title: Up-regulation of proliferating cell nuclear antigen (PCNA) is closely associated with high-risk human papillomavirus (HPV) and progression of cervical intraepithelial neoplasia (CIN), but does not predict disease outcome in cervical cancer.
abstract: OBJECTIVE
  Proliferating cell nuclear antigen (PCNA) is essential for DNA replication of mammalian cells and their small DNA tumour viruses. The E7 oncoprotein of high-risk human papillomavirus (HPV) is known to activate PCNA, shown to be up-regulated in CIN and cervical cancer (CC), but still incompletely studied as an intermediate endpoint marker in this disease.
  
  
  METHODS
  As part of our HPV-PathogenISS study, a series of 150 CCs and 152 CIN lesions were examined using immunohistochemical (IHC) staining for PCNA, and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6+, SPF). Follow-up data were available from all SCC patients, and 67 of the CIN lesions had been monitored with serial PCR for HPV after cone treatment.
  
  
  RESULTS
  Expression of PCNA increased in parallel with the grade of CIN, with major up-regulation upon transition to CIN3 (OR 21.77; 95%CI 6.59-71.94) (p = 0.0001). Intense PCNA expression was 100% specific indicator of CIN, with 100% PPV, but suffers from low sensitivity (34.8%) and NPV (10.8%). PCNA expression was also significantly associated to HR-HPV with OR 3.02 (95%CI 1.71-5.34) (p = 0.0001), and this association was not confounded by the histological grade (Mantel-Haenszel common OR = 2.03; 95%CI 1.06-3.89) (p = 0.033). Expression of PCNA did not predict clearance/persistence of HR-HPV after treatment of CIN, and it was not a prognostic predictor in CC in univariate or in multivariate analysis.
  
  
  CONCLUSIONS
  Up-regulation of PCNA was closely associated with HR-HPV and progressive CIN, most feasibly explained by the abrogation of normal cell cycle control by the E7 ongogene, reverting the p21(Cip1)-mediated inhibition of PCNA. However, the fact that PCNA is also expressed in normal squamous epithelium precludes the use of this marker as a potential screening tool for CC.
authors.affiliation: Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità (ISS), Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Branca
authors.forename: M
authors.initials: M
authors.lastname: Ciotti
authors.forename: C
authors.initials: C
authors.lastname: Giorgi
authors.forename: D
authors.initials: D
authors.lastname: Santini
authors.forename: L
authors.initials: L
authors.lastname: Di Bonito
authors.forename: S
authors.initials: S
authors.lastname: Costa
authors.forename: A
authors.initials: A
authors.lastname: Benedetto
authors.forename: D
authors.initials: D
authors.lastname: Bonifacio
authors.forename: P
authors.initials: P
authors.lastname: Di Bonito
authors.forename: P
authors.initials: P
authors.lastname: Paba
authors.forename: L
authors.initials: L
authors.lastname: Accardi
authors.forename: S
authors.initials: S
authors.lastname: Syrjänen
authors.forename: C
authors.initials: C
authors.lastname: Favalli
authors.forename: K
authors.initials: K
authors.lastname: Syrjänen
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis; D002294:Carcinoma, Squamous Cell / Q000175:diagnosis / Q000628:therapy / Q000821:virology*; D002453:Cell Cycle; D002584:Cervix Uteri / Q000473:pathology; D019092:Conization; D015344:DNA Probes, HPV; D018450:Disease Progression; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D027383:Papillomaviridae / Q000145:classification / Q000235:genetics; D030361:Papillomavirus Infections / Q000175:diagnosis / Q000503:physiopathology*; D011237:Predictive Value of Tests; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D014412:Tumor Virus Infections / Q000503:physiopathology*; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000175:diagnosis / Q000628:therapy / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000145:classification / Q000628:therapy / Q000821:virology*
chemical_list: D014408:Biomarkers, Tumor; D015344:DNA Probes, HPV; D018809:Proliferating Cell Nuclear Antigen