Hsa-microRNA-370-3p targeting Snail and Twist1 suppresses IL-8/STAT3-driven hepatocellular carcinoma metastasis.
Hsa-microRNA-370-3p targeting Snail and Twist1 suppresses IL-8/STAT3-driven hepatocellular carcinoma metastasis.
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靶向 Snail 和 Twist1 的 Hsa-microRNA-370-3p 抑制 IL-8/STAT3 驱动的肝细胞癌转移
作者：
促炎因子白细胞介素-8（IL-8）与肝细胞癌（HCC）患者的不良预后相关。白细胞介素-8通过上调Snail和Twist 1增强肝癌侵袭，但这种调节是否依赖于微小RNA（miR）尚不清楚。在这项研究中，hsa-miR-370 - 3 p被筛选为靶向Snail和Twist 1的候选miRNA，其表达被IL-8下调。使用荧光素酶测定和RNA电泳迁移率变动测定来评估miR-370 - 3 p与靶向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 - 3 p修饰的潜在机制。使用功能获得和丧失研究、Transwell试验和异种移植裸鼠模型研究促肿瘤活性和抗肿瘤活性。分析了HCC患者中白细胞介素-8和miR-370 - 3 p水平的临床相关性。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诱导上皮-间质转化并促进肝癌细胞在体外和体内的迁移、侵袭和转移。MicroRNA-370 - 3 p与Twist 1和Snail mRNA的3′-UTR区域内的同源mRNA直接特异性相互作用，并减弱IL-8对肝癌细胞的促肿瘤作用。白细胞介素-8通过将组蛋白去乙酰化酶1（HDAC 1）募集到miR-370 - 3 p启动子，通过信号转导和转录激活因子3（STAT 3）激活来负性调节miR-370 - 3 p。STAT 3和HDAC拮抗剂抑制肝癌细胞的迁移和侵袭。高miR-370 - 3 p和低IL-8水平的患者的总生存期较长。总之，我们的研究阐明了依赖于HDAC 1募集的新轴IL-8/STAT 3/miR-370 - 3 p/Twist 1和Snail，这表明miR-370 - 3 p在HCC转移中的诊断和治疗潜力。我们的研究结果表明，具有高水平IL-8的HCC患者表现出更多的转移和更短的生存期。IL-8诱导EMT并促进肝癌细胞在体外和体内的迁移、侵袭和转移。miR-370 - 3 p与Twist 1和Snail mRNA的3 '-UTR区域内的同源mRNA直接特异性相互作用，并减弱IL-8对肝癌细胞的促肿瘤作用。IL-8通过将HDAC 1募集到miR-370 - 3 p启动子中，通过STAT 3激活来负调节microRNA-370 - 3 p。STAT 3和HDAC拮抗剂抑制肝癌细胞的迁移和侵袭。高miR-370 - 3 p和低IL-8水平的患者的总生存期较长。IL-8/STAT 3/microRNA-370 - 3 p/Twist 1和Snail轴调节HCC转移。
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. Our results showed that HCC patients with high levels of IL‐8 exhibited more metastasis and shorter survival. IL‐8 induced EMT and promoted liver cancer cell migration, invasion, and metastasis both in vitro and in vivo. miR‐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. IL‐8 negatively modulated microRNA‐370‐3p through STAT3 activation by recruiting HDAC1 to miR‐370‐3p promoter. 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. The IL‐8/STAT3/microRNA‐370‐3p/Twist1 and Snail axis modulated HCC metastasis.
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影响因子：
12.8
作者：
Leivonen SK;Icay K;Jäntti K;Siren I;Liu C;Alkodsi A;Cervera A;Ludvigsen M;Hamilton-Dutoit SJ;d'Amore F;Karjalainen-Lindsberg ML;Delabie J;Holte H;Lehtonen R;Hautaniemi S;Leppä S
通讯作者：
Leppä S
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
28.5
作者：
Guo F;Parker Kerrigan BC;Yang D;Hu L;Shmulevich I;Sood AK;Xue F;Zhang W
通讯作者：
Zhang W
影响因子：
2.7
作者：
Lu, Ming;Wang, Yong;Zhu, Yufang
通讯作者：
Zhu, Yufang
影响因子：
6.4
作者：
Lang, K;Niggemann, B;Entschladen, F
通讯作者：
Entschladen, F