Zhang Xian, Li Aihua, Wu Jie, Wu Yu, Ma Xiaoping, Liu Yanjun, Chen Qingfa, Zhang Yan
Department of Gynecology and Obstetrics, Liaocheng People's Hospital and Liaocheng Clinical School of Shandong First Medical University, Liaocheng, Shandong 252000, China.
Department of Pathology, Affiliated Hospital of Qingdao University, Qingdao, Shandong 266000, China.
Asian Biomed (Res Rev News). 2022 Aug 31;16(4):181-189. doi: 10.2478/abm-2022-0022. eCollection 2022 Aug.
Dickkopf 2 () plays an important role in multiple cancers. Its potential value in the clinical diagnosis of cervical cancer has remained unclear.
To investigate the expression and promoter methylation levels of in cervical cancer and their clinicopathological associations.
We 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 and methylation 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).
DKK2 mRNA expression was downregulated in all cancer cell lines and cervical cancer tissues, whereas hypermethylation of was higher in cervical cancer tissue samples. methylation in cervical cancer was significantly higher than that in HSIL (χ = 8.346, = 0.004), whereas methylation in HSIL was significantly higher than that in normal cervical samples (χ = 7.934, = 0.005) and in LSIL samples (χ = 4.375, = 0.037). silencing 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 (χ = 5.239, = 0.022) and low DKK2 mRNA expression (χ = 3.958, = 0.047) compared with patients with no lymph node metastasis. Patients with high-risk human papillomavirus infection exhibited increased promoter methylation frequency (χ = 6.279, = 0.015).
epigenetic changes of DKK2 may play a key role in the development of cervical cancer, suggesting that hypermethylation could be used as a triage test for screening, early diagnosis, or risk prediction of cervical cancer.
Dickkopf 2（DKK2）在多种癌症中发挥重要作用。其在宫颈癌临床诊断中的潜在价值尚不清楚。
研究DKK2在宫颈癌中的表达及启动子甲基化水平及其与临床病理的相关性。
我们使用基因表达综合数据库、Oncomine、癌症基因组图谱以及阿拉巴马大学伯明翰分校癌症数据分析数据库、逆转录聚合酶链反应（RT-PCR）和甲基化特异性PCR分析，来预测和检测79例宫颈癌患者及63例宫颈上皮内瘤变患者（包括25例低级别鳞状上皮内病变（LSIL）和38例高级别鳞状上皮内病变（HSIL））的细胞系和宫颈癌组织中DKK2 mRNA的表达及甲基化水平。
DKK2 mRNA表达在所有癌细胞系和宫颈癌组织中均下调，而宫颈癌组织样本中DKK2的高甲基化水平更高。宫颈癌中的甲基化显著高于HSIL（χ² = 8.346，P = 0.004），而HSIL中的甲基化显著高于正常宫颈样本（χ² = 7.934，P = 0.005）和LSIL样本（χ² = 4.375，P = 0.037）。通过在细胞系中用甲基转移酶抑制剂5-氮杂-2'-脱氧胞苷（5-Aza-dC）处理，证实了其启动子高甲基化导致的DKK2沉默。与无淋巴结转移的患者相比，有淋巴结转移的患者启动子甲基化频率增加（χ² = 5.239，P = 0.022）且DKK2 mRNA表达较低（χ² = 3.958，P = 0.047）。高危型人乳头瘤病毒感染的患者启动子甲基化频率增加（χ² = 6.279，P = 0.015）。
DKK2的表观遗传变化可能在宫颈癌的发生发展中起关键作用，提示DKK2高甲基化可作为宫颈癌筛查、早期诊断或风险预测的分流检测指标。
