Effect of Human Papillomavirus on Cell Cycle–Related Proteins p16, Ki-67, Cyclin D1, p53, and ProEx C in Precursor Lesions of Cervical Carcinoma

Abstract

In-depth study of cell cycle proteins and human papillomavirus (HPV) genotyping can provide useful information about the malignant potential of precursor lesions of cervical carcinoma (CC). Immunostaining of cell cycle-related proteins (p16, cyclin D1, Ki-67, p53, and ProEx C) was evaluated using tissue microarrays, and HPV genotypes were identified in 144 cervical tissue specimens encompassing normal or benign epithelial lesions, low- and high-grade squamous intraepithelial lesions (LSIL and HSIL, respectively), and CC. In addition, 14 cases with atypical immature metaplasia (AIM) were included to compare their immunohistochemical features with those of well-established precursor lesions. Expression of p16, Ki-67, and ProEx C was most associated with the severity of dysplasia. Positive expression of p16, Ki-67, and ProEx C and negative expression of p53 seem to be related to HPV-16 infection. AIM cases show an immunohistochemical pattern more similar to LSIL than to HSIL. Immunohistochemical assessment of cell cycle proteins may help to distinguish normal and benign conditions of the cervix from precursor lesions of CC.

The RNA-binding protein La contributes to cell proliferation and CCND1 expression

“…The finding that CCND1 protein is elevated in those lysates is in agreement with recent studies demonstrating elevated CCND1 expression in cervical cancer (Nichols et al, 1996;Cheung et al, 2001;Carreras et al, 2007;Conesa-Zamora et al, 2009). Although, in one study, CCND1 expression was reduced in most of the analyzed samples, CCND1 was elevated in invasive cancer and it correlates with lower overall survival (Bae et al, 2001).…”

Cyclin D1 immunoreactivity in normal endocervix and diagnostic value in reactive and neoplastic endocervical lesions

“…Earlier immunohistological studies of squamous lesions have shown conflicting results, some authors reporting absent or reduced staining compared with normal epithelium similar to our findings, [17][18][19][20][21][22] whereas others have recorded increased cyclin D1 expression, particularly in high-grade CIN or squamous carcinoma. [23][24][25] The reasons for these discrepancies are not entirely clear although variations in immunohistochemical techniques and interpretation of staining results may be relevant. 26 It is also notable that some investigations have shown increased cyclin D1 mRNA in a proportion of intraepithelial or invasive cervical neoplasms in the absence of protein expression, suggesting that posttranscriptional mechanisms such as protein degradation may be important in some cases.…”

The Indicators of Predicting Disease Outcome in HPV Carcinogenesis

“…The ProExC signal is intense, diffuse and comprises the entire thickness of the epithelium in HSIL, with a variable pattern of the staining in LSIL, and is usually negative in reparative or reactive immature squamous metaplasias (Pinto et al, 2010). ProEx C positive expression seems to be more specifically associated with SIL than Ki-67 positive expression (Conesa-Zamora et al, 2009). ProExC immunostaining, when compared with p16 immunostaining, have similar specificity for CIN 2+ and higher specificity for CIN 3+ but lower sensitivity for CIN 2+ and CIN 3+ (Guo et al, 2011).…”

“…Among cyclins and cyclin dependent kinases (CDKs) that governed cell cycle, p53, Rb and CDK inhibitors (p15, p16, p18, p19, p21, p27) play a special role by arresting the cell cycle until damaged DNA is completely repaired. Therefore, the cell cycle regulators may shed light on the understanding of HPVmediated cervical carcinogenesis (Conesa-Zamora et al, 2009). …”

“…An increase in cyclin D1 expression was observed from CIN 3 to invasive carcinoma as a consequence of the inability of overexpressed p16 to inactivate CDK4/6, the partner of cyclin D1. The authors suggested that the immunohistochemical expression of cyclin D1 might be a marker in cervical cancer progression only if restricted beyond to the lower third layer (Conesa-Zamora et al, 2009). …”