Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils
Long non-coding RNA HOTTIP enhances IL-6 expression to potentiate immune escape of ovarian cancer cells by upregulating the expression of PD-L1 in neutrophils
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长链非编码RNA HOTTIP通过上调中性粒细胞中程序性死亡配体1（PD-L1）的表达，增强白细胞介素-6（IL-6）的表达，从而促进卵巢癌细胞的免疫逃逸 。
DOI：
10.1186/s13046-019-1394-6
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发表时间：
2019-09-18
影响因子：
11.3
通讯作者：
Li, Dong
中科院分区：
文献类型：
--
作者：
Shang, Anquan;Wang, Weiwei;Li, Dong
工作背景：HOXA远端转录物（HOTTIP）已被证明是评估多种癌症预后的重要生物标志物。然而，HOTTIP在卵巢癌（OC）中的潜在功能，卵巢癌是全球女性中的一种常见癌症，仍然难以捉摸。因此，本研究旨在阐明HOTTIP在OC的发展中的功能相关性。方法：PD-L1和IL-6的阳性表达采用免疫组化染色在收集的OC和正常组织中测定。采用流式细胞术、Western blot分析及Pearson相关系数分析IL-6与PD-L1的相关性。HOTTIP、c-jun和IL-6之间的相互作用用RIP、ChIP和双荧光素酶报告基因分析来研究。结果：HOTTIP、IL-6和PD-L1在OC组织中均高表达，HOTTIP对OC细胞增殖和浸润的抑制作用明显优于HOTTIP。OC组织中IL-6与PD-L1、HOTTIP与IL-6呈正相关。HOTTIP通过与c-jun结合促进IL-6的表达，从而促进中性粒细胞PD-L1的表达和免疫逃逸，同时抑制T细胞增殖和肿瘤免疫治疗。综上所述，我们的研究表明HOTTIP可以促进中性粒细胞分泌IL-6，从而上调PD-L1的表达，从而抑制T细胞的活性并最终加速OC细胞的免疫逃逸。我们的研究提供了一个潜在的治疗策略，通过在OC的HOTTIP为靶点。
Background: Long non-coding RNA (lncRNA) HOXA transcript at the distal tip (HOTTIP), has been demonstrated to be a vital biomarker when evaluating the prognosis of multiple cancers. Nevertheless, the potential function of HOTTIP in ovarian cancer (OC), a prevalent cancer among women worldwide, remains elusive. Hence, the current study aimed to elucidate the functional relevance of HOTTIP in the development of OC.Methods: Positive expression of PD-L1 and IL-6 was determined using immunohistochemical staining in the collected OC and normal tissues. The correlation of IL-6 and PD-L1 was analyzed using flow cytometry, Western blot analysis as well as Pearson's correlation coefficient. The interaction among HOTTIP, c-jun and IL-6 was investigated with the use of RIP, ChIP and dual luciferase reporter gene assays. Finally, the effects of HOTTIP on T cell proliferation and infiltration were identified through gain- and loss-of-function studies in vitro and in vivo.Results: HOTTIP, IL-6 and PD-L1 were all highly expressed in OC tissues. A positive correlation was observed between IL-6 and PD-L1 and that between HOTTIP and IL-6 in OC tissues. HOTTIP was noted to promote the expression of IL-6 by binding to c-jun, which resulted in a promoted PD-L1 expression in neutrophils and immune escape while inhibiting T cell proliferation as well as tumor immunotherapy.Conclusion: Taken together, our study unveiled that HOTTIP could promote the secretion of IL-6, and consequently up-regulate the expression of PD-L1 in neutrophils, thus inhibiting the activity of T cells and ultimately accelerating immune escape of OC cells. Our study provides a potential therapeutic strategy by targeting HOTTIP in OC.