The POU2F1/miR-4490/USP22 axis regulates cell proliferation and metastasis in gastric cancer.
The POU2F1/miR-4490/USP22 axis regulates cell proliferation and metastasis in gastric cancer.
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POU2F1/miR-4490/USP22轴调节胃癌细胞增殖和转移
DOI：
10.1007/s13402-020-00553-1
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发表时间：
2020-12
期刊：
影响因子：
--
通讯作者：
Wang J
中科院分区：
文献类型：
--
作者：
Xiao Y;Liu S;Li J;Dai W;Tang W;Xiang L;Zhang W;Lin J;Wang J;Wu X;Liu G;Liu Y;Chen Y;Zhu H;Wang Y;Lin Z;Yang Q;Chen T;Sun Y;Li A;Xiong J;Wang J
越来越多的证据表明microRNA的异常表达有助于肿瘤的发展。然而，microRNA-4490（miR-4490）在胃癌（GC）中的生物学作用仍有待阐明。为了探索miR-4490在GC中的功能，我们进行了集落形成、EdU掺入、qRT-PCR、Western印迹、原位杂交（ISH）、免疫组织化学（IHC）、流式细胞术、ChIP和双荧光素酶报告基因测定。此外，还观察了胃癌细胞的生长、迁移和侵袭能力。我们发现，miR-4490在原发性GC样品和GC衍生的细胞系中与正常对照相比显著下调，并且该表达水平与GC恶性程度呈负相关。外源性miR-4490的表达不仅能抑制胃癌细胞的增殖和细胞周期进程，还能显著抑制胃癌细胞的迁移、侵袭和上皮-间质转化（EMT）。在机制上，我们发现miR-4490直接靶向USP 22，其介导体外和体内GC细胞增殖和EMT诱导的转移的抑制。此外，我们通过荧光素酶和ChIP测定发现，转录因子POU 2F 1可以直接结合到miR-4490和USP 22启动子内的POU 2F 1结合位点，并通过这样做来调节它们的转录。斯皮尔曼相关分析显示，在原发性胃癌组织中，USP 22和POU 2F 1表达之间呈正相关，而miR-4490和USP 22以及miR-4490和POU 2F 1表达之间呈负相关。基于我们的研究结果，我们得出结论，miR-4490作为一种肿瘤抑制因子，POU 2F 1/miR-4490/USP 22轴在调节GC细胞的生长、侵袭和EMT中起重要作用。本文的在线版本（10.1007/s13402-020-00553-1）包含补充材料，可供授权用户使用。
Growing evidence indicates that aberrant expression of microRNAs contributes to tumor development. However, the biological role of microRNA-4490 (miR-4490) in gastric cancer (GC) remains to be clarified. To explore the function of miR-4490 in GC, we performed colony formation, EdU incorporation, qRT-PCR, Western blotting, in situ hybridization (ISH), immunohistochemistry (IHC), flow cytometry, ChIP and dual-luciferase reporter assays. In addition, the growth, migration and invasion capacities of GC cells were evaluated. We found that miR-4490 was significantly downregulated in primary GC samples and in GC-derived cell lines compared with normal controls, and that this expression level was negatively correlated with GC malignancy. Exogenous miR-4490 expression not only reduced cell cycle progression and proliferation, but also significantly inhibited GC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro. Mechanistically, we found that miR-4490 directly targets USP22, which mediates inhibition of GC cell proliferation and EMT-induced metastasis in vitro and in vivo. Moreover, we found through luciferase and ChIP assays that transcription factor POU2F1 can directly bind to POU2F1 binding sites within the miR-4490 and USP22 promoters and, by doing so, modulate their transcription. Spearman’s correlation analysis revealed a positive correlation between USP22 and POU2F1 expression and negative correlations between miR-4490 and USP22 as well as miR-4490 and POU2F1 expression in primary GC tissues. Based on our results we conclude that miR-4490 acts as a tumor suppressor, and that the POU2F1/miR-4490/USP22 axis plays an important role in the regulation of growth, invasion and EMT of GC cells. The online version of this article (10.1007/s13402-020-00553-1) contains supplementary material, which is available to authorized users.
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