MicroRNA-361-Mediated Inhibition of HSP90 Expression and EMT in Cervical Cancer Is Counteracted by Oncogenic lncRNA NEAT1
MicroRNA-361-Mediated Inhibition of HSP90 Expression and EMT in Cervical Cancer Is Counteracted by Oncogenic lncRNA NEAT1
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DOI：
10.3390/cells9030632
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发表时间：
2020-03-01
期刊：
影响因子：
6
通讯作者：
Watari, Hidemichi
中科院分区：
文献类型：
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作者：
Xu, Daozhi;Dong, Peixin;Watari, Hidemichi
上皮-间质转化（EMT）是宫颈癌（CC）转移的关键过程，microRNAs（miRNAs）调控EMT相关基因的表达。然而，miR-361在CC相关EMT中的确切作用及其在CC中的功能机制仍不清楚。通过一系列细胞功能测定来探索miR-361在CC细胞中的功能作用。荧光素酶报告基因测定用于证明miR-361、HSP 90和长链非编码RNA（lncRNA）NEAT 1之间的潜在相互作用。我们检测到与正常组织相比，miR-361在CC组织中的表达减少，并且miR-361过表达通过直接靶向关键EMT激活剂HSP 90来抑制CC细胞的侵袭和EMT表型。此外，我们检测到热休克蛋白90在癌组织中的表达水平明显高于正常组织，热休克蛋白90的高表达预示着预后较差。我们进一步确定NEAT 1在CC组织中是一种显著上调的lncRNA，并且NEAT 1的高表达与CC患者的生存率较差相关。NEAT 1直接抑制miR-361表达，并在CC细胞侵袭和球体形成中发挥致癌作用。结论：这些结果表明，miR-361直接靶向HSP 90，以抑制侵袭和EMT特征，NEAT 1作为致癌lncRNA发挥功能，抑制miR-361表达，并诱导CC细胞中的EMT和球体形成，从而为这种恶性肿瘤中的分子途径提供关键见解。
Epithelial-mesenchymal transition (EMT) is a key process contributing to cervical cancer (CC) metastasis, and microRNAs (miRNAs) modulate the expression of genes implicated in EMT. However, the accurate role of miR-361 in CC-associated EMT and the mechanisms underlying its function in CC remains largely unknown. The functional roles of miR-361 in CC cells were explored by a series of cell functional assays. Luciferase reporter assays were used to demonstrate the potential interaction between miR-361, HSP90, and long non-coding RNA (lncRNA) NEAT1. We detected a reduction of miR-361 expression in CC tissues compared with normal tissues, and miR-361 overexpression inhibited invasion and EMT phenotypes of CC cells by directly targeting a key EMT activator HSP90. Additionally, we detected significantly higher levels of HSP90 in CC tissues compared with normal tissues, and high expression of HSP90 predicted a poorer prognosis. We further identified NEAT1 as a significantly upregulated lncRNA in CC tissues and high expression of NEAT1 was associated with worse survival in CC patients. NEAT1 directly repressed miR-361 expression and played an oncogenic role in CC cell invasion and sphere formation. Conclusions: These results demonstrated that miR-361 directly targets HSP90 to inhibit the invasion and EMT features, and NEAT1 functions as an oncogenic lncRNA that suppresses miR-361 expression and induces EMT and sphere formation in CC cells, thus providing critical insights into the molecular pathways operating in this malignancy.