MicroRNA-204-5p is a tumor suppressor and potential therapeutic target in head and neck squamous cell carcinoma
MicroRNA-204-5p is a tumor suppressor and potential therapeutic target in head and neck squamous cell carcinoma
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MicroRNA-204-5p是一种肿瘤抑制因子，也是头颈鳞状细胞癌的潜在治疗靶点
DOI：
10.7150/thno.38507
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Wang, Cheng
中科院分区：
文献类型：
--
作者：
Zhuang, Zehang;Yu, Pei;Wang, Cheng
阐明控制 HNSCC 侵袭性的分子机制可能为患者提供临床治疗策略。在这项研究中，在 HNSCC 中鉴定并探索了一个作为肿瘤抑制因子发挥作用的新型中枢 miR-204-5p。方法：基于 miRNA 微阵列、生物信息学分析鉴定出一种新的中枢 miR-204-5p，并在不同的 HNSCC 患者队列中进行验证。通过体外和体内功能获得和功能丧失测定来研究 miR-204-5p 及其下游和上游调节机制的功能作用。通过一系列分子生物学实验研究了 miR-204-5p 和 SNAI2/SUZ12/HDAC1/STAT3 复合物之间的相互作用。然后，在 HNSCC 样本中评估 miR-204-5p 及其靶标的临床相关性。 HNSCC 患者来源的异种移植（PDX）模型用于评估 miR-204-5p 的治疗价值。结果：我们发现 miR-204-5p 作为肿瘤抑制因子在 HNSCC 中普遍受到抑制，可以抑制肿瘤生长、转移和干细胞性。从机制上讲，miR-204-5p 通过靶向 SNAI2、SUZ12、HDAC1 和 JAK2 来抑制上皮间质转化 (EMT) 和 STAT3 信号传导。在这些靶标中，我们进一步表明 SNAI2、SUZ12 和 HDAC1 在 CDH1 启动子上形成抑制复合物，以维持 HNSCC 中的 EMT。反过来，SNAI2/SUZ12/HDAC1 复合物与 miR-204-5p 调控区上的 STAT3 相互作用，抑制 miR-204-5p 的转录。此外，我们还表明，miR-204-5p 的减少表明 HNSCC 患者预后不良，而 agomiR-204-5p 的给药可抑制 HNSCC PDX 模型中的肿瘤生长和转移。结论：miR-204-5p-SNAI2/SUZ12/HDAC1/STAT3调节回路在维持HNSCC的侵袭性中具有关键作用，表明miR-204-5p可能作为临床干预的有前景的治疗靶点。
Elucidation of the molecular mechanisms governing aggressiveness of HNSCC may provide clinical therapeutic strategies for patients. In this study, a novel hub miR-204-5p functioning as tumor suppressor has been identified and explored in HNSCC. Methods: A novel hub miR-204-5p was identified based on miRNA microarray, bioinformatics analysis and validated in different HNSCC patient cohorts. The functional role of miR-204-5p and its downstream and upstream regulatory machinery were investigated by gain-of-function and loss-of-function assays in vitro and in vivo. Interactions among miR-204-5p and SNAI2/SUZ12/HDAC1/STAT3 complex were examined by a series of molecular biology experiments. Then, the clinical relevance of miR-204-5p and its targets were evaluated in HNSCC samples. HNSCC patient-derived xenograft (PDX) model was used to assess the therapeutic value of miR-204-5p. Results: We reveal that miR-204-5p as a tumor suppressor is commonly repressed in HNSCC, which can inhibit tumor growth, metastasis and stemness. Mechanically, miR-204-5p suppresses epithelial-mesenchymal transition (EMT) and STAT3 signaling by targeting SNAI2, SUZ12, HDAC1 and JAK2. Among these targets, we further showed that SNAI2, SUZ12, and HDAC1 form a repressive complex on CDH1 promoter to maintain EMT in HNSCC. In turn, the SNAI2/SUZ12/HDAC1 complex interacts with STAT3 on miR-204-5p-regulatory regions to suppress the transcription of miR-204-5p. Moreover, we also show that decrease of miR-204-5p indicates a poor prognosis in HNSCC patients and administration of agomiR-204-5p inhibits tumor growth and metastasis in HNSCC PDX models. Conclusion: miR-204-5p-SNAI2/SUZ12/HDAC1/STAT3 regulatory circuit has a critical role in maintaining aggressiveness of HNSCC, suggesting that miR-204-5p might serve as a promising therapeutic target for clinical intervention.