Integrative analysis of DNA methylation and gene expression identified cervical cancer-specific diagnostic biomarkers

Cervical cancer is the leading cause of death among women with cancer worldwide.Here,we performed an integrative analysis of Illumina HumanMethylation450K and RNA-seq data from TCGA to identify cervical cancer-specific DNA methylation markers.We first identified differentially methylated and expressed genes and examined the correlation between DNA methylation and gene expression.The DNA methylation profiles of 12 types of cancers,including cervical cancer,were used to generate a candidate set,and machine-learning techniques were adopted to define the final cervical cancer-specific markers in the candidate set.Then,we assessed the protein levels of marker genes by immunohistochemistry by using tissue arrays containing 93 human cervical squamous cell carcinoma samples and cancer-adjacent normal tissues.Promoter methylation was negatively correlated with the local regulation of gene expression.In the distant regulation of gene expression,the methylation of hypermethylated genes was more likely to be negatively correlated with gene expression,while the methylation of hypomethylated genes was more likely to be positively correlated with gene expression.Moreover,we identified four cervical cancer-specific methylation markers,cg07211381(RAB3C),cg12205729(GABRA2),cg20708961(ZNF257),and cg26490054(SLC5A8),with 96.2%sensitivity and 95.2%specificity by using the tenfold cross-validation of TCGA data.The four markers could distinguish tumors from normal tissues with a 94.2,100,100,and 100%AUC in four independent validation sets from the GEO database.Overall,our study demonstrates the potential use of methylation markers in cervical cancer diagnosis and may boost the development of new epigenetic therapies.

E6-induced selective translation of WNT4 and JIP2 promotes the progression of cervical cancer via a noncanonical WNT signaling pathway

mRNA translation reprogramming occurs frequently in many pathologies,including cancer and viral infection.It remains largely unknown whether viral-induced alterations in mRNA translation contribute to carcinogenesis.Most cervical cancer is caused by high-risk human papillomavirus infection,resulting in the malignant transformation of normal epithelial cells mainly via viral E6 and E7 oncoproteins.Here,we utilized polysome profiling and deep RNA sequencing to systematically evaluate E6-regulated mRNA translation in HPV18-infected cervical cancer cells.We found that silencing E6 can cause over a two-fold change in the translation efficiency of~653 mRNAs,most likely in an eIF4E-and eIF2α-independent manner.In addition,we identified that E6 can selectively upregulate the translation of WNT4,JIP1,and JIP2,resulting in the activation of the noncanonical WNT/PCP/JNK pathway to promote cell proliferation in vitro and tumor growth in vivo.Ectopic expression of WNT4/JIP2 can effectively rescue the decreased cell proliferation caused by E6 silencing,strongly suggesting that the WNT4/JIP2 pathway mediates the role of E6 in promoting cell proliferation.Thus,our results revealed a novel oncogenic mechanism of E6 via regulating the translation of mRNAs.