HPV16 CpG Methylation Contributes to Cervical Carcinogenesis by Regulating HPV16 Tumorigenesis‐Related Genes

ABSTRACT

HPV16 CpG methylation is associated with cervical carcinogenesis and the expression of HPV16 tumorigenesis‐related genes. However, the genome‐wide methylation profile of HPV16 CpG sites during cervical carcinogenesis has not been fully characterized, and the regulatory role of HPV16 CpG methylation in the expression of these genes in cervical carcinogenesis remains unclear. This study aims to comprehensively map HPV16 CpG methylation patterns across different cervical carcinogenesis stages and elucidate its regulatory effect on the expression of HPV16 tumorigenesis‐related genes as well as biological alterations in cervical cancer cells. A total of 341 participants diagnosed with various stages of cervical lesions and normal cervix were enrolled to evaluate the associations between HPV16 CpG methylation, expression of HPV16 tumorigenesis‐related genes, and cervical carcinogenesis. Demethylation of HPV16 CpG sites in Caski cells using 5‐Aza‐dC was performed to assess subsequent changes in the expression of HPV16 tumorigenesis‐related genes and cellular biological functions. HPV16 hypermethylation was associated with an increased risk of cervical cancer and precancerous lesions. Thirty‐six specific CpG sites across various regions of the HPV16 genome exhibited progressively elevated methylation levels correlating with lesion severity. Effects of HPV16 CpGs methylation on cervical carcinogenesis were partially mediated by HPV16 oncoproteins. Demethylation of HPV16 CpGs significantly suppressed HPV16 oncogene expression, promoted apoptosis, and inhibited proliferation, migration, and invasion in cervical cancer cells. This study provides novel insights into the role of HPV16 CpG methylation in cervical carcinogenesis through the modulation of HPV16 oncogenes. This might represent a promising therapeutic strategy for impeding cervical cancer progression.