AbstractBackgroundDickkopf 2 (DKK2) plays an important role in multiple cancers. Its potential value in the clinical diagnosis of cervical cancer has remained unclear.ObjectivesTo investigate the expression and promoter methylation levels ofDKK2in cervical cancer and their clinicopathological associations.MethodsWe used the Gene Expression Omnibus, Oncomine, Cancer Genome Atlas, and University of ALabama at Birmingham CANcer data analysis databases, reverse transcription-PCR, and methylation-specific PCR analysis to predict and examine the expression of DKK2 mRNA andDKK2methylation levels in cell lines and cervical cancer tissues from 79 patients with cervical cancer and 63 with cervical precancerous lesions including 25 with low-grade squamous intraepithelial lesions (LSIL) and 38 patients with high-grade squamous intraepithelial lesions (HSIL).ResultsDKK2 mRNA expression was downregulated in all cancer cell lines and cervical cancer tissues, whereas hypermethylation ofDKK2was higher in cervical cancer tissue samples.DKK2methylation in cervical cancer was significantly higher than that in HSIL (χ2= 8.346,P= 0.004), whereasDKK2methylation in HSIL was significantly higher than that in normal cervical samples (χ2= 7.934,P= 0.005) and in LSIL samples (χ2= 4.375,P= 0.037).DKK2silencing caused by its promoter hypermethylation was confirmed by treatment with the methyltransferase inhibitor 5-Aza-dC in cell lines. Patients with lymph node metastasis exhibited increased promoter methylation frequency (χ2= 5.239,P= 0.022) and low DKK2 mRNA expression (χ2= 3.958,P= 0.047) compared with patients with no lymph node metastasis. Patients with high-risk human papillomavirus infection exhibited increased promoter methylation frequency (χ2= 6.279,P= 0.015).ConclusionsDKK2epigenetic changes of DKK2 may play a key role in the development of cervical cancer, suggesting thatDKK2hypermethylation could be used as a triage test for screening, early diagnosis, or risk prediction of cervical cancer.