Abstract
The goal of this study is to clarify whether the expression of metallothionein (MT) could affect the prognosis and the metastatic potential of squamous cell carcinoma (SCC) of the oesophagus. In paraffin-embedded specimens resected from 57 patients, MT mRNA and protein expressions were detected by in situ hybridization and immunohistochemistry respectively. The expression of MT was evaluated in respect of clinicopathologic variables and patients’ survival. MT mRNA expression was significantly associated with the proportion of lymph node metastasis (71% in MT mRNA-positive tumours vs 42% in MT mRNA-negative tumours; P = 0.0343) and that of distant metastasis (29% in MT mRNA-positive tumours vs 5% in MT mRNA-negative tumours; P = 0.0452). In respect of MT protein expression, the frequency of distant metastasis was more common in MT-positive tumours than in MT-negative tumours (30% in MT-positive tumours vs 8% in MT-negative tumours; P = 0.0446). The survival rate of the patients with MT protein-negative tumours was significantly better than that of the patients with MT protein-positive tumours (P = 0.0340). There was a positive correlation between the expression of MT protein and that of proliferating cell nuclear antigen (P = 0.0018). Therefore, we conclude that MT expression, both at the mRNA and protein levels, may be a potential marker predicting metastatic and proliferative activities of oesophageal SCC.
Similar content being viewed by others
Article PDF
Change history
16 November 2011
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Abdel-Mageed, A & Agrawal, KC (1997) Antisense down-regulation of metallothionein induces growth arrest and apoptosis in human breast carcinoma cells. Cancer Gene Ther 4: 199–207
Adams, JC (1981) Heavy metal intensification of DAB-based HRP reaction products. J Histochem Cytochem 29: 775
Al-Sheneber, IF, Shibata, HR, Sampalis, J & Jothy, S (1993) Prognostic significance of proliferating cell nuclear antigen expression in colorectal cancer. Cancer 71: 1954–1959
Chin, JL, Banerjee, D, Kadhim, SA, Kontozoglou, TE, Chauvin, PJ & Cherian, MG (1993) Metallothionein in testicular germ cell tumors and drug resistance. Cancer 72: 3029–3035
Chiu, R, Boyle, WJ, Meek, J, Smeal, T, Hunter, T & Karin, M (1988) The c-fos protein interacts with jun/AP-1 to stimulate transcription of AP-1 responsive genes. Cell 54: 541–552
Fresno, M, Wu, W, Rodriguez, JM & Nadji, M (1993) Localization of metallothionein in breast carcinomas. An immunohistochemical study. Virchows Arch A 423: 215–219
Goulding, H, Jasani, B, Pereira, H, Reid, A, Galea, M, Bell, JA, Elston, CW, Robertson, JF, Blamey, RW, Nicholson, RA, Schmid, KW & Ellis, IO (1995) Metallothionein expression in human breast cancer. Br J Cancer 72: 968–972
Haga, A, Nagase, H, Kito, H & Sato, T (1996a) Enhanced invasiveness of tumour cells after host exposure to heavy metals. Eur J Cancer 32A: 2342–2347
Haga, A, Nagase, H, Kito, H & Sato, T (1996b) Effect of metallothioneins on transformation of gelatinase A from human fibroblast WI-38 cells. Cancer Lett 105: 175–180
Hall, PA, Levison, DA, Woods, AL, Yu, CCW, Kellock, DB, Watkins, JA, Barnes, DM, Gillett, CE, Camplejohn, R, Dover, R, Waseem, NH & Lane, DP (1990) Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: an index of cell proliferation with evidence of deregulated expression in some neoplasms. J Pathol 162: 285–294
Hickey, K, Grehan, D, Reid, IM, O’Briain, S, Walsh, TN & Hennessy, TPJ (1994) Expression of epidermal growth factor receptor and proliferating cell nuclear antigen predicts response of esophageal squamous cell carcinoma to chemoradiotherapy. Cancer 74: 1693–1698
Hishikawa, Y, Abe, S, Kinugasa, S, Yoshimura, H, Monden, N, Igarashi, M, Tachibana, M & Nagasue, N (1997) Overexpression of metallothionein correlates with chemoresistance to cisplatin and prognosis in esophageal cancer. Oncology 54: 342–347
Hollstein, MC, Metcalf, RA, Welsh, JA, Montesano, R & Harris, CC (1990) Frequent mutation of the p53 gene in human esophageal cancer. Proc Natl Acad Sci USA 87: 9958–9961
Hu, E, Mueller, E, Oliviero, S, Papaioannou, VE, Johnson, R & Spiegelman, BM (1994) Targeted disruption of the c-fos gene demonstrates c-fos-dependent and -independent pathways for gene expression stimulated by growth factors or oncogenes. EMBO J 13: 3094–3103
Jain, S, Filipe, MI, Hall, PA, Waseem, N, Lane, DP & Levison, DA (1991) Prognostic value of proliferating cell nuclear antigen in gastric carcinoma. J Clin Pathol 44: 655–659
Jasani, B & Schmid, KW (1997) Significance of metallothionein overexpression in human tumours. Histopathology 31: 211–214
Jasani, B & Elmes, ME (1991). Immunohistochemical detection of metallothionein. In: Methods in Enzymology Metallobiochemistry, Part B, Metallothionein and Related Molecules, Riordan JF and Vallee BL (eds), pp. 95–107. Academic Press: San Diego
Karin, M & Richards, RI (1982) Human metallothionein genes – primary structure of the metallothionein-II gene and a related processed gene. Nature 299: 797–802
Karin, M, Eddy, RL, Henry, WM, Haley, LL, Byers, MG & Shows, TB (1984) Human metallothionein genes are clustered on chromosome 16. Proc Natl Acad Sci USA 81: 5494–5498
Kasahara, K, Fujiwara, Y, Nishio, K, Ohmori, T, Sugimoto, Y, Komiya, K, Matsuda, T & Saijo, N (1991) Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. Cancer Res 51: 3237–3242
Kelley, SL, Basu, A, Teicher, BA, Hacker, MP, Hamer, DH & Lazo, JS (1988) Overexpression of metallothionein confers resistance to anticancer drugs. Science 241: 1813–1815
Kinugasa, S, Tachibana, M, Hishikawa, Y, Abe, S, Yoshimura, H, Monden, M, Dhar, DK & Nagasue, N (1996) Prognostic significance of proliferating cell nuclear antigen (PCNA) in squamous cell carcinoma of the esophagus. Jpn J Clin Oncol 26: 405–410
Kitagawa, Y, Ueda, M, Ando, N, Shinozawa, Y, Shimizu, N & Abe, O (1991) Significance of int-2/hst-1 coamplification as a prognostic factor in patients with esophageal squamous carcinoma. Cancer Res 51: 1504–1508
Koji, T & Brenner, RM (1993) Localization of estrogen receptor messenger ribonucleic acid in rhesus monkey uterus by nonradioactive in situ hybridization with digoxigenin-labeled oligodeoxynucleotides. Endocrinology 132: 382–392
Koji, T & Nakane, PK (1996) Recent advances in molecular histochemical techniques: in situ hybridization and southwestern histochemistry. J Electron Microsc 45: 119–127
Kondo, Y, Kuo, S, Watkins, SC & Lazo, JS (1995) Metallothionein localization and cisplatin resistance in human hormone-independent prostatic tumor cell lines. Cancer Res 55: 474–477
Le Beau, MM, Diaz, MO, Karin, M & Rowley, JD (1985) Metallothionein gene cluster is split by chromosome 16 rearrangements in myelomocytic leukaemia. Nature 313: 709–711
Lee, W, Mitchell, P & Tjian, R (1987) Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements. Cell 49: 741–752
Lim, K, Evans, A, Adams, M, Fish, R, Dhundee, J, Dallimore, N & Jasani, B (1996) Association of immunohistochemically detectable metallothionein (IDMT) expression with malignant transformation in cervical neoplasia. J Pathol 178: 48A
Mandard, AM, Marnay, J, Gignoux, M, Segol, P, Blanc, L, Ollivier, JM, Borel, B & Mandard, JC (1984) Cancer of the esophagus and associated legions: detailed pathologic study of 100 esophagectomy specimens. Hum Pathol 15: 660–669
Meltzer, SJ, Yin, J, Huang, Y, McDaniel, TK, Newkirk, C, Iseri, O, Vogelstein, B & Resau, JH (1991) Reduction to homozygosity involving p53 in esophageal cancers demonstrated by polymerase chain reaction. Proc Natl Acad Sci USA 88: 4976–4980
Miyake, S, Nagai, K, Yoshino, K, Oto, M, Endo, M & Yuasa, Y (1994) Point mutations and allelic deletion of tumor suppressor gene DCC in human esophageal squamous cell carcinomas and their relation to metastasis. Cancer Res 54: 3007–3010
Mulder, TPJ, Verspaget, HW, Janssens, AR, De Bruin, PAF, Griffioen, G & Lamers, CBHW (1990) Neoplasia-related changes of two copper (Cu)/Zinc (Zn) proteins in the human colon. Free Radical Bio Med 10: 501–506
Nagel, WW & Vallee, B (1995) Cell cycle regulation of metallothionein in human colonic cancer cells. Proc Natl Acad Sci USA 92: 579–583
Öfner, D, Maier, H, Riedmann, B, Bammer, T, Rumer, A, Winde, G, Böcker, W, Jasani, B & Schmid, KW (1994) Immunohistochemical metallothionein expression in colorectal adenocarcinoma: correlation with tumour stage and patient survival. Virchows Arch 425: 491–497
Ohshio, G, Imamura, T, Okada, N, Wang, ZH, Yamaki, K, Kyogoku, T, Suwa, H, Yamabe, H & Imamura, M (1996) Immunohistochemical study of metallothionein in pancreatic carcinomas. J Cancer Res Clin 122: 351–355
Orrigner, MB (1997) Tumors of the esophagus. In: Textbook of Surgery, Sabiston DC Jr (ed), WB Saunders: Philadelphia pp. 744–758
Oyama, T, Takei, H, Hikino, T, Iino, Y & Nakajima, T (1996) Immunohistochemical expression of metallothionein in invasive breast cancer in relation to proliferative activity, histology and prognosis. Oncology 53: 112–117
Ransone, LJ & Verma, IM (1990) Nuclear proto-oncogenes fos and jun. Annu Rev Cell Biol 6: 539–557
Schmid, KW, Ellis, IO, Gee, JMW, Darke, BM, Lees, WE, Kay, J, Cryer, A, Stark, JM, Hittmair, A, Öfner, D, Dünser, M, Margreiter, R, Daxenbichler, G, Nicholson, RI, Bier, B, Böcker, W & Jasani, B (1993) Presence and possible significance of immunocytochemically demonstrable metallothionein over-expression in primary invasive ductal carcinoma of the breast. Virchows Arch A 422: 153–159
Shulte, EKW, Lyon, HO & Hoyer, PE (1992) Simultaneous quantification of DNA and RNA in tissue sections. A comparative analysis of the methyl green-pyronin technique with the gallocyanin chromalum and Feulgen procedures using image cytometry. Histochem J 24: 305–310
Skroch, P, Inouye, C & Karin, M (1991) Regulation of human and yeast metallothionein gene transcription by heavy metal ions. In: Metallothionein in Biology and Medicine, Klaassen CD, Suzuki KT (eds), CRC Press: Boca Raton, Florida pp. 61–74
Steele, GD Jr, Davis, S, Yow, H, Wong, JM, Rivers, EN, Summerhayes, IC, Ravikumar, TS & Chen, LB (1990) Alterations of gene expression in human colorectal cancer. Arch Surg 25: 493–497
Stracke, ML & Liotta, LA (1995) Molecular mechanisms of tumor cell metastasis. In: The Molecular Basis of Cancer, Mendelsohn J, Howley PM, Israel MA, Liotta LA (eds), WB Saunders: Philadelphia pp. 233–247
Tohyama, C, Suzuki, JS, Hemelraad, J, Nishimura, N & Nishimura, H (1993) Induction of metallothionein and its localization in the nucleus of rat hepatocytes after partial hepatectomy. Hepatology 18: 1193–1201
Yoshii, A, Koji, T, Ohsawa, N & Nakane, PK (1995) In situ localization of ribosomal RNAs is a reliable reference for hybridizable RNA in tissue sections. J Histochem Cytochem 43: 321–328
Zelger, B, Hittmair, A, Schir, M, Öfner, C, Öfner, D, Fritsch, PO, Böcker, W, Jasani, B & Schmid, KW (1993) Immunohistochemically demonstrated metallothionein expression in malignant melanoma. Histopathology 23: 257–264
Zelger, B, Sidoroff, A, Hopfl, R, Öfner, D, Jasani, B & Schmid, KW (1994) Metallothionein expression in nonmelanoma skin cancer. Appl Immunohistochem 2: 254–260
Zheng, H, Liu, J, Choo, KH, Michalska, AE & Klaassen, CD (1996) Metallothionein-I and -II knock-out mice are sensitive to cadmium-induced liver mRNA expression of c-jun and p53. Toxicol Appl Pharm 136: 229–235
Author information
Authors and Affiliations
Rights and permissions
From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/
About this article
Cite this article
Hishikawa, Y., Koji, T., Dhar, D. et al. Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus. Br J Cancer 81, 712–720 (1999). https://doi.org/10.1038/sj.bjc.6690753
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.bjc.6690753
Keywords
This article is cited by
-
Metallothionein-3 promotes cisplatin chemoresistance remodelling in neuroblastoma
Scientific Reports (2021)
-
Zinc and Metallothionein in the Development and Progression of Dental Caries
Biological Trace Element Research (2019)
-
The roles of metallothioneins in carcinogenesis
Journal of Hematology & Oncology (2018)
-
Novel roles of DC-SIGNR in colon cancer cell adhesion, migration, invasion, and liver metastasis
Journal of Hematology & Oncology (2017)
-
Effect of HPV on tumor expression levels of the most commonly used markers in HNSCC
Tumor Biology (2016)