Abstract
Squamous cell carcinoma (SCC) and adenocarcinoma (AC) represent the major cervical cancer histotypes. Both histotypes are caused by infection with high-risk HPV (hrHPV) and are associated with deregulated microRNA expression. Histotype-dependent expression has been observed for miR-9-5p, showing increased expression in SCC and low expression in AC. Here, we studied the regulation and functionality of miR-9-5p in cervical SCCs and ACs using cervical tissue samples and hrHPV-containing cell lines. Expression and methylation analysis of cervical tissues revealed that low levels of miR-9-5p in ACs are linked to methylation of its precursor genes, particularly miR-9-1. Stratification of tissue samples and hrHPV-containing cell lines suggested that miR-9-5p depends on both histotype and hrHPV type, with higher expression in SCCs and HPV16-positive cells. MiR-9-5p promoted cell viability and anchorage independence in cervical cancer cell lines SiHa (SCC, HPV16) and CaSki (metastasized SCC, HPV16), while it played a tumor suppressive role in HeLa (AC, HPV18). TWIST1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), was established as a novel miR-9-5p target. Our results show that miR-9-5p plays a dual role in cervical cancer in a histotype- and hrHPV type-dependent manner. MiR-9-5p mediated silencing of TWIST1 suggests two distinct mechanisms towards EMT in cervical cancer.
Highlights
Cervical cancer is caused by a persistent infection with high-risk types of the human papillomavirus [1,2,3]
MiR-9-5p expression was higher in Squamous cell carcinoma (SCC) and ACs harboring a copy number gain of miR-9-1 compared to carcinomas without a 1q gain (Figure 1b)
To examine whether low expression levels of miR-9-5p in ACs could be explained by hypermethylation of one or more of the three miR-9-5p precursor genes, the methylation status of the three miR-9 promoter regions were analyzed by Quantitative Methylation-Specific PCR (qMSP) in 24 SCC and 17 AC tissue samples (Figure 1c)
Summary
Cervical cancer is caused by a persistent infection with high-risk types of the human papillomavirus (hrHPV) [1,2,3]. 80%) and adenocarcinoma (AC, 10–20%) represent the most prevalent cervical cancer subtypes [4,5]. SCCs develop through a series of precancerous lesions, which arise from squamous epithelial cells present in the ectocervix, whereas columnar epithelial cells in the endocervix give rise to ACs. most SCCs are caused by HPV16, while. HPV18 is linked to cervical ACs [6,7]. During cervical cancer development multiple miRNAs become deregulated, leading to aberrant gene expression and disease progression [8,9,10,11].
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