Down-regulated nucleoside diphosphate kinase nm23-H1 expression is unrelated to high-risk human papillomavirus but associated with progression of cervical intraepithelial neoplasia and unfavourable prognosis in cervical cancer.

Abstract

OBJECTIVE:

One of the factors leading to an invasive phenotype is the nm23 family of metastases-associated genes. Of the six known members, nm23-H1 is the most frequently studied potential anti-metastatic gene in cervical cancer. However, the possible molecular links to oncogenic human papillomavirus (HPV) are completely unexplored as yet.

MATERIALS AND METHODS:

As a part of the HPV-Pathogen Istituto Superiore di Sanità study, a series of 150 squamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions were examined by immunohistochemical staining for nm23-H1, and tested for HPV by polymerase chain reaction (PCR) with three sets of primers (MY09/11, GP5(+)/GP6(+) and short PCR fragment). Follow-up data were available on all patients with SCC, and 67 CIN lesions were monitored by serial PCR for clearance or persistence of HPV after cone treatment.

RESULTS:

A linear decrease (p = 0.001) was observed in nm23-H1 expression, starting from CIN1 (85% with normal expression), with the most dramatic down regulation on transition from CIN2 (70% normal) to CIN3 (39%) and further to SCC (25%). Reduced expression was associated with CIN3 or cancer at an odds ratio 8.72 (95% confidence interval 4.13 to 18.41). Nm23-H1 was of no use as a marker of the high-risk human papillomavirus (HR-HPV) type, and it did not predict clearance or persistence of HR-HPV after treatment of CIN. Importantly, nm23-H1 expression was a significant prognostic factor in cervical cancer, reduced expression being associated with lower survival (p = 0.022) in univariate analysis. In the multivariate (Cox) regression model, however, only the International Federation of Gynecology and Obstetrics stage (p = 0.001) and age (p = 0.011) remained independent prognostic predictors.

CONCLUSIONS:

Down-regulated nm23-H1 expression is markedly associated with progression from CIN2 to CIN3, and predicts poor prognosis in cervical cancer. Nm23-H1 down regulation is probably orchestrated by mechanisms independent of HR-HPV oncoproteins and is possibly related to the emergence of a proteolytic phenotype.

• Authors: M Branca, C Giorgi, M Ciotti, D Santini, L Di Bonito, S Costa, A Benedetto, D Bonifacio, P Di Bonito, P Paba, L Accardi, L Mariani, M Ruutu, C Favalli, K Syrjänen, HPV-Pathogen Istituto Superiore di Sanità Study Group
• Journal: Journal of clinical pathology (J Clin Pathol) Vol. 59 Issue 10 Pg. 1044-51 (Oct 2006) ISSN: 0021-9746 [Print] England
• PMID: 16537673 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Nucleoside-Diphosphate Kinase

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Biomarkers, Tumor (genetics, metabolism)
• Carcinoma, Squamous Cell (enzymology, pathology, virology)
• Disease Progression
• Down-Regulation
• Epidemiologic Methods
• Female
• Humans
• Middle Aged
• Nucleoside-Diphosphate Kinase (genetics, metabolism)
• Papillomaviridae (classification, isolation & purification)
• Papillomavirus Infections (complications, enzymology)
• Polymerase Chain Reaction (methods)
• Prognosis
• Uterine Cervical Neoplasms (enzymology, pathology, virology)
• Uterine Cervical Dysplasia (enzymology, pathology, virology)