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Differences in the immunohistochemical expression of the 17 kDa protein encoded by the human nm23-H1 gene were studied in premalignant lesions and invasive squamous cell carcinoma (SCC) (N = 8) of the cervix using routine streptavidin-biotin immunohistochemistry and a polyclonal antibody to the nm23-H1 protein. The premalignant lesions were koilocytic atypia due to wart virus infection (N = 5), low-grade cervical intraepithelial neoplasia (CIN) (N = 7) and high-grade CIN (N = 7). The carcinomas were either moderately (N = 3) or poorly differentiated (N = 5). The non-neoplastic controls were normal squamous epithelium from cases with uterine prolapse (N = 7) and normal squamous epithelium not affected by the infective or neoplastic areas of some of the cases with wart virus infection (N = 2) and carcinoma (N = 2). Moderate to strong cytoplasmic and, occasionally, nuclear immunostaining for the nm23-H1 protein was seen in all cells above the basal layer of the normal squamous epithelium. However, most of the cervical SCC show a relative reduction in nm23-H1 immunoreactivity (7/8 cases; 88%). This difference in nm23-H1 expression was statistically significant (P = 0.0006; Chi-squared test with continuity correction). All of the cases with wart virus infection (N = 5; 100%) displayed moderately strong nm23-H1 immunostaining throughout the squamous epithelium except for the basal layer where no staining was observed. The cases that had low-grade squamous dysplasia of the cervix (CIN I-II) (N = 7; 100%) also displayed moderate to strong nm23-H1 immunoreactivity in the epithelium except for the basal layer (CIN I) or the lower two-thirds of the epithelium (CIN II). nm23-H1 Immunoreactivity was either absent or was significantly reduced in all of the high-grade CIN (CIN III) cases (N = 7; 100%) in which only the nondysplastic superficial third of the squamous epithelium displayed nm23-H1 immunolabeling. The difference in nm23-H1 expression between low-grade and high-grade CIN cases was statistically significant (P = 0.0013; Chi-squared test with continuity correction). Similarly, the difference between low-grade CIN and SCC cases in the expression of nm23-H1 was also significant (P = 0.0041; Chi-squared test with continuity correction). However, no statistically significant difference in nm23-H1 immunoreactivity was found between cases of high-grade CIN and SCC. In conclusion, nm23-H1 protein immunoreactivity is reduced in high-grade CIN and cervical SCC but not in low-grade CIN. These findings suggest that reduced expression of the protein may be important early in the sequential development of cervical squamous neoplasia.