Dysregulation of RUNX2/Activin-A Axis upon miR-376c Downregulation Promotes Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma
Dysregulation of RUNX2/Activin-A Axis upon miR-376c Downregulation Promotes Lymph Node Metastasis in Head and Neck Squamous Cell Carcinoma
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DOI：
10.1158/0008-5472.can-16-1188
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发表时间：
2016-12-15
期刊：
影响因子：
11.2
通讯作者：
Shiah, Shine-Gwo
中科院分区：
文献类型：
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作者：
Chang, Wei-Min;Lin, Yuan-Feng;Shiah, Shine-Gwo
头颈癌的表观遗传相关性可能阐明其致病根源。通过基因集富集分析，我们发现致癌转录因子RUNX2在伴有淋巴结转移的头颈部鳞状细胞癌（HNSCC）中广泛上调，也预示着HNSCC患者预后不良。异位RUNX2的强制表达促进了HNSCC的转移能力，而RUNX2的沉默则抑制了这些特征。机制研究表明，操纵激活素A （INHBA）的水平可以挽救或损害runx2介导的HNSCC细胞的转移能力。此外，我们发现在RUNX2的30个非翻译区编码的miR-376c-3p在调节RUNX2在高转移性HNSCC细胞中的表达中起关键作用，在HNSCC细胞中，它通常下调。在这种情况下恢复miR-376c表达抑制RUNX2/INHBA轴的表达以及转移能力。在临床上，我们观察到HNSCC标本中miR-376c-3p的表达与RUNX2/INHBA轴呈负相关。总之，我们的研究结果定义了一种新的途径，在这种途径中，miR-376c下调导致RUNX2/INHBA轴的失调促进了HNSCC的淋巴结转移。AACR (C) 2016人。
Epigenetic correlates of the head and neck cancer may illuminate its pathogenic roots. Through a gene set enrichment analysis, we found that the oncogenic transcription factor RUNX2 is widely upregulated in the head and neck squamous cell carcinoma (HNSCC) with lymph node metastasis, where it also predicts poor prognosis in patients with HNSCC. Enforced expression of ectopic RUNX2 promoted the metastatic capabilities of HNSCC, whereas RUNX2 silencing inhibited these features. Mechanistic investigations showed that manipulating levels of activin A (INHBA) could rescue or compromise the RUNX2-mediated metastatic capabilities of HNSCC cells. Furthermore, we found that miR-376c-3p encoded within the 30-untranslated region of RUNX2 played a pivotal role in regulating RUNX2 expression in highly metastatic HNSCC cells, where it was downregulated commonly. Restoring miR-376c expression in this setting suppressed expression of RUNX2/INHBA axis along with metastatic capability. Clinically, we observed an inverse relationship between miR-376c-3p expression and the RUNX2/INHBA axis in HNSCC specimens. In summary, our results defined a novel pathway in which dysregulation of the RUNX2/INHBA axis due to miR-376c downregulation fosters lymph node metastasis in HNSCC. (C)2016 AACR.