The p16 protein plays a key role in controlling cell growth by inhibiting the cyclin-dependent kinase-4 and preventing phosphorylation of pRb, which maintains the Gj checkpoint. Several studies (33,34) have suggested that p16 is overexpressed in CIN and invasive adenocarcinoma as a result from HPV E7-mediated degradation of pRb through an ubiquitin-dependent mechanism. However, studies by methylation-specific polymerase chain reaction in situ showed that neoplastic cells with aberrantly methylated p16 were associated with the loss of p16 protein expression (35). Thus, suggesting that p16 hypermethylation can negate the seemingly protective role of p16 overexpression in response to HPV infection. p16 silencing by aberrant methylation is strongly associated with active tobacco use in squamous cell cervical cancer and highgrade dysplasia (36).
The Ki-67 protein plays an important although not entirely characterized role in cell proliferation. Its antigen is expressed during the cell cycle with the exception of the G0 phase, and has been used as a marker for proliferation in various tumors, including cervical carcinoma. Previous studies have shown that application of Ki67 immuno-quantitative analyses of CIN1 and CIN2 in histological biopsies has strong independent predictive value for grade, presence of oncogenic HPV, and progression of the disease (37,38). The best Ki67-feature combination to predict whether a subsequent higher CIN grade or cancer will be detected in the follow-up, is the 90th percentile of the stratification index (Si90) and the percent of Ki67-positive cells in the middle third layer of the epithelium (38). Ki67 prognostic value exceeds that of CIN grade (as CIN1 or CIN2) and the presence of HR-HPV types assessed by PCR, highlighting its clinical relevance in cervical cancer outcome.
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