Down-regulation of 14q32-encoded miRNAs and tumor suppressor role for miR-654-3p in papillary thyroid cancer.
Down-regulation of 14q32-encoded miRNAs and tumor suppressor role for miR-654-3p in papillary thyroid cancer.
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DOI：
10.18632/oncotarget.14162
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发表时间：
2017-02-07
期刊：
影响因子：
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通讯作者：
Kimura ET
中科院分区：
文献类型：
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作者：
Geraldo MV;Nakaya HI;Kimura ET
甲状腺乳头状癌（PTC）是甲状腺最常见的恶性肿瘤。一部分PTC病例表现为分化丧失和侵袭行为，伴有放射性碘治疗抵抗和转移。虽然microRNAs（miRNAs）成为PTC有前途的分子标记物，但它们在PTC进展过程中观察到的分化丧失中的作用仍有待充分了解。我们在BRAFT 1799 A转基因动物（Tg-Braf）和甲状腺癌细胞系中进行了PTC进展过程中miRNA表达的大规模分析，并确定了来自14 q32区域的几种miRNA的显著下调。来自癌症基因组图谱（TCGA）的数据证实了人类PTC中14 q32区域的miRNA的整体下调。这些miRNAs可能抑制的调控网络表明，关键的癌症相关的生物学过程，如细胞增殖，粘附，迁移和血管生成。在下调的miRNAs中，我们观察到miR-654- 3 p水平随着Tg-Braf小鼠长期PTC进展而降低，并与EMT呈负相关。miR-654- 3 p的体外恢复降低了细胞增殖和迁移，并诱导了转移相关基因的重编程，表明该miRNA具有肿瘤抑制作用。总之，我们在PTC进展的体内模型中显示了14 q32编码的miRNA的全局下调。这些miRNAs参与的潜在回路表明，这些miRNAs可能在PTC的病理生理学中发挥关键作用，因此与新治疗策略的开发相关。
Papillary thyroid carcinoma (PTC) is the most prevalent malignant neoplasia of the thyroid gland. A fraction of PTC cases show loss of differentiation and aggressive behavior, with radioiodine therapy resistance and metastasis. Although microRNAs (miRNAs) emerged as promising molecular markers for PTC, their role in the loss of differentiation observed during PTC progression remains to be fully understood. We performed the large-scale analysis of miRNA expression during PTC progression in BRAFT1799A-transgenic animals (Tg-Braf) and thyroid cancer cell lines and identified the marked downregulation of several miRNAs from the region 14q32. Data from The Cancer Genome Atlas (TCGA) confirmed the global downregulation of miRNAs from the 14q32 region in human PTC. The regulatory network potentially suppressed by these miRNAs suggests that key cancer-related biological processes such as cell proliferation, adhesion, migration and angiogenesis. Among the downregulated miRNAs, we observed that miR-654-3p levels decrease with long-term PTC progression in Tg-Braf mice and inversely correlate with EMT. The in vitro restoration of miR-654-3p decreased cell proliferation and migration and induced reprogramming of metastasis-related genes, suggesting a tumor suppressor role for this miRNA. In conclusion, we show global downregulation of 14q32-encoded miRNAs in an in vivo model of PTC progression. The potential circuitry in which these miRNAs are involved suggests that these miRNAs could play a key role in the pathophysiology of PTC and therefore be relevant for the development of new therapeutic strategies.