Hypoxia downregulated miR-4521 suppresses gastric carcinoma progression through regulation of IGF2 and FOXM1.
Hypoxia downregulated miR-4521 suppresses gastric carcinoma progression through regulation of IGF2 and FOXM1.
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缺氧下调 miR-4521 通过调节 IGF2 和 FOXM1 抑制胃癌进展
DOI：
10.1186/s12943-020-01295-2
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发表时间：
2021-01-06
期刊：
影响因子：
37.3
通讯作者：
Deng M
中科院分区：
文献类型：
--
作者：
Xing S;Tian Z;Zheng W;Yang W;Du N;Gu Y;Yin J;Liu H;Jia X;Huang D;Liu W;Deng M
背景MicroRNAs（miRNAs）作为肿瘤进展的重要调节因子，在肿瘤治疗中具有重要的应用前景。然而，我们对它们在胃癌（GC）转移中的作用的理解是有限的。本研究的目的是寻找与胃癌转移相关的新的miRNA，并探讨其调控机制及其在胃癌治疗中的意义。方法利用胃癌基因组学数据库中的胃腺癌（stomach adenocarcinoma，STAD）miRNASeq数据集，比较胃癌不同分期和不同转移状态microRNA的表达谱。利用上述方法，挑选出miR-4521用于进一步研究。采用定量逆转录聚合酶链反应（qRT-PCR）和原位杂交（ISH）检测胃癌组织中miR-4521的表达。使用重复transwell测定建立高侵袭性和低侵袭性细胞亚系。进行功能获得和功能丧失分析以研究miR-4521的功能及其在体外和体内的上游和下游调控机制。此外，我们研究了miR-4521在小鼠异种移植物model.ResultsIn这项研究中，我们发现，miR-4521的表达在胃癌组织中下调与相邻的正常组织相比，其下调与先进的临床分期，转移状态和不良的患者预后呈正相关。功能实验表明，miR-4521在体内外均能抑制胃癌细胞的侵袭和转移。进一步的研究表明，低氧通过诱导ETS 1抑制miR-4521的表达，miR-4521减轻低氧介导的转移，而miR-4521通过靶向IGF 2和FOXM 1使AKT/GSK 3 β/Snai 1通路失活，从而抑制上皮-间充质转化（EMT）过程和转移。此外，我们证明，治疗交付的合成miR-4521抑制胃癌进展vivo.ConclusionsOur结果表明，重要的作用，miR-4521在调节胃癌转移和肿瘤细胞的缺氧反应，以及这种miRNA在胃癌的治疗意义。
BackgroundMicroRNAs (miRNAs) show considerable promise as therapeutic agents to improve tumor treatment, as they have been revealed as crucial modulators in tumor progression. However, our understanding of their roles in gastric carcinoma (GC) metastasis is limited. Here, we aimed to identify novel miRNAs involved in GC metastasis and explored their regulatory mechanisms and therapeutic significance in GC.MethodsThe microRNA expression profiles of GC tumors at different stages and at different metastasis statuses were compared respectively using the stomach adenocarcinoma (STAD) miRNASeq dataset in TCGA. Using the above method, miR-4521 was picked out for further study. miR-4521 expression in GC tissues was examined by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and in situ hybridization (ISH). Highly and lowly invasive cell sublines were established using a repetitive transwell assay. Gain-of-function and loss-of-function analyses were performed to investigate the functions of miR-4521 and its upstream and downstream regulatory mechanisms in vitro and in vivo. Moreover, we investigated the therapeutic role of miR-4521 in a mouse xenograft model.ResultsIn this study, we found that miR-4521 expression was downregulated in GC tissues compared with adjacent normal tissues and that its downregulation was positively correlated with advanced clinical stage, metastasis status and poor patient prognosis. Functional experiments revealed that miR-4521 inhibited GC cell invasion and metastasis in vitro and in vivo. Further studies showed that hypoxia repressed miR-4521 expression via inducing ETS1 and miR-4521 mitigated hypoxia-mediated metastasis, while miR-4521 inactivated the AKT/GSK3β/Snai1 pathway by targeting IGF2 and FOXM1, thereby inhibiting the epithelial-mesenchymal transition (EMT) process and metastasis. In addition, we demonstrated that therapeutic delivery of synthetic miR-4521 suppressed gastric carcinoma progression in vivo.ConclusionsOur results suggest an important role for miR-4521 in regulating GC metastasis and hypoxic response of tumor cells as well as the therapeutic significance of this miRNA in GC.
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影响因子：
45.3
作者：
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通讯作者：
Hill, RP
影响因子：
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作者：
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