Down-regulated nucleoside diphosphate (NDP) kinase nm23-H1 expression is unrelated to high-risk human papillomavirus (HPV) but associated with progression of CIN and unfavourable prognosis of cervical cancer

摘要

Objective: One of the factors leading to an invasive phenotype is the nm23 family of metastasesassociated\udgenes. Of the six known members, nm23-H1 is the most frequently studied potential antimetastatic\udgene in cervical cancer. However, the possible molecular links to oncogenic human\udpapillomavirus (HPV) are completely unexplored as yet.\udMaterials and methods: As a part of the HPV-Pathogen Istituto Superiore di Sanita` study, a series of 150\udsquamous cell carcinomas (SCCs) and 152 cervical intraepithelial neoplasia (CIN) lesions were examined\udby immunohistochemical staining for nm23-H1, and tested for HPV by polymerase chain reaction (PCR)\udwith three sets of primers (MY09/11, GP5+/GP6+ and short PCR fragment). Follow-up data were\udavailable on all patients with SCC, and 67 CIN lesions were monitored by serial PCR for clearance or\udpersistence of HPV after cone treatment.\udResults: A linear decrease (p = 0.001) was observed in nm23-H1 expression, starting from CIN1 (85%\udwith normal expression), with the most dramatic down regulation on transition from CIN2 (70% normal) to\udCIN3 (39%) and further to SCC (25%). Reduced expression was associated with CIN3 or cancer at an\udodds ratio 8.72 (95% confidence interval 4.13 to 18.41). Nm23-H1 was of no use as a marker of the\udhigh-risk human papillomavirus (HR-HPV) type, and it did not predict clearance or persistence of HR-HPV\udafter treatment of CIN. Importantly, nm23-H1 expression was a significant prognostic factor in cervical\udcancer, reduced expression being associated with lower survival (p = 0.022) in univariate analysis. In the\udmultivariate (Cox) regression model, however, only the International Federation of Gynecology and\udObstetrics stage (p = 0.001) and age (p = 0.011) remained independent prognostic predictors.\udConclusions: Down-regulated nm23-H1 expression is markedly associated with progression from CIN2 to\udCIN3, and predicts poor prognosis in cervical cancer. Nm23-H1 down regulation is probably\udorchestrated by mechanisms independent of HR-HPV oncoproteins and is possibly related to the\udemergence of a proteolytic phenotype.