| ObjectiveCervical cancer (CC) remains one of the greatest killers of women worldwide. HPV infection, especially high-risk HPV 16 infection, is a necessary cause of CC, but there are cofactors may facilitate development of CC. Epidemiological evidence remains uncertain for the role of folate in the development of CC. Because of the close association between folate, DNA methylation and cervical cancer, it is expected that folate may play its important role in cervical lesions through its effect on DNA methylation. In oeder to test this hypothesis, this study was conduvted to investigate the roles of HPV 16 and serum folate on cervical lesions, and to explore the interaction between HPV 16 and serum folate. To explore the significance of DNMT1 expression and FHIT gene aberrant methylation in cervical lesions and to investigate the association between serum folate, expression of DNMT1 and FHIT gene methylation..MethodsA hospital-based case-control study was conducted. The study population comprises 100 cases of cervical cancer newly diagnosed by pathological methods in Shanxi Tumor Hospital during Jun.2008 to Aug.2009,101 cervical intraepithelial neoplasia patients diagnosed by pathology and 109 controls of chronic cervicitis at the same time from the Second Clinical Hospital of Shanxi Medical University. Any participant who had cerebrovascular disease, haemolyticus disease, digestive system disease, VitB supplement within 3 months and other dysplasias were considered ineligible for study. Fasting blood and cervix tissues were collected. HPV16 was gained by PCR, serum folate was measured by using radioimmunoassay. FHIT gene methylation was detected by methylation-specific PCR (MSP) and the expression of DNMT1 protein was examined by western blotting.Results(1) The rate of HPV 16 infection in cervical cancer (61.0%) and cervical intraepithelial neoplasia (38.6%) were both significantly higher than that in controls (20.2%) (χ2=36.29, P=0.000;χ2=8.64, P=0.003).(2) The levels of serum folate in cervical cancer (1.86±2.14 ng/ml) was significantly lower than that in controls (3.19±2.50 ng/ml), but the difference between cervical cancer and cervical intraepithelial neoplasia (2.60±2.46 ng/ml) was not statistically significant; By Quartile based on serum folate of control, there was a dose-responded relationship between increased risk of cervical cancer and decreased serum folate (χ2趋势1=14.842, P1=0.000), but there was not a dose-responded relationship between increased risk of cervical intraepithelial neoplasia and decreased serum folate (χ2趋势2=2.301, P2=0.129).(3) The expression of DNMT1 was significantly higher in cervical cancer (2.93±0.36) and cervical intraepithelial neoplasia (1.87±0.33) than in cervicitis (0.89±0.30), and the expression was higher in cervical cancer than in cervical intraepithelial neoplasia, the differences were all statistically significant (P= 0.000, P= 0.000, P=0.000).(4) The rate of FHIT aberrant methylation was significantly higher in cervical cancer groups (39.0%) when compared with cervicitis control (2.8%) (χ2=42.67, P=0.00), while the difference of the rate between cervical intraepithelial neoplasia (3.0%) and cervicitis control was not statistically significant (χ2=0.00, P=1.00). The aberrant methylation was increasing along with the progress of cervical lesion (χ2趋势=53.56, P=0.000).(5) The analysis of biological interaction between serum folate levels and DNMT1 expression indicatated that there was a positive addictive interaction both in cervical cancer and cervical intraepithelial neoplasia.(6) It indicated that there were positive addictive interactions between serum folate levels and FHIT gene CpG methylation, DNMT1 expression and FHIT gene CpG methylation in cervical cancer, but our study failed to confirm the interaction between both of them in cervical intraepithelial neoplasia.(7) HPV16, the levels of serum folate, FHIT gene methylation, young age at first sextual intercourse, more frequencies of pregnancy, levels of education were involved in multiple logistic regression models in cervical cancer; The HPV16, young age at first sextual intercourse and frequencies of pregnancy were involved in multiple logistic regression models in cervical intraepithelial neoplasia.Conclusions(1) Low levels of serum folate might be a risk factor in cervical cancer; The DNMT1 protein expression has an important role both in cervical cancer and cervical intraepithelial neoplasia, there might be a positive additive interaction in cervical cancer.(2) FHIT aberrant methylation is a risk factor in cervical cancer.(3) There might be a conspiracy between serum folate status and DNMT1, serum folate status and FHIT gene aberrant methylation, DNMT1 protein and FHIT gene aberrant methylation in cervical cancer.(4) HPV16 infection, young age at first sextual intercourse, more frequencies of pregnancy were main risk factors for cervical cance and cervical intraepithelial neoplasia r; The levels of education was protective factors for cervical cancer. |
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