Skip to main content
British Journal of Cancer logoLink to British Journal of Cancer
. 2000 Feb 21;82(6):1198–1203. doi: 10.1054/bjoc.1999.1063

Correlation of metallothionein expression with apoptosis in nasopharyngeal carcinoma

A Jayasurya 1, B H Bay 1, W M Yap 2, N G Tan 3
PMCID: PMC2363356  PMID: 10735506

Abstract

The expression of metallothionein (MT), an intracellular ubiquitous low molecular weight protein thiol with antioxidant properties, was studied in nasopharyngeal cancer (NPC) and correlated with the apoptotic index. Immunohistochemical staining of randomly selected, formalin-fixed and paraffin-embedded normal and malignant nasopharyngeal tissues were analysed for the expression of MT using the commercially available E9 antibody directed against MT I and MT II isoforms. The corresponding apoptosis labelling indices were evaluated by the TUNEL method. Localization of MT at the ultrastructural level was studied by immunogold labelling. All the tumour sections (17 specimens) showed MT-immunopositivity. A direct correlation between the percentage of MT-positive cells and the staining intensity was noted (P< 0.001; Pearson's r = 0.95). There was absence of cytoplasmic staining and only nuclear staining (with localization in the nucleoplasm) was demonstrated in the tumour cells. In normal epithelium of the nasopharynx, the basal layer was stained. An inverse relationship was observed between the level of MT expression and the apoptotic index in the NPC tissues (P = 0.0059; Pearson's r = –0.6380). The results suggest that overexpression of MT in NPC may protect the tumour cells from entering into the apoptotic process and thereby contribute to tumour expansion. Preferential localization of MT in the nuclei of NPC cells may possibly enhance radioresistance since radiotherapy is known to eradicate tumour cells by free radical-induced apoptosis. © 2000 Cancer Research Campaign

Keywords: nasopharyngeal cancer, metallothionein immunohistochemistry, nuclear localization, apoptosis, ultrastructure

Full Text

The Full Text of this article is available as a PDF (309.4 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Aoki Y., Suzuki K. T. Detection of metallothionein by western blotting. Methods Enzymol. 1991;205:108–114. doi: 10.1016/0076-6879(91)05092-a. [DOI] [PubMed] [Google Scholar]
  2. Bahnson R. R., Banner B. F., Ernstoff M. S., Lazo J. S., Cherian M. G., Banerjee D., Chin J. L. Immunohistochemical localization of metallothionein in transitional cell carcinoma of the bladder. J Urol. 1991 Dec;146(6):1518–1520. doi: 10.1016/s0022-5347(17)38155-7. [DOI] [PubMed] [Google Scholar]
  3. Bailet J. W., Mark R. J., Abemayor E., Lee S. P., Tran L. M., Juillard G., Ward P. H. Nasopharyngeal carcinoma: treatment results with primary radiation therapy. Laryngoscope. 1992 Sep;102(9):965–972. doi: 10.1288/00005537-199209000-00002. [DOI] [PubMed] [Google Scholar]
  4. Bay B. H., Chan Y. G., Yick T. Y., Leong H. K. Electron microscopic observations and X-ray microanalysis of a multinucleated giant cell. J Electron Microsc (Tokyo) 1998;47(4):359–361. doi: 10.1093/oxfordjournals.jmicro.a023604. [DOI] [PubMed] [Google Scholar]
  5. Briehl M. M., Baker A. F. Modulation of the antioxidant defence as a factor in apoptosis. Cell Death Differ. 1996 Jan;3(1):63–70. [PubMed] [Google Scholar]
  6. Buttke T. M., Sandstrom P. A. Oxidative stress as a mediator of apoptosis. Immunol Today. 1994 Jan;15(1):7–10. doi: 10.1016/0167-5699(94)90018-3. [DOI] [PubMed] [Google Scholar]
  7. Cai L., Wang G. J., Xu Z. L., Deng D. X., Chakrabarti S., Cherian M. G. Metallothionein and apoptosis in primary human hepatocellular carcinoma (HCC) from northern China. Anticancer Res. 1998 Nov-Dec;18(6B):4667–4672. [PubMed] [Google Scholar]
  8. Cherian M. G., Howell S. B., Imura N., Klaassen C. D., Koropatnick J., Lazo J. S., Waalkes M. P. Role of metallothionein in carcinogenesis. Toxicol Appl Pharmacol. 1994 May;126(1):1–5. doi: 10.1006/taap.1994.1083. [DOI] [PubMed] [Google Scholar]
  9. Germain I., Têtu B., Brisson J., Mondor M., Cherian M. G. Markers of chemoresistance in ovarian carcinomas: an immunohistochemical study of 86 cases. Int J Gynecol Pathol. 1996 Jan;15(1):54–62. doi: 10.1097/00004347-199601000-00009. [DOI] [PubMed] [Google Scholar]
  10. Jin R., Bay B., Tan P., Tan B. K. Metallothionein expression and zinc levels in invasive ductal breast carcinoma. Oncol Rep. 1999 Jul-Aug;6(4):871–875. doi: 10.3892/or.6.4.871. [DOI] [PubMed] [Google Scholar]
  11. Kelley S. L., Basu A., Teicher B. A., Hacker M. P., Hamer D. H., Lazo J. S. Overexpression of metallothionein confers resistance to anticancer drugs. Science. 1988 Sep 30;241(4874):1813–1815. doi: 10.1126/science.3175622. [DOI] [PubMed] [Google Scholar]
  12. Kontozoglou T. E., Banerjee D., Cherian M. G. Immunohistochemical localization of metallothionein in human testicular embryonal carcinoma cells. Virchows Arch A Pathol Anat Histopathol. 1989;415(6):545–549. doi: 10.1007/BF00718648. [DOI] [PubMed] [Google Scholar]
  13. Kouvidou C., Stefanaki K., Dai Y., Tzardi M., Koutsoubi K., Darivianaki K., Karidi E., Rontogianni D., Zois E., Kakolyris S. P21/waf1 protein expression in nasopharyngeal carcinoma. Comparative study with PCNA, p53 and MDM-2 protein expression. Anticancer Res. 1997 Jul-Aug;17(4A):2615–2619. [PubMed] [Google Scholar]
  14. Kuo S. M., Kondo Y., DeFilippo J. M., Ernstoff M. S., Bahnson R. R., Lazo J. S. Subcellular localization of metallothionein IIA in human bladder tumor cells using a novel epitope-specific antiserum. Toxicol Appl Pharmacol. 1994 Mar;125(1):104–110. doi: 10.1006/taap.1994.1054. [DOI] [PubMed] [Google Scholar]
  15. Kägi J. H., Schäffer A. Biochemistry of metallothionein. Biochemistry. 1988 Nov 15;27(23):8509–8515. doi: 10.1021/bi00423a001. [DOI] [PubMed] [Google Scholar]
  16. Lazo J. S., Pitt B. R. Metallothioneins and cell death by anticancer drugs. Annu Rev Pharmacol Toxicol. 1995;35:635–653. doi: 10.1146/annurev.pa.35.040195.003223. [DOI] [PubMed] [Google Scholar]
  17. Lo K. W., Mok C. H., Huang D. P., Liu Y. X., Choi P. H., Lee J. C., Tsao S. W. p53 mutation in human nasopharyngeal carcinomas. Anticancer Res. 1992 Nov-Dec;12(6B):1957–1963. [PubMed] [Google Scholar]
  18. McCormick C. C., Lin L. Y. Quantification and identification of metallothioneins by gel electrophoresis and silver staining. Methods Enzymol. 1991;205:71–78. doi: 10.1016/0076-6879(91)05087-c. [DOI] [PubMed] [Google Scholar]
  19. Meyn R. E., Stephens L. C., Milas L. Programmed cell death and radioresistance. Cancer Metastasis Rev. 1996 Mar;15(1):119–131. doi: 10.1007/BF00049491. [DOI] [PubMed] [Google Scholar]
  20. Oh Y., Mao L. Biomarkers in head and neck carcinoma. Curr Opin Oncol. 1997 May;9(3):247–256. doi: 10.1097/00001622-199709030-00006. [DOI] [PubMed] [Google Scholar]
  21. Roychowdhury D. F., Tseng A., Jr, Fu K. K., Weinburg V., Weidner N. New prognostic factors in nasopharyngeal carcinoma. Tumor angiogenesis and C-erbB2 expression. Cancer. 1996 Apr 15;77(8):1419–1426. doi: 10.1002/(SICI)1097-0142(19960415)77:8<1419::AID-CNCR1>3.0.CO;2-7. [DOI] [PubMed] [Google Scholar]
  22. Schmid K. W., Ellis I. O., Gee J. M., Darke B. M., Lees W. E., Kay J., Cryer A., Stark J. M., Hittmair A., Ofner D. Presence and possible significance of immunocytochemically demonstrable metallothionein over-expression in primary invasive ductal carcinoma of the breast. Virchows Arch A Pathol Anat Histopathol. 1993;422(2):153–159. doi: 10.1007/BF01607167. [DOI] [PubMed] [Google Scholar]
  23. Shanmugaratnam K., Chan S. H., de-Thé G., Goh J. E., Khor T. H., Simons M. J., Tye C. Y. Histopathology of nasopharyngeal carcinoma: correlations with epidemiology, survival rates and other biological characteristics. Cancer. 1979 Sep;44(3):1029–1044. doi: 10.1002/1097-0142(197909)44:3<1029::aid-cncr2820440335>3.0.co;2-5. [DOI] [PubMed] [Google Scholar]
  24. Sundelin K., Jadner M., Norberg-Spaak L., Davidsson A., Hellquist H. B. Metallothionein and Fas (CD95) are expressed in squamous cell carcinoma of the tongue. Eur J Cancer. 1997 Oct;33(11):1860–1864. doi: 10.1016/s0959-8049(97)00216-5. [DOI] [PubMed] [Google Scholar]
  25. Tan Y., Sinniah R., Bay B. H., Singh G. Metallothionein expression and nuclear size in benign, borderline, and malignant serous ovarian tumours. J Pathol. 1999 Sep;189(1):60–65. doi: 10.1002/(SICI)1096-9896(199909)189:1<60::AID-PATH387>3.0.CO;2-J. [DOI] [PubMed] [Google Scholar]
  26. Woo E. S., Kondo Y., Watkins S. C., Hoyt D. G., Lazo J. S. Nucleophilic distribution of metallothionein in human tumor cells. Exp Cell Res. 1996 May 1;224(2):365–371. doi: 10.1006/excr.1996.0146. [DOI] [PubMed] [Google Scholar]
  27. Zelger B., Hittmair A., Schir M., Ofner C., Ofner D., Fritsch P. O., Böcker W., Jasani B., Schmid K. W. Immunohistochemically demonstrated metallothionein expression in malignant melanoma. Histopathology. 1993 Sep;23(3):257–263. doi: 10.1111/j.1365-2559.1993.tb01198.x. [DOI] [PubMed] [Google Scholar]
  28. Zhang X. H., Takenaka I. Incidence of apoptosis and metallothionein expression in renal cell carcinoma. Br J Urol. 1998 Jan;81(1):9–13. doi: 10.1046/j.1464-410x.1998.00506.x. [DOI] [PubMed] [Google Scholar]

Articles from British Journal of Cancer are provided here courtesy of Cancer Research UK

RESOURCES