Co-Expression of p53 and Bcl-2 Proteins in Human Papillomavirus-Induced Premalignant Lesions of the Uterine Cervix: Correlation with Progression to Malignancy

Abstract

Objective(s): To analyze aberrant expression of the apoptotic protein p53 and the anti-apoptotic protein Bcl-2 in premalignant lesions of the uterine cervix induced by human papillomavirus (HPV) infection and its significance for early diagnosis of cervical cancer. Materials and Methods: Cytological adequate smears (n = 382) from various grades of squamous intraepithelial lesions (SILs; n = 142), ‘atypical squamous cells of unknown significance’ (ASCUS; n = 128) and normal tissue (n = 112) were investigated immunocytochemically for aberrant expression of p53 and Bcl-2 proteins using the streptavidin-biotin-peroxidase method; HPV status was analyzed in cervical smears using general and type-specific primers. Results: HPV-DNA of any type was detected in 25.7% (98/382) of cases. HPV16 was seen in 58.2% (57/98), HPV18 in 20.4% (20/98) and other HPV types in 21.4% (21/98). Abnormal nuclear expression of p53 protein and cytoplasmic expression of Bcl-2 protein were noted in cervical dysplasia and an association with the presence of HPV16/HPV18 was noted. The intensity of immunoreactivity for p53 and Bcl-2 proteins varied between different cytological grades of cervical smears. Follow-up data revealed that cases with high-risk HPV and co-induced expression of apoptosis-regulatory proteins presented a trend to progressive disease. Conclusions: The detection of both p53 and Bcl-2 proteins in cervical smears can be used as independent diagnostic marker for early-stage HPV-associated cervical cancer.

Expression of P-glycoprotein is Positively Correlated with p53 in Human Papilloma Virus Induced Squamous Intraepithelial Lesions of Uterine Cervix: Poor Prognosis Association

“…Studies have shown the over-expression of p53 not only in primary and recurrent CIS cases but also in pre-malignant dysplastic lesions (Bremer et al, 1995;Park et al, 1999;Oh et al, 2004;Singh et al, 2009). In this study, both frequency and intensity of p53 expression was gradually increased along with the severity of lesion and was associated with HPV presence (Tables 2 and 3).…”

“…Similarly in NI-HPV types cases (n = 34), most of the cases were from HSIL group (n=10) followed by LSIL (n=13), which suggested that other HPV types are also involved in progression of SILs. According to earlier reports HPV infection is frequently detectable in SIL and CIS cases (Schlecht et al, 2003;Evans et al, 2006) and HPV-16 and 18 are considered as most aggressive HPV subtypes (Singh et al, 2009). Precursor lesions of the uterine cervix those with oncogenic HPV-16 and 18 infections persist longer and progress more quickly than with non-oncogenic infections or without HPV (Schlecht et al, 2003).…”

“…In this study association between p53 over-expression and HPV infection was noted (Table 3), confirming the inactivation of p53 protein by complex formation with E6 oncoprotein and subsequent stabilization. Altered expression and inactivation of p53 protein in HPV infected cases is well associated with disease progression (Singh et al, 2009;Oh et al, 2004) and reflects the presence of HPV in cervical cells (Scheffner et al, 1990;Nair et al, 2000), thus, could be a useful parameter for clinical interpretations of HPV presence in low resource hospital settings. Along with these, in some of the HPV negative cases also p53 over-expression was noted in our study (Table 3); this might be evoked via pathways other than HPV infection through gene mutation, hypomethylation or hypermethylation, which suggested that some of the observed cervical preneoplastic and neoplastic lesions could be induced in a heterogeneous way.…”

“…Aberration of p53 gene which is among the most frequent alteration in human malignancies, additionally, plays an important role in determining the resistance of cancer cells to chemotherapy (Linn et al, 1996;Perego et al, 1996). In cervical carcinoma over expression of p53 protein and its correlation with aggressive biological behavior is documented (Helland et al, 1993;Oh et al, 2004;Singh et al, 2009).…”

The Indicators of Predicting Disease Outcome in HPV Carcinogenesis

“…Guimarães et al, (2005) found by immunohistochemical techniques that expression of Bcl2 in HPV-infected cervical biopsies is not useful for predicting the progression of HPV-related SIL. On the other hand, Singh et al, (2009) noted cytoplasmic expression of Bcl2 protein in cervical dysplasia, a various intensity of immunoreactivity between different cytological grades of cervical smears and an association with the presence of HPV16/HPV18.…”