Methylation-mediated silencing and tumour suppressive function of hsa-miR-124 in cervical cancer

Abstract

BackgroundA substantial number of microRNAs (miRNAs) is subject to epigenetic silencing in cancer. Although epigenetic silencing of tumour suppressor genes is an important feature of cervical cancer, little is known about epigenetic silencing of miRNAs. Since DNA methylation-based silencing of hsa-miR-124 occurs in various human cancers, we studied the frequency and functional effects of hsa-miR-124 methylation in cervical carcinogenesis.ResultsQuantitative MSP analysis of all 3 loci encoding the mature hsa-miR-124 (hsa-miR-124-1/-2/-3) showed methylation in cervical cancer cell lines SiHa, CaSki and HeLa as well as in late passages of human papillomavirus (HPV) type 16 or 18 immortalised keratinocytes. Treatment of SiHa cells with a demethylating agent reduced hsa-miR-124 methylation levels and induced hsa-miR-124 expression. In HPV-immortalised keratinocytes increased methylation levels were related to reduced hsa-miR-124 expression and higher mRNA expression of IGFBP7, a potential hsa-miR-124 target gene. Ectopic hsa-miR-124 expression in SiHa and CaSki cells decreased proliferation rates and migratory capacity. Combined hsa-miR-124-1 and/or hsa-miR-124-2 methylation analysis of 139 cervical tissue specimens showed an increasing methylation frequency from 0% in normal tissues up to 93% in cervical carcinomas. Increased methylation levels of hsa-miR-124-1 and hsa-miR-124-2 were significantly correlated with reduced hsa-miR-124 expression in cervical tissue specimens. Combined hsa-miR-124-1 and/or hsa-miR-124-2 methylation analysis of 43 cervical scrapes of high-risk HPV positive women was predictive of underlying high-grade lesions.ConclusionsDNA methylation-based silencing of hsa-miR-124 is functionally involved in cervical carcinogenesis and may provide a valuable marker for improved detection of cervical cancer and its high-grade precursor lesions.

Downregulation of microRNA-124 is an independent prognostic factor in patients with colorectal cancer

“…As a potential tumor suppressor gene, miR-124 has been shown to regulate growth, proliferation, apoptosis, migration and invasion of tumor cell in certain cancers [11, 14, 17 21, 22]. The tumor-specific hypermethylation-mediated silencing of miR-124 was a relatively frequent molecular event in gastric, cervical and breast cancer [11,16,17]. Moreover, some studies suggested that miR-124 have prognostic and therapeutic potential in hepatocellular cancer and non-small cell lung cancer [12,13,15].…”

“…The down-regulation of miR-124 has also been observed in gastric, cervical and breast cancer, which may be caused by DNA methylation-based silencing [11,16,17]. Additionally, miR-124 has been involved in invasion and metastasis process of hepatocellular cancer, by directly targeting the rho-kinase2 (ROCK2) and an enhancer of the zeste homologue 2 (EZH2) genes [15].…”

“…Recently, as one of the most abundantly expressed miRNAs in the central nervous system, miR-124 has been shown to play a significant role in the pathogenesis of various cancers [10][11][12][13][14][15].…”

Quantitative analysis of the relationship between microRNA‑124a, -34b and -203 gene methylation and cervical oncogenesis

“…To our knowledge, a substantial number of miRNAs are subject to epigenetic silencing in cancer, but only one study has investigated the epigenetic mechanisms (particularly methylation) that govern miRNA expression in cervical cancer (17).…”

198 Hsa-mir-124-3 CpG island methylation is associated with advanced tumours and disease recurrence of patients with clear cell renal cell carcinoma

“…Methylation of the mir-124-3 locus was then identified as an independent prognosticator for both disease-free and overall survival in ALL ). Contribution of mir-124-3 epigenetics to tumour progression is also indicated by gradually increasing methylation levels found in a series of premalignant and malignant cervical tissues of differing biological aggressiveness (Wilting et al, 2010). Although DNA hypermethylation is a frequently observed characteristic in RCC (Baldewijns et al, 2008) only few loci currently including COL14A1 (Morris et al, 2010), GREM1 (van Vlodrop et al, 2010), SFRP1 and DAL-1/ 4.1B (Yamada et al, 2006), were associated with RCC prognosis, provided clinicopathological parameters have been considered as covariates in multi-or bivariate analyses.…”