Long noncoding RNA NEAT1 drives aggressive endometrial cancer progression via miR-361-regulated networks involving STAT3 and tumor microenvironment-related genes
Long noncoding RNA NEAT1 drives aggressive endometrial cancer progression via miR-361-regulated networks involving STAT3 and tumor microenvironment-related genes
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DOI：
10.1186/s13046-019-1306-9
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发表时间：
2019-07-08
影响因子：
11.3
通讯作者：
Watari, Hidemichi
中科院分区：
文献类型：
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作者：
Dong, Peixin;Xiong, Ying;Watari, Hidemichi
背景高级别子宫内膜样癌和浆液性子宫内膜癌是一种侵袭性的子宫内膜癌亚型，目前尚无有效的治疗方法。肿瘤细胞与其周围微环境之间的相互通信驱动肿瘤进展。长链非编码RNA（lncRNA）是肿瘤发生和转移的关键介质。然而，鲜为人知的是，lncRNA在积极的EC进展和肿瘤微环境modeling.MethodsWe进行了一个基于阵列的lncRNA分析的亲本HEC-50 EC细胞群体和衍生物具有高度侵入性，球体形成，和紫杉醇（TX）耐药特性的作用。我们在体外和体内研究了lncRNA NEAT 1在介导侵袭性EC进展中的作用，并探讨了NEAT 1下游的分子事件。（NEAT 1、H19、PVT 1、UCA 1、MIR 7 - 3 HG、SNHG 16、HULC、RMST、BCAR 4和LINC 00152）和10种表达下调的lncRNA（MEG 3、GAS 5、DIO 3 OS、MIR 155 HG、LINC 00261、FENDRR、MIAT、TMEM 161 B-AS 1、HAND 2-AS 1和NBR 2）在高度侵袭性、成球和TX抗性衍生物中的表达。NEAT 1表达在早期EC组织样本中显著上调，NEAT 1高表达预示预后不良。用小发夹RNA（shRNA）抑制NEAT 1表达减少了细胞增殖、侵袭、球体形成和异种移植肿瘤生长，并改善了侵袭性EC细胞中的TX反应。我们发现NEAT 1作为肿瘤抑制因子microRNA-361（miR-361）的致癌海绵发挥作用，其通过直接靶向癌基因STAT 3来抑制增殖、侵袭、球体形成和TX抗性。此外，miR-361还能抑制MEF 2D、ROCK 1、WNT 7A、VEGF-A、PDE 4 B和KPNA 4等多个促转移基因和肿瘤微环境相关基因的表达。这些数据支持抑制NEAT 1信号传导作为克服侵袭性EC进展和化学抗性的潜在治疗策略的基本原理。
BackgroundHigh-grade endometrioid and serous endometrial cancers (ECs) are an aggressive subtype of ECs without effective therapies. The reciprocal communication between tumor cells and their surrounding microenvironment drives tumor progression. Long noncoding RNAs (lncRNAs) are key mediators of tumorigenesis and metastasis. However, little is known about the role of lncRNAs in aggressive EC progression and tumor microenvironment remodeling.MethodsWe performed an array-based lncRNA analysis of a parental HEC-50 EC cell population and derivatives with highly invasive, sphere-forming, and paclitaxel (TX)-resistant characteristics. We characterized the roles of the lncRNA NEAT1 in mediating aggressive EC progression in vitro and in vivo and explored the molecular events downstream of NEAT1.ResultsWe identified 10 lncRNAs with upregulated expression (NEAT1, H19, PVT1, UCA1, MIR7-3HG, SNHG16, HULC, RMST, BCAR4 and LINC00152) and 10 lncRNAs with downregulated expression (MEG3, GAS5, DIO3OS, MIR155HG, LINC00261, FENDRR, MIAT, TMEM161B-AS1, HAND2-AS1 and NBR2) in the highly invasive, sphere-forming and TX-resistant derivatives. NEAT1 expression was markedly upregulated in early-stage EC tissue samples, and high NEAT1 expression predicted a poor prognosis. Inhibiting NEAT1 expression with small hairpin RNAs (shRNAs) diminished cellular proliferation, invasion, sphere formation, and xenograft tumor growth and improved TX response in aggressive EC cells. We showed that NEAT1 functions as an oncogenic sponge for the tumor suppressor microRNA-361 (miR-361), which suppresses proliferation, invasion, sphere formation and TX resistance by directly targeting the oncogene STAT3. Furthermore, miR-361 also suppressed the expression of multiple prometastatic genes and tumor microenvironment-related genes, including MEF2D, ROCK1, WNT7A, VEGF-A, PDE4B, and KPNA4.ConclusionsNEAT1 initiates a miR-361-mediated network to drive aggressive EC progression. These data support a rationale for inhibiting NEAT1 signaling as a potential therapeutic strategy for overcoming aggressive EC progression and chemoresistance.