Hsa-microRNA-370-3p targeting Snail and Twist1 suppresses IL-8/STAT3-driven hepatocellular carcinoma metastasis,Cancer Science

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Hsa-microRNA-370-3p targeting Snail and Twist1 suppresses IL-8/STAT3-driven hepatocellular carcinoma metastasis
Cancer Science ( IF 4.5 ) Pub Date : 2022-09-09 , DOI: 10.1111/cas.15571
Siqi Peng _{1,

2,

3} , Yutong Chen ₁ , Ting Li ₁ , Junjie Mao _{2,

3,

4} , Pengfei Yang ₅ , Baojia Zou ₆ , Lisi Luo ₁ , Weiyu Zhang _{2,

3} , Wen Wang ₁ , Rongzhi Xie ₁ , Jian Li ₆ , Linjuan Zeng ₁

Affiliation

The pro-inflammatory factor interleukin-8 (IL-8) is related to poor prognosis in hepatocellular carcinoma (HCC) patients. Interleukin-8 enhanced HCC invasion by upregulating Snail and Twist1, whether this modulation relies on microRNAs (miR) is unclear. In this study, hsa-miR-370-3p was screened as candidate miRNA targeting Snail and Twist1, and its expression was downregulated by IL-8. Luciferase assays and RNA electrophoretic mobility shift assays were used to evaluate the interaction between miR-370-3p and targeted mRNAs. Coimmunoprecipitation, luciferase, and ChIP assays were undertaken to investigate the mechanisms underlying IL-8-mediated modification of miR-370-3p. Gain- and loss-of-function studies, Transwell assays, and a xenograft nude mouse model were used to investigate pro- and antitumor activities. Interleukin-8 and miR-370-3p levels were analyzed for clinical relevance in HCC patients. Our results showed that HCC patients with high levels of IL-8 experienced more metastasis and shorter survival. Interleukin-8 induced epithelial–mesenchymal transition and promoted liver cancer cell migration, invasion, and metastasis both in vitro and in vivo. MicroRNA-370-3p interacted with its cognate mRNA within the 3′-UTR regions of Twist1 and Snail mRNA directly and specifically and attenuated IL-8 protumoral effects on liver cancer cells. Interleukin-8 negatively modulated miR-370-3p through signal transducer and activator of transcription 3 (STAT3) activation by recruiting histone deacetylase 1 (HDAC1) to miR-370-3p promoter. The STAT3 and HDAC antagonists inhibited liver cancer cell migration and invasion. Patients with high miR-370-3p and low IL-8 levels had longer overall survival. In conclusion, our study elucidated a novel axis IL-8/STAT3/miR-370-3p/Twist1 and Snail relying on HDAC1 recruitment, which showed both diagnostic and therapeutic potentials of miR-370-3p in HCC metastasis.

中文翻译：

靶向 Snail 和 Twist1 的 Hsa-microRNA-370-3p 抑制 IL-8/STAT3 驱动的肝细胞癌转移

促炎因子白介素 8 (IL-8) 与肝细胞癌 (HCC) 患者的不良预后有关。白细胞介素 8 通过上调 Snail 和 Twist1 增强 HCC 侵袭，这种调节是否依赖于 microRNA (miR) 尚不清楚。本研究筛选hsa-miR-370-3p作为靶向Snail和Twist1的候选miRNA，其表达被IL-8下调。荧光素酶测定和 RNA 电泳迁移率变动测定用于评估 miR-370-3p 和靶向 mRNA 之间的相互作用。进行免疫共沉淀、荧光素酶和 ChIP 测定以研究 IL-8 介导的 miR-370-3p 修饰的潜在机制。获得和丧失功能研究、Transwell 测定和异种移植裸鼠模型用于研究促肿瘤和抗肿瘤活性。分析了 Interleukin-8 和 miR-370-3p 水平在 HCC 患者中的临床相关性。我们的研究结果表明，具有高水平 IL-8 的 HCC 患者经历了更多的转移和更短的生存期。白细胞介素 8 在体外和体内诱导上皮-间质转化并促进肝癌细胞迁移、侵袭和转移。MicroRNA-370-3p 与其在 Twist1 和 Snail mRNA 的 3'-UTR 区域内的同源 mRNA 直接且特异性地相互作用，并减弱 IL-8 对肝癌细胞的促肿瘤作用。白细胞介素 8 通过信号转导和转录激活因子 3 (STAT3) 激活负调节 miR-370-3p，方法是将组蛋白脱乙酰酶 1 (HDAC1) 募集到 miR-370-3p 启动子。STAT3 和 HDAC 拮抗剂抑制肝癌细胞迁移和侵袭。高 miR-370-3p 和低 IL-8 水平的患者总生存期更长。总之，我们的研究阐明了依赖于 HDAC1 募集的新型轴 IL-8/STAT3/miR-370-3p/Twist1 和 Snail，这显示了 miR-370-3p 在 HCC 转移中的诊断和治疗潜力。

更新日期：2022-09-09

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