Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus

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.

[1]  J. Sampalis,et al.  Prognostic significance of proliferating cell nuclear antigen expression in colorectal cancer , 1993 .

[2]  I. Verma,et al.  Nuclear proto-oncogenes fos and jun. , 1990, Annual review of cell biology.

[3]  J. Skandalakis,et al.  Tumors of the Esophagus , 2000, World Journal of Surgery.

[4]  D. Lane,et al.  Prognostic value of proliferating cell nuclear antigen in gastric carcinoma. , 1991, Journal of clinical pathology.

[5]  W. Böcker,et al.  Immunohistochemically demonstrated metallothionein expression in malignant melanoma , 1993, Histopathology.

[6]  A. Mandard,et al.  Cancer of the esophagus and associated lesions: detailed pathologic study of 100 esophagectomy specimens. , 1984, Human pathology.

[7]  M. Karin,et al.  Human metallothionein genes—primary structure of the metallothionein-II gene and a related processed gene , 1982, Nature.

[8]  C. Klaassen,et al.  Metallothionein-I and -II knock-out mice are sensitive to cadmium-induced liver mRNA expression of c-jun and p53. , 1996, Toxicology and applied pharmacology.

[9]  N. Saijo,et al.  Metallothionein content correlates with the sensitivity of human small cell lung cancer cell lines to cisplatin. , 1991, Cancer research.

[10]  R. Tjian,et al.  Purified transcription factor AP-1 interacts with TPA-inducible enhancer elements , 1987, Cell.

[11]  Simon C Watkins,et al.  Metallothionein localization and cisplatin resistance in human hormone-independent prostatic tumor cell lines. , 1995, Cancer research.

[12]  T. Koji,et al.  Localization of estrogen receptor messenger ribonucleic acid in rhesus monkey uterus by nonradioactive in situ hybridization with digoxigenin-labeled oligodeoxynucleotides. , 1993, Endocrinology.

[13]  J. Adams.  Heavy metal intensification of DAB-based HRP reaction product. , 1981, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[14]  T. Hunter,et al.  The c-fos protein interacts with c-Jun AP-1 to stimulate transcription of AP-1 responsive genes , 1988, Cell.

[15]  J L Buck,et al.  Tumors of the esophagus. , 1994, Seminars in roentgenology.

[16]  D. Lane,et al.  Proliferating cell nuclear antigen (PCNA) immunolocalization in paraffin sections: An index of cell proliferation with evidence of deregulated expression in some, neoplasms , 1990, The Journal of pathology.

[17]  Y. Hishikawa,et al.  Prognostic significance of proliferating cell nuclear antigen (PCNA) in squamous cell carcinoma of the esophagus. , 1996, Japanese journal of clinical oncology.

[18]  菱川善隆.  Overexpression of Metallothionein Correlates with Chemoresistance to Cisplatin and Prognosis in Esophageal Cancer , 1997 .

[19]  J. Rowley,et al.  Metallothionein gene cluster is split by chromosome 16 rearrangements in myelomonocytic leukaemia , 1985, Nature.

[20]  J. Chin,et al.  Metallothionein in testicular germ cell tumors and drug resistance: Clinical correlation , 1993, Cancer.

[21]  B. Vogelstein,et al.  Reduction to homozygosity involving p53 in esophageal cancers demonstrated by the polymerase chain reaction. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[22]  D. Hamer,et al.  Overexpression of metallothionein confers resistance to anticancer drugs. , 1988, Science.

[23]  B. Jasani,et al.  Immunohistochemical detection of metallothionein. , 1991, Methods in enzymology.

[24]  H. Nagase,et al.  Effect of metallothioneins on transformation of gelatinase A from human fibroblast WI-38 cells. , 1996, Cancer letters.

[25]  Y. Yuasa,et al.  Point mutations and allelic deletion of tumor suppressor gene DCC in human esophageal squamous cell carcinomas and their relation to metastasis. , 1994, Cancer research.

[26]  E. Hu,et al.  Targeted disruption of the c‐fos gene demonstrates c‐fos‐dependent and ‐independent pathways for gene expression stimulated by growth factors or oncogenes. , 1994, The EMBO journal.

[27]  H. Goulding,et al.  Metallothionein expression in human breast cancer. , 1995, British Journal of Cancer.

[28]  K. Schmid,et al.  Significance of metallothionein overexpression in human tumours , 1997, Histopathology.

[29]  R. Eddy,et al.  Human metallothionein genes are clustered on chromosome 16. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[30]  T. Ravikumar,et al.  Alterations of gene expression in human colorectal cancer. Biological implications. , 1990, Archives of surgery.

[31]  M. Karin,et al.  Regulation of human and yeast metallothionein gene transcription by heavy metal ions. , 1993, Progress in clinical and biological research.

[32]  T. Koji,et al.  In situ localization of ribosomal RNAs is a reliable reference for hybridizable RNA in tissue sections. , 1995, The journal of histochemistry and cytochemistry : official journal of the Histochemistry Society.

[33]  W. Dinjens,et al.  EXPRESSION OF NUCLEOPHOSMIN/B23 IN NORMAL AND NEOPLASTIC COLORECTAL MUCOSA , 1996, The Journal of pathology.

[34]  R Montesano,et al.  Frequent mutation of the p53 gene in human esophageal cancer. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[35]  B. Vallee,et al.  Cell cycle regulation of metallothionein in human colonic cancer cells. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[36]  T. Nakajima,et al.  Immunohistochemical expression of metallothionein in invasive breast cancer in relation to proliferative activity, histology and prognosis. , 1996, Oncology.

[37]  A. Abdel-Mageed,et al.  Antisense down-regulation of metallothionein induces growth arrest and apoptosis in human breast carcinoma cells. , 1997, Cancer gene therapy.

[38]  H. Nagase,et al.  Enhanced invasiveness of tumour cells after host exposure to heavy metals. , 1996, European journal of cancer.

[39]  T. Koji,et al.  Recent advances in molecular histochemical techniques: in situ hybridization and southwestern histochemistry. , 1996, Journal of electron microscopy.

[40]  C. Tohyama,et al.  Induction of metallothionein and its localization in the nucleus of rat hepatocytes after partial hepatectomy , 1993, Hepatology.

[41]  H. Verspaget,et al.  Neoplasia-related changes of two copper (Cu)/zinc (Zn) proteins in the human colon. , 1990, Free radical biology & medicine.

[42]  Y. Kitagawa,et al.  Significance of int-2/hst-1 coamplification as a prognostic factor in patients with esophageal squamous carcinoma. , 1991, Cancer research.