Abstract
The abnormally methylated tumor suppressor genes (TSGs) associated with cervical cancer are unclear. DNA methylation data, RNA-seq expression profiles, and overall survival data were downloaded from TCGA CESC database. DMGs and DEGs were obtained through CHAMP and DESeq packages, respectively. TSGs were downloaded from TSGene 2.0. Candidate hypermethylated/down-regulated TSGs were further evaluated and pyrosequencing was used to confirm their difference in methylation levels of selected TSGs in cervical cancer patients. A total of 25946 differentially methylated CpGs corresponding to 2686 hypermethylated genes and 4898 hypomethylated genes between cervical cancer and adjacent normal cervical tissues were found in this study. Besides, 693 DEGs (109 up-regulated and 584 down-regulated) were discovered in cervical cancer tissues. Then, 192 hypermethylated/down-regulated genes were obtained in cervical cancer compared to adjacent tissues. Interestingly, 26 TSGs were found in hypermethylated/down-regulated genes. Among these genes, low expression of MRVI1 and NTRK3 was associated with poor overall survival in cervical cancer. Moreover, GEO data showed that MRVI1 and NTRK3 were significantly decreased in cervical cancer tissues. The expression levels of MRVI1 and NTRK3 were negatively correlated with the methylation levels of their promoter CpG sites. Additionally, elevated methylation levels of MRVI1 and NTRK3 promoter were further verified in cervical cancer tissues by pyrosequencing experiments. Finally, the ROC results showed that the promoter methylation levels of MRVI1 and NTRK3 had the ability to discriminate cervical cancer from healthy samples. The study contributes to our understanding of the roles of MRVI1 and NTRK3 in cervical cancer.
Highlights
Cervical cancer is the fourth most common cancer and the fourth leading cause of cancer death in women [1]
In this study, hypermethylated and significantly lower expressions of tumor suppressor genes (TSGs) MRVI1 and NTRK3 were discovered in cervical cancers than that in normal cervical tissues using the bioinformatics
The differences of MRVI1 and NTRK3 expressions between cervical cancer specimens and normal cervical tissues were further verified via three Gene Expression Omnibus (GEO) datasets
Summary
Cervical cancer is the fourth most common cancer and the fourth leading cause of cancer death in women [1]. The prognosis varies depending on the stage of cervical cancer. Epigenetic variations could change the expression of tumor suppressor genes (TSGs) in cervical cancer [4]. DNA methylation is an important part of epigenetics [5, 6] and the regulatory effect of DNA methylation on gene expression has been studied extensively [7, 8]. Aberrant methylation of TSGs could silence the expression of TSGs to promote tumor formation [10]. Compared with the control samples, the promoter methylation frequency of TSG (including RARB, CADM1, PAX1, and DAPK1) in patients with invasive cervical cancer is higher [14]. Changes in DNA methylation and related abnormal TSGs expression have not been systematically elucidated in cervical cancer
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