title: Down-regulation of E-cadherin is closely associated with progression of cervical intraepithelial neoplasia (CIN), but not with high-risk human papillomavirus (HPV) or disease outcome in cervical cancer.
abstract: OBJECTIVE
  E-cadherin plays a pivotal role in maintenance of normal adhesion in epithelial cells but has also been shown to suppress tumour invasion and participate in cell signalling. Known to be capable of reversing the invasive phenotype of high-risk human papillomavirus (HPV)-transformed keratinocytes, E-cadherin is down-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 E-cadherin, and tested for HPV using PCR with three primer sets (MY09/11, GP5+/GP6, SPF). Follow-up data were available from all squamous cell carcinoma (SCC) patients, and 67 CIN lesions were monitored with serial PCR for HPV after cone treatment.
  
  
  RESULTS
  Expression of E-cadherin was reduced in parallel with the increasing grade of CIN, with major down-regulation upon transition to CIN3 and further to invasive cancer (OR 6.95; 95% CI 2.67-18.09) (p = 0.0001). Negative markedly reduced E-cadherin expression was a 90.9% specific indicator of CIN, with 97.4% PPV, but suffered from low sensitivity (27.0%) and NPV (9.1%). E-cadherin expression was completely unrelated to HR-HPV (p = 0.982), and did not predict clearance/persistence of HR-HPV after treatment of CIN. Similarly, E-cadherin expression was not a prognostic predictor of CC in univariate or multivariate analysis.
  
  
  CONCLUSIONS
  Down-regulation of E-cadherin was closely associated with progressive CIN and cell proliferation. It is tempting to speculate that part of this cell proliferation is mediated through the canonic Wnt signalling pathway, after liberation of transcriptionally competent beta-catenin from the E-cadherin/catenin complex, most notably orchestrated by E6 and E7 oncoproteins of HR-HPV. Such a liberation of beta-catenin would abrogate the negative transcriptional control of E-cadherin on the Lef/TCF/beta-catenin responsive genes. The exact role of HR-HPV oncoproteins E6 and E7 in this process remains to be seen in future studies.
authors.affiliation: Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Saniti (ISS), Rome, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Branca
authors.forename: C
authors.initials: C
authors.lastname: Giorgi
authors.forename: M
authors.initials: M
authors.lastname: Ciotti
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: L
authors.initials: L
authors.lastname: Mariani
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; D015820:Cadherins / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D027383:Papillomaviridae / Q000145:classification; D030361:Papillomavirus Infections / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D016133:Polymerase Chain Reaction; D011379:Prognosis; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000378:metabolism* / Q000473:pathology / Q000821:virology
chemical_list: D015820:Cadherins