Methylation-mediated transcriptional repression of microRNAs during cervical carcinogenesis

Abstract

Deregulated expression of microRNAs (miRNAs) is common and biologically relevant in cervical carcinogenesis and appears only partly related to chromosomal changes. We recently identified 32 miRNAs showing decreased expression in high-grade cervical intraepithelial neoplasia (CIN) and carcinomas not associated with a chromosomal loss, 6 of which were located within a CpG island. This study aimed to investigate to what extent these miRNAs are subject to DNA methylation-mediated transcriptional repression in cervical carcinogenesis. Methylation-specific PCR (MSP) analysis on a cell line panel representing different stages of human papillomavirus (HPV) induced transformation revealed an increase in methylation of hsa-miR-149, -203 and -375 with progression to malignancy, whereas expression of these miRNAs was restored upon treatment with a demethylating agent. All three miRNAs showed significantly increased levels of methylation in cervical carcinomas, whereas methylation levels of hsa-miR-203 and -375 were also significantly increased in high-grade CIN. A pilot analysis showed that increased hsa-miR-203 methylation was also detectable in HPV-positive cervical scrapes of women with high-grade CIN compared with controls. Similar to recent findings on hsa-miR-375, ectopic expression of hsa-miR-203 in cervical cancer cells decreased both the proliferation rate and anchorage independent growth. We found evidence for methylation-mediated transcriptional repression of hsa-miR-149, -203 and -375 in cervical cancer. Methylation of the latter two was already apparent in precancerous lesions and represent functionally relevant events in HPV-mediated transformation. Increased hsa-miR-203 methylation was detectable in scrapes of women with high-grade CIN, indicating that methylated miRNAs may provide putative markers to assess the presence of (pre)cancerous lesions.

miR-203 Suppresses Tumor Growth and Angiogenesis by Targeting VEGFA in Cervical Cancer

“…Recently, hypermethylation of miR-203 promoter has been found in HCC, cervical cancer and CML [12,13,17,32]. In this study, we confirmed that the mechanism of miR-203 downregulation was closely associated with the hypermethylation in its promoter region.…”

“…Recent studies found that miR-203 was significantly deregulated in cervical carcinoma [11,12,13]; however, the underlying mechanisms by which miR-203 affects tumor growth and angiogenesis are still not well elucidated. In the present study, we confirmed that miR-203 expression levels were significantly down-regulated in cervical cancer tissues and cell lines.…”

“…Several miRNAs are down-regulated in cervical cancer, such as miR-214, miR-143, miR-375 and miR-23b [7,8,9,10], suggesting their potential involvement in the development of this malignancy. Recently, miR-203 has been reported to be deregulated in cervical cancer compared with normal cervical squamous epithelial specimens, and its downregulation is closely associated with promoter hypermethylation [11,12,13]. The involvement of miR-203 in the tumorigenesis and development of bladder, breast, and prostate cancers, as well as hepatocellular carcinoma have also been reported [14,15,16,17].…”

Clinical implications of (epi)genetic changes in HPV-induced cervical precancerous lesions

“…in cervical cancers has been linked to increased promoter methylation of respective genes 73,74,83,84 . These data are fully in line with the concept that an increase in specific genetic and epigenetic alterations reflects a longer duration of existence of the underlying lesion.…”

Association of miR-149C>T and miR-499A>G polymorphisms with the risk of hepatocellular carcinoma in the Chinese population

“…MiR-149C>T polymorphisms have been widely investigated in various cancers, such as gastric cancer, lung cancer, colorectal cancer, nasopharyngeal carcinoma, and breast cancer (Luo et al, 2012;Wang et al, 2012;Øster et al, 2013;Wilting et al, 2013;Zhang et al, 2013). Two studies reported that miRNA-149C>T polymorphisms are associated with the development of HCC (Liu et al, 2010;Kim et al, 2012).…”