Geraldo Murilo V, Kimura Edna T
Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of Sao Paulo, Sao Paulo, Brazil.
Department of Structural and Functional Biology, Institute of Biology, State University of Campinas, Campinas, Brazil.
PLoS One. 2015 Nov 4;10(11):e0141726. doi: 10.1371/journal.pone.0141726. eCollection 2015.
Papillary thyroid carcinoma (PTC) is a well-differentiated thyroid tumor that accounts for approximately 80% of thyroid cancer cases. On other hand, anaplastic thyroid carcinoma (ATC) is a less frequent, but aggressive subtype, with poor prognosis. MicroRNAs (miRNAs), small non-coding RNAs, have emerged as potent post-transcriptional regulators of gene expression, which modulate the expression of cancer-related genes. Computational analyses estimate that a single miRNA may modulate hundreds of mRNA targets and, at the same time, cooperate with others to regulate one single mRNA transcript. Due to the large number of predicted targets and possible interactions, only a small number of miRNAs have characterized biological roles, and the panorama of miRNA-mediated regulation in thyroid cancer remains to be understood. Taking into consideration the large amount of gene expression data deposited in public databases we aligned miRNA target prediction and gene expression data from public PTC and ATC datasets to construct a network of post-transcriptional regulation in thyroid cancer. After a gene set enrichment analysis we identified signaling pathways and biological processes potentially modulated by the miRNAs deregulated in PTC and ATC. Our results show miRNA-mRNA interaction that could contribute with the de-regulation of key tumor-host mediators, such as extra-cellular matrix molecules, interleukins and interleukin receptors, which could drive a more aggressive behavior and tumor progression. Moreover, our analysis through The Cancer Genome Atlas (TCGA) database revealed that aberrant expression of ECM and cytokines genes is frequent in PTC and is associated with aggressive behavior and decreased overall survival rate. In conclusion, we shed light on the post-transcriptional regulation of gene expression in differentiated and undifferentiated thyroid cancers, revealing a potential role of miRNAs in modulation of tumor-host interaction molecules, particularly ECM molecules and immune system mediators, which could stimulate crosstalk between tumors and the immune system to generate a more aggressive behavior. We propose a novel putative miRNA:mRNA network that could lead to a new path toward functional studies.
乳头状甲状腺癌（PTC）是一种分化良好的甲状腺肿瘤，约占甲状腺癌病例的80%。另一方面，间变性甲状腺癌（ATC）是一种较少见但侵袭性强的亚型，预后较差。微小RNA（miRNA）是一类小的非编码RNA，已成为基因表达强有力的转录后调节因子，可调节癌症相关基因的表达。计算分析估计，单个miRNA可能调节数百个mRNA靶标，同时与其他miRNA协同调节单个mRNA转录本。由于预测的靶标数量众多且可能存在相互作用，仅有少数miRNA具有明确的生物学作用，甲状腺癌中miRNA介导的调节全景仍有待了解。考虑到公共数据库中存储的大量基因表达数据，我们将来自公共PTC和ATC数据集的miRNA靶标预测与基因表达数据进行比对，以构建甲状腺癌的转录后调节网络。经过基因集富集分析，我们确定了可能由PTC和ATC中失调的miRNA调节的信号通路和生物学过程。我们的结果显示了miRNA-mRNA相互作用，这可能导致关键肿瘤-宿主介质（如细胞外基质分子、白细胞介素和白细胞介素受体）的失调，从而推动更具侵袭性的行为和肿瘤进展。此外，我们通过癌症基因组图谱（TCGA）数据库的分析表明，细胞外基质和细胞因子基因的异常表达在PTC中很常见，并且与侵袭性行为和总体生存率降低相关。总之，我们揭示了分化型和未分化型甲状腺癌中基因表达的转录后调节，揭示了miRNA在调节肿瘤-宿主相互作用分子（特别是细胞外基质分子和免疫系统介质）中的潜在作用，这可能刺激肿瘤与免疫系统之间的相互作用，从而产生更具侵袭性的行为。我们提出了一个新的假定miRNA:mRNA网络，这可能为功能研究开辟一条新途径。
