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.
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.


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.
Branca
M
M
Unità Citoistopatologia, Centro Nazionale di Epidemiologia, Sorveglianza e Promozione della Salute, Istituto Superiore di Sanità (ISS), Rome, Italy.
Giorgi
C
C
Ciotti
M
M
Santini
D
D
Di Bonito
L
L
Costa
S
S
Benedetto
A
A
Bonifacio
D
D
Di Bonito
P
P
Paba
P
P
Accardi
L
L
Mariani
L
L
Ruutu
M
M
Favalli
C
C
Syrjänen
K
K
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000473:pathology / Q000821:virology; D018450:Disease Progression; D015536:Down-Regulation; D004812:Epidemiologic Methods; D005260:Female; D006801:Humans; D008875:Middle Aged; D009701:Nucleoside-Diphosphate Kinase / Q000235:genetics / Q000378:metabolism*; D027383:Papillomaviridae / Q000145:classification / Q000302:isolation & purification*; D030361:Papillomavirus Infections / Q000150:complications / Q000201:enzymology*; D016133:Polymerase Chain Reaction / Q000379:methods; D011379:Prognosis; D002583:Uterine Cervical Neoplasms / Q000201:enzymology* / Q000473:pathology / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000201:enzymology* / Q000473:pathology / Q000821:virology
D014408:Biomarkers, Tumor; D009701:Nucleoside-Diphosphate Kinase