Interaction between folate deficiency and aberrant expression related to fragile histidine triad gene in the progression of cervical cancerization

Abstract

To explore the interaction between folate deficiency and aberrant expression related to fragile histidine triad (FHIT) gene in the progression of cervical cancerization. A total number of 80 patients with histological diagnosis of cervix inflammation (CI), 55 cervical intraepithelial neoplasm I (CIN I), 55 cervical intraepithelial neoplasm II/III (CIN II/III) and 64 cervical squamous cell carcinoma (SCC) were included in this study. Levels of serum folate were detected by microbiological assay method and the methylation status of FHIT gene CpG islands was tested by methylation-specific PCR (MSP). FHIT protein levels were measured by Western blot. In vitro, cervical cancer cell lines CaSki (HPV16-positive) was treated with different concentrations of folate. Proliferation and apoptosis of cells, methylation of FHIT gene and the levels of FHIT protein expression were measured in each group. All analyses were performed with SPSS (version 17.0) statistical software. Differences among groups were assessed by chi-square test, Kruskal-Wallis test. Spearman correlation, and the interaction effects were evaluated by additive model. The levels of serum folate (H = 59.08, P < 0.001) and FHIT protein expression (H = 50.93, P < 0.001) decreased gradually along with the severity of cervix lesions, while the methylation rates of FHIT gene CpG islands increased (trend χ² = 28.34, P < 0.001). Both levels of serum folate levels and FHIT protein expression were positively correlated (r = 0.213, P = 0.001), with an additive interaction seen between them in CIN I, CIN II/III, SCC groups. In vitro, both rates related to proliferation inhibition (r = 0.98, P < 0.001) and apoptosis (r = 0.99, P < 0.001) together with the levels of FHIT protein expression (r = 0.97, P < 0.001) were all increased gradually with the increase of folate concentration while the methylation status of FHIT gene CpG islands all changed from positive to negative gradually. Results from our study revealed that both folate deficiency and FHIT protein aberrant low expression might increase the risk of developing cervical cancer and cervix precancerous lesions, and thus play a synergistic action in the progression of cervical cancerization.