Predictive significance of the alterations of p16INK4A, p14ARF, p53, and proliferating cell nuclear antigen expression in the progression of cervical cancer.
OBJECTIVE
The purpose of this research was to evaluate the clinical significance of p16INK4A, p14ARF, p53, and proliferating cell nuclear antigen (PCNA) expression in tumor progression of cervical cancer.


METHODS
Seventeen patients (40 samples) with consecutive cervical lesions from normal squamous epithelium, inflammation of the cervix to cervical intraepithelial neoplasm (CIN) and invasive cervical squamous cell cancer (SCC), or from CIN to SCC were collected for this study. Expression of p16INK4A, p14ARF, p53, and PCNA were detected by immunohistochemistry on paraffin-embedded sections. Human papillomavirus DNA was detected simultaneously with PCR and typed according to its DNA sequence.


RESULTS
p16INK4A overexpression was significantly higher in CIN (75%) and in SCC (75%) than in normal or inflammation of the cervix (12.5%; P < 0.01, P < 0.05, respectively). The positive rate of p14ARF expression was higher in SCC (83%) than in normal/inflammation of the cervix (25%; P < 0.05). PCNA expression was negative in normal or inflammation of the cervix, but an increased in expression was seen in 63.2% in CIN and 100% in SCC (P < 0.01, P < 0.05). When the time interval for disease progression from initial biopsy to CIN 3 or invasive cancer was compared with states of p16INK4A expression, cases stained positive for p16INK4A progressed within 64.2 months as compared with 122.3 months among those stained negatively (P < 0.01). Cases with increased p14ARF expression also had a short time interval for disease progression of 78.8 months as compared with 108.3 months in cases that were p14ARF negative. Cases with stable or decreased p53 expression had the shortest time interval for progression of 32.3 months in contrast to cases with no p53 expression (113.9 months). However, cases with increasing p53 expression progressed within 60.8 months.


CONCLUSIONS
Our results suggested that altered states of p16INK4A, p14ARF, p53, and PCNA may be valuable markers to predict the progression of cervical neoplasia.
Wang
Jian-Liu
JL
Department of Molecular Medicine, Center for Molecular Medicine, Karolinska Institute, Cancer Center Karolinska, Karolinska University Hospital, Stockholm, Sweden.
Zheng
Bi-Ying
BY
Li
Xi-Dan
XD
Angström
Tord
T
Lindström
Mikael S
MS
Wallin
Keng-Ling
KL
D000328:Adult; D000368:Aged; D002584:Cervix Uteri / Q000378:metabolism; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000096:biosynthesis*; D004247:DNA / Q000737:chemistry; D004279:DNA, Viral / Q000378:metabolism; D018450:Disease Progression; D004848:Epithelium / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation; D008875:Middle Aged; D018307:Neoplasms, Squamous Cell / Q000378:metabolism; D027383:Papillomaviridae / Q000235:genetics; D016133:Polymerase Chain Reaction; D018809:Proliferating Cell Nuclear Antigen / Q000096:biosynthesis*; D012307:Risk Factors; D013997:Time Factors; D025803:Tumor Suppressor Protein p14ARF / Q000096:biosynthesis*; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis*; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000378:metabolism* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000378:metabolism
D019941:Cyclin-Dependent Kinase Inhibitor p16; D004279:DNA, Viral; D018809:Proliferating Cell Nuclear Antigen; D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D004247:DNA