Promoter Methylation-Regulated miR-145-5p Inhibits Laryngeal Squamous Cell Carcinoma Progression by Targeting FSCN1.
Promoter Methylation-Regulated miR-145-5p Inhibits Laryngeal Squamous Cell Carcinoma Progression by Targeting FSCN1.
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启动子甲基化调节的 miR-145-5p 通过靶向 FSCN1 抑制喉鳞状细胞癌进展
DOI：
10.1016/j.ymthe.2018.09.018
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发表时间：
2019-02-06
期刊：
影响因子：
--
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Gao W;Zhang C;Li W;Li H;Sang J;Zhao Q;Bo Y;Luo H;Zheng X;Lu Y;Shi Y;Yang D;Zhang R;Li Z;Cui J;Zhang Y;Niu M;Li J;Wu Z;Guo H;Xiang C;Wang J;Hou J;Zhang L;Thorne RF;Cui Y;Wu Y;Wen S;Wang B
喉鳞状细胞癌是一种常见的头颈部恶性肿瘤，预后差。然而，喉鳞状细胞癌的发病机制仍不清楚。在这里，我们证明了在喉鳞状细胞癌的临床队列中肌成束蛋白肌动蛋白捆绑蛋白1（FSCN 1）的表达增加和microRNA-145- 5 p（miR-145- 5 p）的表达减少。荧光素酶分析显示miR-145- 5 p是FSCN 1的负调控因子。重要的是，低miR-145- 5 p表达与TNM（肿瘤、淋巴结、转移）状态和转移相关。此外，低miR-145- 5 p/高FSCN 1表达的病例显示预后不良，这些特征共同作为生存的独立预后指标。功能获得和功能丧失研究表明，miR-145- 5 p过表达或FSCN 1敲低通过抑制上皮-间充质转化沿着诱导细胞周期停滞和凋亡来抑制LSCC迁移、侵袭和生长。此外，miR-145- 5 p启动子的超甲基化表明miR-145- 5 p的抑制通过表观遗传失活而产生。使用miR-145- 5 p agomir或FSCN 1小干扰RNA（siRNA）可以抑制体内LSCC肿瘤生长，这突出了临床翻译的潜力。总的来说，我们的研究结果表明，miR-145- 5 p通过抑制FSCN 1在抑制LSCC进展中起着关键作用。miR-145- 5 p和FSCN 1是喉鳞癌重要的潜在预后标志物和治疗靶点。Gao等人证明miR-145- 5 p表达是LSCC的预后，低表达与较差的结果相关。在这种病理学的基础上，miR-145- 5 p抑制FSCN 1表达，但其失活促进上皮向间充质转化（EMT）、增殖和存活。miR-145- 5 p agomir抑制了体内LSCC的生长，突出了作为生物标志物和治疗靶点的潜力。
Laryngeal squamous cell carcinoma (LSCC) is a common form of head and neck cancer with poor prognosis. However, the mechanism underlying the pathogenesis of LSCC remains unclear. Here, we demonstrated increased expression of fascin actin-bundling protein 1 (FSCN1) and decreased expression of microRNA-145-5p (miR-145-5p) in a clinical cohort of LSCC. Luciferase assay revealed that miR-145-5p is a negative regulator of FSCN1. Importantly, low miR-145-5p expression was correlated with TNM (tumor, node, metastasis) status and metastasis. Moreover, cases with low miR-145-5p/high FSCN1 expression showed poor prognosis, and these characteristics together served as independent prognostic indicators of survival. Gain- and loss-of-function studies showed that miR-145-5p overexpression or FSCN1 knockdown inhibited LSCC migration, invasion, and growth by suppressing the epithelial-mesenchymal transition along with inducing cell-cycle arrest and apoptosis. Additionally, hypermethylation of the miR-145-5p promoter suggested that repression of miR-145-5p arises through epigenetic inactivation. LSCC tumor growth in vivo could be inhibited by using miR-145-5p agomir or FSCN1 small interfering RNA (siRNA), which highlights the potential for clinical translation. Collectively, our findings indicate that miR-145-5p plays critical roles in inhibiting the progression of LSCC by suppressing FSCN1. Both miR-145-5p and FSCN1 are important potential prognostic markers and therapeutic targets for LSCC. Gao et al. demonstrate that miR-145-5p expression is prognostic for LSCC with low expression associated with poorer outcomes. Underlying this pathology, miR-145-5p suppresses FSCN1 expression, but its inactivation facilitates epithelial-to-mesenchymal transition (EMT), proliferation, and survival. LSCC growth in vivo is inhibited by miR-145-5p agomir, highlighting potential as a biomarker and therapeutic target.
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