EXPRESSION OF METASTASIS-RELATED NM23-H1 AND NM23-H2 GENES IN OVARIANCARCINOMAS - CORRELATION WITH CLINICOPATHOLOGY, EGFR, C-ERBB-2, AND C-ERBB-3 GENES, AND SEX STEROID-RECEPTOR EXPRESSION

To verify the role of metastasis-related nm23 genes in carcinogenesis and progression of ovarian carcinoma, we analyzed the mRNA levels of t he nm23 genes of both isoforms, -H1 and -H2, together with those of th e epidermal growth factor receptor, the c-erbB-2, and the c-erbB-3 gen es in 45 ovarian carcinomas and 5 benign cystadenomas. Expressions of nm23 gene products/nucleoside diphosphate kinases, epidermal growth fa ctor receptor, erbB-2 protein, and sex steroid receptor status in ovar ian carcinomas were also examined by immunohistochemistry. The mRNA le vels of nm23-H1 and nm23-H2 were higher in carcinoma tissues compared with benign tumors (H1, P < 0.01). The mRNA levels of c-erbB-2 and c-e rbB-3 were also elevated in carcinoma tissues, and there was a positiv e correlation between mRNA levels of the nm23-H1 and the c-erbB-2 gene s (r = 0.58; P < 0.05). Correlation of immunohistochemical staining be tween nucleoside diphosphate kinases and erbB-2 protein was also obser ved in ovarian carcinoma tissues. Sex steroid receptor positivity was related to a higher expression of nucleoside diphosphate kinases. Expr ession levels of the nm23 genes in ovarian carcinomas were not related to either histological subtype or local extension and peritoneal diss emination. Among stage III ovarian carcinomas, however, tumors possess ing lymph node metastasis showed significantly lower nm23-H1 mRNA leve ls than those without nodal involvement (P < 0.05). Stage IV carcinoma s also exhibited lower nm23-H1 and nm23-H2 expression levels compared with other stages (P < 0.05). These results suggest that expression of the nm23 genes, especially nm23-H1, is activated, accompanied by c-er bB-2 and c-erbB-3 overexpressions, in early stages of the carcinogenic process of ovarian carcinoma and reduction of nm23-H1 expression occu rs in association with lymph nodal and/or distant metastasis.