Correlation of GI Cyclins and Cyclin-Dependent Kinase Inhibitors Relative to Human Papillomavirus Infection in the Uterine Cervical Lesions

Abstract

We attempted to investigate the relationship between GI cyclins and cyclin-dependent kinase inhibitors (CDKIs) while also taking into account earlier studies about the relationship between GI cyclins and human papillomavirus (HPV) status. Previously, we observed that cyclin D was downregulated in cases associated with HPV, while cyclin E played a leading role in neoplastic transformation. In this study, we analyzed the expression of CDKIs such as p21WAFI/CIPI, pI6INK4A, and p27KIP1 by means of immunohistochemistry in 22 cases of normal cervix, six cases of adenocarcinoma, 30 cases of cervical intraepithelial neoplasia (CIN), and 41 cases of squamous cell carcinoma (SCC). Stratum intermedium and parabasalis demonstrated strong intranuclear staining for all CDKIs. Reserve-cell hyperplasia and koilocytes revealed strong expression of CDKIs, whereas the neoplastic transformation in squamous lesions showed significantly decreased expression (ANOVA, p<.05). While normal endocervical cells revealed focal and weak expression to CDKIs, adenocarcinoma as well as glandular dysplasia revealed strong expression for all CDKIs but pI6INK4A. Both p16INK4A and cyclin D were negative in adenocarcinoma, and p16INK4A may be independent of cyclin D. There was strong correlation between cyclin E and p27KIP1, and cyclin E and p2 1wAFI/cIPl as well as among CDKIs. P16INK4A expression in case of SCC in cases associated with HPV type 16/18 was higher than in those lacking any type of HPV (t-test, p=.023). Downregulation of cyclin D in SCC associated with HPV seems to be inversely correlated with a relative overexpression of p16INK4A. On the other hand, p2lWAFI/CIPI and p27KIP1 demonstrated lower expressions in HPV-positive cases than in cases devoid of HPV, but they were not statistically significant. In conclusion, all CDKIs were downregulated in neoplastic transformation, with p1 6INK4A being relatively increased in SCC cases associated with HPV where cyclin D was kept inert. In addition, cyclin E could be activated in neoplastic transformation by eluding p2lWAFI/cIP1 and p27KIPI.

Keywords

GI cyclin cyclin-dependent kinase inhibitors human papillomavirus

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