Abstract
BackgroundThe aim of this study was to evaluate epigenetic status of cyclin A1 in human papillomavirus-associated cervical cancer. Y. Tokumaru et al., Cancer Res 64, 5982-7 (Sep 1, 2004)demonstrated in head and neck squamous-cell cancer an inverse correlation between cyclin A1 promoter hypermethylation and TP53 mutation. Human papillomavirus-associated cervical cancer, however, is deprived of TP53 function by a different mechanism. Therefore, it was of interest to investigate the epigenetic alterations during multistep cervical cancer development.MethodsIn this study, we performed duplex methylation-specific PCR and reverse transcriptase PCR on several cervical cancer cell lines and microdissected cervical cancers. Furthermore, the incidence of cyclin A1 methylation was studied in 43 samples of white blood cells, 25 normal cervices, and 24, 5 and 30 human papillomavirus-associated premalignant, microinvasive and invasive cervical lesions, respectively.ResultsWe demonstrated cyclin A1 methylation to be commonly found in cervical cancer, both in vitro and in vivo, with its physiological role being to decrease gene expression. More important, this study demonstrated that not only is cyclin A1 promoter hypermethylation strikingly common in cervical cancer, but is also specific to the invasive phenotype in comparison with other histopathological stages during multistep carcinogenesis. None of the normal cells and low-grade squamous intraepithelial lesions exhibited methylation. In contrast, 36.6%, 60% and 93.3% of high-grade squamous intraepithelial lesions, microinvasive and invasive cancers, respectively, showed methylation.ConclusionThis methylation study indicated that cyclin A1 is a potential tumor marker for early diagnosis of invasive cervical cancer.
Highlights
The aim of this study was to evaluate epigenetic status of cyclin A1 in human papillomavirusassociated cervical cancer
[1] When exposed to and infected by one of the high-risk human papillomaviruses (HPV), vulnerable cervical epithelium may enter a complex multistep process and develop an invasive carcinoma. [2,3,4] The spectrum of histologic alterations during the intricate processes of multistep carcinogenesis can be classified as premalignant lesions, including low-grade and high-grade squamous intraepithelial lesions (SILs), and malignant invasive cervical cancers
[13] Similar to head and neck squamous-cell cancer (HNSCC), the majority of CC is of squamous cell origin and its molecular carcinogenesis strongly correlates with impaired TP53 function. [16,17,18] unlike HNSCC, the functional loss of TP53 in CC is not ascribed to gene mutation, but is processed by viral and host protein-protein interaction
Summary
The aim of this study was to evaluate epigenetic status of cyclin A1 in human papillomavirusassociated cervical cancer. Y. Tokumaru et al, Cancer Res 64, 5982-7 (Sep 1, 2004)demonstrated in head and neck squamous-cell cancer an inverse correlation between cyclin A1 promoter hypermethylation and TP53 mutation. [1] When exposed to and infected by one of the high-risk human papillomaviruses (HPV), vulnerable cervical epithelium may enter a complex multistep process and develop an invasive carcinoma. [2,3,4] The spectrum of histologic alterations during the intricate processes of multistep carcinogenesis can be classified as premalignant lesions, including low-grade and high-grade squamous intraepithelial lesions (SILs), and malignant invasive cervical cancers. The expression of CCNA1 has been demonstrated to be downregulated in several cancers, such as nasopharyngeal carcinoma and head and neck squamous-cell cancer (HNSCC). In comparison with HNSCC, it was of interest to determine if CCNA1 is methylated in HPV-associated squamous cell CC
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