Glutathione transferase P1-1 expression in human melanoma metastases: correlation to N-RAS mutations and expression.
Expression of the detoxication enzyme glutathione transferase P1-1 (GST P1-1) at elevated levels has been noted in many types of human tumors, including melanomas. The products of the human H-RAS, K-RAS and N-RAS genes play a key role in intracellular signal transduction leading to transcriptional activation of AP-1 (Fos/Jun) responsive genes. The oncogenic mutated forms of the ras proteins are constitutively active and interfere with normal signal transduction. Mutated RAS genes as well as increased expression of wild-type ras proteins are common features in human tumors including melanoma. We have characterized 30 melanoma metastases from 23 melanoma patients with reference to N-RAS expression and mutation as well as to GST P1 expression (immunohistochemistry and genetic analysis). Twenty-three of 30 samples (70%) had high N-Ras p21 and/or N-RAS codon 61 mutations and 18 of these 23 samples also had high GST P1-1 immunoreactivity. Seven of 30 (23%) samples had low N-Ras p21 immunoreactivity and no detectable N-RAS codon 61 mutations. Six of these 7 samples (86%) also had low GST P1-1 immunoreactivity. The results indicate a statistically significant correlation (Spearman correlation coefficient, r = 0.56, p = 0.001, 2-tailed test) and provide, for the first time, indirect evidence for a possible coregulation of N-RAS and GST P1 in human malignant melanoma which should be further evaluated.
Platz
A
A
Department of Oncology, Radiumhemmet, Karolinska Hospital, Stockholm, Sweden.
Jungnelius
U
U
Grafström
E
E
Lagerlöf
B
B
Mannervik
B
B
Ringborg
U
U
D014408:Biomarkers, Tumor / Q000235:genetics; D003062:Codon / Q000235:genetics; D005260:Female; D005455:Fluorescent Antibody Technique; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D016762:Genes, fos / Q000235:genetics; D016758:Genes, jun / Q000235:genetics; D011905:Genes, ras / Q000235:genetics*; D005982:Glutathione Transferase / Q000235:genetics*; D006801:Humans; D008297:Male; D008545:Melanoma / Q000201:enzymology* / Q000235:genetics / Q000556:secondary*; D009154:Mutation / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D012878:Skin Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000556:secondary*; D014158:Transcription, Genetic
D014408:Biomarkers, Tumor; D003062:Codon; D005982:Glutathione Transferase