Search

The associations between human papillomavirus (HPV) infection or hormonal exposure and cervical cancer risk are well established. However, to the best of our knowledge, the association between high endogenous estradiol levels in conjunction with HPV/HPV16 infection and the risk of cervical squamous cell carcinoma remains unknown. To investigate this, the current study conducted a matched case-control study in Shanxi Province, China, in which clinical samples were obtained from 74 females with newly diagnosed uterine cervix squamous cell carcinoma and 74 matched healthy females who were selected from 582 healthy females according to age, place of residence, marital status and menopausal status. From all participants, DNA was extracted from cells obtained from a cervical smear and serum was separated from venous blood withdrawn during days 5–8 of the menstrual cycle. HPV/HPV16 DNA and estradiol expression levels in the serum were measured by general polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. Significant differences were identified in the positive HPV and HPV16 DNA expression rates between patients and controls, with odds ratios (95% confidence interval) of 3.74 (1.84–7.59) and 4.04 (1.97–8.28), respectively. Expression levels of estradiol in patients were significantly higher compared with the controls (P<0.001), however, this was only identified when the HPV16 E2 or E6 oncogene status was negative. Considering 40 ng/ml as the cut-off estradiol level, 78.38% of patients exhibited high estradiol levels, which was significantly higher than the percentage of controls (P<0.001). An additive interaction pattern was revealed between estradiol expression levels and HPV/HPV16 infection. The results suggest that among the various types of HPV, HPV16 may be most likely to cause uterine cervix squamous cell carcinoma and an abnormally high level of endogenous estradiol may further increase this risk. Therefore, estradiol therapy may represent a new treatment strategy for cases of cervical cancer associated with HPV infection. [ABSTRACT FROM AUTHOR]

Aberrant DNA methylation is a recognized feature in various types of human cancer, and folate has a vital role in the epigenetics of mammalian cells by supplying methyl groups for DNA methylation reactions. Fragile histidine triad (FHIT) is a tumor suppressor gene that is frequently silenced in cervical cancer (CC) and preneoplastic lesions. Promoter hypermethylation was previously observed in CC, and its epigenetic silencing has been observed at mRNA or protein levels. Changes in folate intake to modulate DNA methylation may be a mechanistic link to cancer, but this remains to be elucidated. The aim of the present study was to evaluate the influences of folate on FHIT gene methylation and expression in the progression of cervical cancerization. In the present study, red blood cell (RBC) folate levels, FHIT gene methylation status, and mRNA and protein expression levels were detected in 254 women, including normal cervix (NC, n=80), cervical intraepithelial neoplasm grade 1 (CIN1, n=55; CIN2/3, n=55) and cervical squamous cell carcinoma (SCC, n=64) samples. The methylation status of FHIT gene and its mRNA and protein expression levels were measured in CaSki (HPV16 positive) and C33A (HPV16 negative) CC cells treated with different concentrations of folate. The results indicated that FHIT gene methylation rate increased with the severity of cervix lesions, however, RBC folate levels, FHIT mRNA and protein expression levels were reduced. The proliferation inhibition rate, apoptosis rate, and FHIT protein and mRNA expression levels increased along with rising concentrations of folate, whereas the degree of FHIT gene methylation gradually weakened in CaSki or C33A cell lines. The present findings indicated that folate deficiency, FHIT gene promoter hypermethylation and reduced expression were significantly associated with cervical carcinogenesis. The results indicated that folate was able to enhance apoptosis and inhibit the cervical cell proliferation while regulating FHIT gene methylation and expression. Adequate intake of folate to maintain normal DNA methylation status is an effective way for cervical lesions prevention, and demethylation treatment may offer a new strategy for therapy of CC. [ABSTRACT FROM AUTHOR]