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hnRNP E1 (heterogeneous nuclear ribonucleoprotein E1) is an important RNA-binding protein (RBPs) that plays a vital role in tumor development. Human papillomavirus 16 (HPV16) contains numerous sites that can bind to RNA/DNA and may be modified by multiple RBPs, which contribute to HPV gene expression and HPV-associated cancer development. However, the effects of hnRNP E1 on HPV16 oncogenes in the development of cervical lesions remain unclear. A total of 816 participants with different grades of cervical lesions were enrolled in a community-based cohort established in Shanxi Province, China. The Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were used to analyze the association between hnRNP E1 mRNA expression and cervical lesions. Cells with up_ and down_regulated hnRNP E1 were established. hnRNP E1 functions were evaluated using cell counting kit-8, flow cytometry analyses, and chromatin immunoprecipitation sequencing. Our results showed that hnRNP E1 expression was linearly dependent on the severity of the cervical lesions. Low expression of HPV16 E2, high expression of E6, and a low ratio of E2 to E6 could increase the risk of cervical lesions. hnRNP E1 expression was correlated with HPV16 oncogene expression. hnRNP E1-relevant genes were involved in the dopaminergic synapses, Wnt signaling pathway, gnRH secretion, and mTOR signaling pathway. hnRNP E1 significantly inhibited cell proliferation, induced apoptosis, arrested the cell cycle at the G0/G1 stage, and decreased HPV16 E6 expression. Our results indicate that hnRNP E1 could downregulate HPV16 E6 oncogene expression and inhibit cervical cancerization, which sheds new light on preventing the carcinogenicity of HPV across a range of diseases by regulating RNA-binding proteins. [ABSTRACT FROM AUTHOR]

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]