¹ Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità (ISS), Rome, Italy
² Department of Infectious, Parasitic and Immunomediated Diseases, ISS
³ Laboratory of Clinical Microbiology and Virology, University Hospital "Policlinico Tor Vergata", Rome
⁴ Dipertimento di Ginecologia e Ostetrica, Azienda Ospedaliera S. Orsola Malpighi, Bologna, Italy
⁵ UCO Anatomia Patologica, Istopatologia e Citodiagnostica, Ospedale Maggiore, Trieste, Italy
⁶ Ginecologia e Ostetrica, IFO, Istituto Regina Elena, Rome
⁷ Department of Oral Pathology, Institute of Dentistry, University of Turku, Turku, Finland

Correspondence to:
K Syrjänen
Department of Oncology & Radiotherapy, Turku University Central Hospital, Savitehtaankatu 1, FIN-20521 Turku, Finland; kari.syrjanen{at}tyks.fi 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.

Abbreviations: CIN, cervical intraepithelial neoplasia; ERK, extracellular signal-regulated kinase; FIGO, International Federation of Gynecology and Obstetrics; HPV, oncogenic human papillomavirus; HR-HPV, high-risk human papillomavirus; IHC, immunohistochemistry; ISS, Istituto Superiore di Sanità; LR-HPV, low-risk human papillomavirus; MMP, matrix metalloproteinase; NDP, nucleoside diphosphate; NPV, negative predictive value; PCR, polymerase chain reaction; PPV, positive predictive value; SCC, squamous cell carcinoma; VEGF, vascular endothelial growth factor

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