miR-9-5p Exerts a Dual Role in Cervical Cancer and Targets Transcription Factor TWIST1
miR-9-5p Exerts a Dual Role in Cervical Cancer and Targets Transcription Factor TWIST1
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DOI：
10.3390/cells9010065
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发表时间：
2020-01-01
期刊：
影响因子：
6
通讯作者：
Steenbergen, Renske D. M.
中科院分区：
文献类型：
--
作者：
Babion, Iris;Jaspers, Annelieke;Steenbergen, Renske D. M.
鳞状细胞癌（SCC）和腺癌（AC）代表主要的宫颈癌组织型。这两种组织型都是由高危 HPV (hrHPV) 感染引起的，并且与 microRNA 表达失调相关。观察到 miR-9-5p 具有组织型依赖性表达，显示在 SCC 中表达增加，在 AC 中表达降低。在这里，我们使用宫颈组织样本和含有 hrHPV 的细胞系研究了 miR-9-5p 在宫颈 SCC 和 AC 中的调节和功能。宫颈组织的表达和甲基化分析表明，AC 中 miR-9-5p 的低水平与其前体基因（尤其是 miR-9-1）的甲基化有关。组织样本和含有 hrHPV 的细胞系的分层表明，miR-9-5p 取决于组织型和 hrHPV 类型，在 SCC 和 HPV16 阳性细胞中表达较高。 MiR-9-5p 在宫颈癌细胞系 SiHa（SCC，HPV16）和 CaSki（转移性 SCC，HPV16）中促进细胞活力和贴壁独立性，同时在 HeLa（AC，HPV18）中发挥肿瘤抑制作用。 TWIST1 是一种参与上皮间质转化 (EMT) 的转录因子，被确立为新的 miR-9-5p 靶标。我们的结果表明，miR-9-5p 以组织型和 hrHPV 类型依赖性方式在宫颈癌中发挥双重作用。 MiR-9-5p 介导的 TWIST1 沉默表明宫颈癌中 EMT 的两种不同机制。
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.