He Qianting, Chen Zujian, Dong Qian, Zhang Leitao, Chen Dan, Patel Aditi, Koya Ajay, Luan Xianghong, Cabay Robert J, Dai Yang, Wang Anxun, Zhou Xiaofeng
Center for Molecular Biology of Oral Diseases, Department of Periodontics, College of Dentistry, University of Illinois at Chicago, Chicago, IL, USA.
Department of Oral and Maxillofacial Surgery, the First Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China.
BMC Cancer. 2016 Aug 25;16(1):685. doi: 10.1186/s12885-016-2716-0.
Oral tongue squamous cell carcinoma (OTSCC) is one of the most aggressive forms of head and neck/oral cancer (HNOC), and is a complex disease with extensive genetic and epigenetic defects, including microRNA deregulation. Identifying the deregulation of microRNA-mRNA regulatory modules (MRMs) is crucial for understanding the role of microRNA in OTSCC.
A comprehensive bioinformatics analysis was performed to identify MRMs in HNOC by examining the correlation among differentially expressed microRNA and mRNA profiling datasets and integrating with 12 different sequence-based microRNA target prediction algorithms. Confirmation experiments were performed to further assess the correlation among MRMs using OTSCC patient samples and HNOC cell lines. Functional analyses were performed to validate one of the identified MRMs: miR-21-15-Hydroxyprostaglandin Dehydrogenase (HPGD) regulatory module.
Our bioinformatics analysis revealed 53 MRMs that are deregulated in HNOC. Four high confidence MRMs were further defined by confirmation experiments using OTSCC patient samples and HNOC cell lines, including miR-21-HPGD regulatory module. HPGD is a known anti-tumorigenic effecter, and it regulates the tumorigenic actions of Prostaglandin E2 (PGE2) by converts PGE2 to its biologically inactive metabolite. Ectopic transfection of miR-21 reduced the expression of HPGD in OTSCC cell lines, and the direct targeting of the miR-21 to the HPGD mRNA was confirmed using a luciferase reporter gene assay. The PGE2-mediated upregulation of miR-21 was also confirmed which suggested the existence of a positive feed-forward loop that involves miR-21, HPGD and PGE2 in OTSCC cells that contribute to tumorigenesis.
We identified a number of high-confidence MRMs in OTSCC, including miR-21-HPGD regulatory module, which may play an important role in the miR-21-HPGD-PGE2 feed-forward loop that contributes to tumorigenesis.
口腔舌鳞状细胞癌（OTSCC）是头颈部/口腔癌（HNOC）中侵袭性最强的形式之一，是一种具有广泛遗传和表观遗传缺陷的复杂疾病，包括微小RNA失调。识别微小RNA-信使核糖核酸调控模块（MRMs）的失调对于理解微小RNA在OTSCC中的作用至关重要。
通过检查差异表达的微小RNA和信使核糖核酸谱数据集之间的相关性，并与12种基于序列的不同微小RNA靶标预测算法相结合，进行了全面的生物信息学分析，以识别HNOC中的MRMs。使用OTSCC患者样本和HNOC细胞系进行验证实验，以进一步评估MRMs之间的相关性。进行功能分析以验证其中一个已识别的MRMs：miR-21-15-羟基前列腺素脱氢酶（HPGD）调控模块。
我们的生物信息学分析揭示了53个在HNOC中失调的MRMs。使用OTSCC患者样本和HNOC细胞系进行的验证实验进一步确定了4个高可信度的MRMs，包括miR-21-HPGD调控模块。HPGD是一种已知的抗肿瘤效应因子，并通过将前列腺素E2（PGE2）转化为其生物无活性代谢物来调节PGE2的致瘤作用。miR-21的异位转染降低了OTSCC细胞系中HPGD的表达，并使用荧光素酶报告基因测定法证实了miR-21对HPGD信使核糖核酸的直接靶向作用。还证实了PGE2介导的miR-21上调，这表明在OTSCC细胞中存在一个涉及miR-21、HPGD和PGE2的正向反馈环，其有助于肿瘤发生。
我们在OTSCC中识别出了许多高可信度的MRMs，包括miR-21-HPGD调控模块，其可能在有助于肿瘤发生的miR-21-HPGD-PGE2正向反馈环中发挥重要作用。
