Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
Oncogene. 2013 Jan 3;32(1):106-16. doi: 10.1038/onc.2012.20. Epub 2012 Feb 13.
Little is known about the alterations in microRNA (miRNA) expression patterns during the consecutive stages of cervical cancer development and their association with chromosomal instability. In this study, miRNA expression in normal cervical squamous epithelium, high-grade precancerous lesions (cervical intraepithelial neoplasia (CIN2-3)), squamous cell carcinomas (SCCs) and adenocarcinomas (AdCAs) was integrated with previously generated chromosomal profiles of the same samples. Significantly differential expression during the consecutive stages of cervical SCC development was observed for 106 miRNAs. Of these differentially expressed miRNAs, 27 showed early transiently altered expression in CIN2-3 lesions only, 46 miRNAs showed late altered expression in SCCs only and 33 showed continuously altered expression in both CIN2-3 and SCCs. Altered expression of five significantly differentially expressed miRNAs, hsa-miR-9 (1q23.2), hsa-miR-15b (3q25.32), hsa-miR-28-5p (3q27.3), hsa-miR-100 and hsa-miR-125b (both 11q24.1), was directly linked to frequent chromosomal alterations. Functional analyses were performed for hsa-miR-9, representing a potential oncogene with increased expression linked to a chromosomal gain of 1q. Hsa-miR-9 overexpression was found to increase cell viability, anchorage-independent growth and migration in vitro. Upon organic raft culturing, hsa-miR-9 hampered differentiation and induced proliferation in all strata of the epithelial layer. These findings support a potential oncogenic function of hsa-miR-9 in cervical cancer. In summary, differential expression of 106 miRNAs, partly associated with chromosomal alterations, was observed during cervical SCC development. Altered expression of hsa-miR-9 associated with a chromosomal gain of chromosome 1q was shown to be functionally relevant, underlining the importance of deregulated miRNA expression in cervical carcinogenesis.
关于微 RNA (miRNA) 表达模式在宫颈癌发展的连续阶段的改变及其与染色体不稳定性的关系知之甚少。在这项研究中,整合了相同样本的 miRNA 表达与先前生成的染色体图谱,研究了正常宫颈鳞状上皮、高级别癌前病变(宫颈上皮内瘤变 (CIN2-3))、鳞状细胞癌 (SCC) 和腺癌 (AdCA) 中的 miRNA 表达。在宫颈癌 SCC 发展的连续阶段观察到 106 个 miRNA 存在显著差异表达。在这些差异表达的 miRNA 中,27 个 miRNA 在 CIN2-3 病变中仅表现出早期短暂改变的表达,46 个 miRNA 在 SCC 中仅表现出晚期改变的表达,33 个 miRNA 在 CIN2-3 和 SCC 中均表现出持续改变的表达。五个显著差异表达的 miRNA,hsa-miR-9 (1q23.2)、hsa-miR-15b (3q25.32)、hsa-miR-28-5p (3q27.3)、hsa-miR-100 和 hsa-miR-125b(均位于 11q24.1),的表达改变与频繁的染色体改变直接相关。对 hsa-miR-9 进行了功能分析,hsa-miR-9 是一种潜在的癌基因,其表达增加与 1q 的染色体增益有关。发现 hsa-miR-9 的过表达可增加体外细胞活力、非锚定依赖性生长和迁移。在有机筏培养中,hsa-miR-9 可阻止上皮层所有层的分化并诱导增殖。这些发现支持 hsa-miR-9 在宫颈癌中具有潜在的致癌功能。总之,在宫颈癌 SCC 发展过程中观察到 106 个 miRNA 的差异表达,部分与染色体改变有关。与 1q 染色体增益相关的 hsa-miR-9 的表达改变被证明具有功能相关性,突出了 miRNA 表达失调在宫颈癌发生中的重要性。