, Soliman AS, Ismail K, Hablas A, Seifeldin IA, Ramadan M, Omar HG, Nriagu J, Wilson ML (2009) Incidence analyses of bladder cancer in the Nile delta region of Egypt. Cancer Epidemiol 33:176–181

    Article  Google Scholar 

  • Golabek T, Darewicz B, Borawska M, Socha K, Markiewicz R, Kudelski J (2012) Copper, zinc, and cu/Zn ratio in transitional cell carcinoma of the bladder. Urol Int 89:342–347

    Article  CAS  Google Scholar 

  • Ho E (2004) Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem 15:572–578

    Article  CAS  Google Scholar 

  • Ionescu JG, Novotny J, Stejskal V, Laetsch A, Blaurock-Busch E, Eisenmann-Klein M (2006) Increased levels of transition metals in breast cancer tissue. Neuro Endocrinol Lett 27:36–39

    CAS  Google Scholar 

  • Ishida S, Andreux P, Poitry-Yamate C, Auwerx J, Hanahan D (2013) Bioavailable copper modulates oxidative phosphorylation and growth of tumors. Proc Natl Acad Sci 110:19507–19512

    Article  CAS  Google Scholar 

  • Kaiafa GD, Saouli Z, Diamantidis MD, Kontoninas Z, Voulgaridou V, Raptaki M, Arampatzi S, Chatzidimitriou M, Perifanis V (2012) Copper levels in patients with hematological malignancies. Euro J Intern Med 23:738–741

    Article  CAS  Google Scholar 

  • Kohzadi S, Sheikhesmaili F, Rahehagh R, Parhizkar B, Ghaderi E, Loqmani H, Shahmoradi B, Mohammadi E, Maleki A (2017) Evaluation of trace element concentration in cancerous and non-cancerous tissues of human stomach. Chemosphere 184:747–752

    Article  CAS  Google Scholar 

  • Lener MR et al (2016) Serum concentrations of selenium and copper in patients diagnosed with pancreatic cancer. Cancer Res Treat 48:1056

    Article  CAS  Google Scholar 

  • Letašiová S, Medveďová A, Šovčíková A, Dušinská M, Volkovová K, Mosoiu C, Bartonová A (2012) Bladder cancer, a review of the environmental risk factors environmental. Health 11:S11

    Google Scholar 

  • Li Q-f, Ding X-q, Kang YJ (2014a) Copper promotion of angiogenesis in isolated rat aortic ring: role of vascular endothelial growth factor. J Nutr Biochem 25:44–49

    Article  CAS  Google Scholar 

  • Li S, Wang M, Chen X, Li SF, Li-Ling J, Xie HQ (2014b) Inhibition of osteogenic differentiation of mesenchymal stem cells by copper supplementation. Cell Prolif 47:81–90

    Article  Google Scholar 

  • Lin C-N, Wang L-H, Shen K-H (2009) Determining urinary trace elements (cu, Zn, Pb, as, and se) in patients with bladder cancer. J Clin Lab Anal 23:192–195. https://doi.org/10.1002/jcla.20318

    Article  CAS  Google Scholar 

  • Majumder S, Chatterjee S, Pal S, Biswas J, Efferth T, Choudhuri SK (2009) The role of copper in drug-resistant murine and human tumors. Biometals 22:377

    Article  CAS  Google Scholar 

  • Majumder S, Dutta P, Choudhuri S (2005) The role of copper in development of drug resistance in murine carcinoma. Med Chem 1:563–573

    Article  CAS  Google Scholar 

  • Mazdak H, Yazdekhasti F, Movahedian A, Mirkheshti N, Shafieian M (2010) The comparative study of serum iron, copper, and zinc levels between bladder cancer patients and a control group. Int Urol Nephrol 42:89–93

    Article  CAS  Google Scholar 

  • Mortada W, Kenawy I, Abdel-Rhman M, El-Gamal G, Moalla S (2017) A new thiourea derivative [2-(3-ethylthioureido) benzoic acid] for cloud point extraction of some trace metals in water, biological and food samples. J Trace Elem Med Biol 44:266–273

    Article  CAS  Google Scholar 

  • Nardinocchi L et al (2010) Zinc downregulates HIF-1α and inhibits its activity in tumor cells in vitro and in vivo. PLoS One 5:e15048

    Article  CAS  Google Scholar 

  • Nasulewicz A, Mazur A, Opolski A (2004) Role of copper in tumour angiogenesis—clinical implications. J Trace Elem Med Biol 18:1–8

    Article  CAS  Google Scholar 

  • O'Dell BL, Sunde RA (1997) Handbook of nutritionally essential mineral elements. CRC Press, Boca Raton

    Book  Google Scholar 

  • Pan Q et al (2002) Copper deficiency induced by tetrathiomolybdate suppresses tumor growth and angiogenesis. Cancer Res 62:4854–4859

    CAS  Google Scholar 

  • Pan Z, Choi S, Ouadid-Ahidouch H, Yang J-M, Beattie JH, Korichneva I (2017) Zinc transporters and dysregulated channels in cancers. Front Biosci (Landmark Ed) 22:623

    Article  CAS  Google Scholar 

  • Prasad AS, Beck FW, Doerr TD, Shamsa FH, Penny HS, Marks SC, Kaplan J, Kucuk O, Mathog RH (1998) Nutritional and zinc status of head and neck cancer patients: an interpretive review. J Am Coll Nutr 17:409–418

    Article  CAS  Google Scholar 

  • Puca R et al (2011) Restoring p53 active conformation by zinc increases the response of mutant p53 tumor cells to anticancer drugs. Cell Cycle 10:1679–1689

    Article  CAS  Google Scholar 

  • Ranasinghe WK et al (2013) The role of hypoxia-inducible factor 1α in determining the properties of castrate-resistant prostate cancers. PLoS One 8:e54251

    Article  CAS  Google Scholar 

  • Rao K et al (2017) Protective effect of zinc preconditioning against renal ischemia reperfusion injury is dose dependent. PLoS One 12:e0180028

    Article  Google Scholar 

  • Roohani N, Hurrell R, Kelishadi R, Schulin R (2013) Zinc and its importance for human health: An integrative review. J Res Medl Sci 18:144

    Google Scholar 

  • Saghiri MA, Asatourian A, Orangi J, Sorenson CM, Sheibani N (2015) Functional role of inorganic trace elements in angiogenesis—part II: Cr, Si, Zn, Cu, and S. Crit Rev Oncol Hematol 96:143–155

    Article  Google Scholar 

  • Sheffer M, Simon AJ, Jacob-Hirsch J, Rechavi G, Domany E, Givol D, D’Orazi G (2011) Genome-wide analysis discloses reversal of the hypoxia-induced changes of gene expression in colon cancer cells by zinc supplementation. Oncotarget 2:1191

    Article  Google Scholar 

  • Shokeir A (2004) Squamous cell carcinoma of the bladder: pathology, diagnosis and treatment. BJU Int 93:216–220

    Article  CAS  Google Scholar 

  • Xie H, Kang YJ (2009) Role of copper in angiogenesis and its medicinal implications. Curr Med Chem 16:1304–1314

    Article  CAS  Google Scholar 

  • Zowczak M, Iskra M, Torliński L, Cofta S (2001) Analysis of serum copper and zinc concentrations in cancer patients. Biol Trace Elem Res 82:1

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We would like to thank Science & Technology development Fund in Egypt (STDF) for the financial support of this study.

Funding

This study was supported financially by the Science and Technology Development Fund (STDF), Egypt, Grant No 5236.

Author information

Authors and Affiliations

  1. Clinical Chemistry Laboratory, Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt

    Wael I. Mortada

  2. Center of Excellence for Genome and Cancer Research, Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt

    Amira Awadalla, Asmaa Ahmed, Eman T. Hamam & Ahmed A. Shokeir

  3. Pathology Laboratory, Urology and Nephrology Center, Mansoura University, Mansoura, 35516, Egypt

    Sherry Khater

  4. Unit of Genetic Engineering and Biotechnology, Faculty of Science, Mansoura University, Mansoura, 35516, Egypt

    Mustafa El-zayat

Authors
  1. Wael I. Mortada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Amira Awadalla
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Sherry Khater
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Asmaa Ahmed
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Eman T. Hamam
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Mustafa El-zayat
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ahmed A. Shokeir
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Wael I. Mortada.

Ethics declarations

Ethics approval and consent to participate

The Institutional Review Board (IRB) of Mansoura Urology and Nephrology Center approved the protocol of the study (Mansoura UNC IRB #RP-17.12.301).

Additional information

Responsible editor: Mohamed Abdel-Daim

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Mortada, W.I., Awadalla, A., Khater, S. et al. Copper and zinc levels in plasma and cancerous tissues and their relation with expression of VEGF and HIF-1 in the pathogenesis of muscle invasive urothelial bladder cancer: a case-controlled clinical study. Environ Sci Pollut Res 27, 15835–15841 (2020). https://doi.org/10.1007/s11356-020-08113-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-020-08113-8

Keywords

Search

Navigation