DLX4和SIM1的异常DNA甲基化是子宫颈低度鳞状上皮内病变疾病进展的预测标志物。

Aberrant DNA methylation of DLX4 and SIM1 is a predictive marker for disease progression of uterine cervical low-grade squamous intraepithelial lesion.

作者信息

Sakane Junichi, Taniyama Kiyomi, Miyamoto Kazuaki, Saito Akihisa, Kuraoka Kazuya, Nishimura Toshinao, Sentani Kazuhiro, Oue Naohide, Yasui Wataru

机构信息

Department of Molecular Pathology, Hiroshima University Institute of Biomedical and Health Sciences, Hiroshima, Japan; Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan; Department of Diagnostic Pathology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan.

出版信息

Diagn Cytopathol. 2015 Jun;43(6):462-70. doi: 10.1002/dc.23256. Epub 2015 Jan 22.

DOI:10.1002/dc.23256

PMID:25614457

Abstract

BACKGROUND

A few uterine cervical low-grade squamous intraepithelial lesions (LSILs) are known to progress with high-risk human papillomavirus (hrHPV).

METHODS

One hundred and thirteen patients were classified into four groups according to their cervical cytology, hrHPV infection, and follow up. Cytology samples were examined for aberrant DNA methylation of DLX4 and SIM1 genes and protein expressions. CaSki cells were treated with 5-Aza-2'-deoxycytidine (5-aza-dC).

RESULTS

Group 1 was negative for intraepithelial lesions or malignancies. LSIL in group 2 showed a continuance of LSIL for longer than 365 days and LSIL in group 3 showed an upgrading to high-grade (H) SIL or higher (HSIL+) within 365 days of LSIL diagnosis. Group 4 was squamous cell carcinoma. All but group 1 were infected with hrHPV. Significant differences existed in the frequency of DNA methylation between groups 2 and 3 (p = 0.044), between groups 3 and 4 (p = 0.020) for DLX4, and between groups 1 and 3 (p = 0.0003), and groups 2 and 3 (p = 0.005) for the SIM1 gene. DLX4 protein expression was significantly reduced in the DLX4 methylation positive tissues (p = 0.008). The 5-aza-dC treatment restored DLX4 mRNA expressions of CaSki cells (p < 0.005). The LSIL cases with DNA methylation of the SIM1 gene, or both genes, progressed faster to HSIL+ than did the others (p = 0.033 and p = 0.045, respectively).

CONCLUSION

Aberrant DNA methylation of the DLX4 and SIM1 genes should be a novel progression marker for uterine cervical LSIL with hrHPV infection.

摘要

背景

已知少数子宫颈低级别鳞状上皮内病变（LSIL）会随着高危型人乳头瘤病毒（hrHPV）进展。

方法

根据宫颈细胞学、hrHPV感染情况及随访结果，将113例患者分为四组。对细胞学样本检测DLX4和SIM1基因的异常DNA甲基化及蛋白表达情况。用5-氮杂-2'-脱氧胞苷（5-aza-dC）处理CaSki细胞。

结果

第1组上皮内病变或恶性肿瘤为阴性。第2组的LSIL持续超过365天，第3组的LSIL在诊断后365天内升级为高级别（H）SIL或更高级别（HSIL+）。第4组为鳞状细胞癌。除第1组外，其他组均感染hrHPV。DLX4基因在第2组和第3组之间（p = 0.044）、第3组和第4组之间（p = 0.020）的DNA甲基化频率存在显著差异；SIM1基因在第1组和第3组之间（p = 0.0003）以及第2组和第3组之间（p = 0.005）存在显著差异。DLX4甲基化阳性组织中DLX4蛋白表达显著降低（p = 0.008）。5-aza-dC处理可恢复CaSki细胞的DLX4 mRNA表达（p < 0.005）。SIM1基因或两个基因均发生DNA甲基化的LSIL病例进展为HSIL+的速度比其他病例更快（分别为p = 0.033和p = 0.045）。