NUDT21 promotes bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation
NUDT21 promotes bladder cancer progression through ANXA2 and LIMK2 by alternative polyadenylation
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NUDT21 通过 ANXA2 和 LIMK2 通过选择性多聚腺苷酸化促进膀胱癌进展
DOI：
10.7150/thno.36030
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发表时间：
2019-01-01
期刊：
影响因子：
12.4
通讯作者：
Hou, Teng
中科院分区：
文献类型：
--
作者：
Xiong, Ming;Chen, Liang;Hou, Teng
目的：NUDT 21是参与选择性多聚腺苷酸化（阿帕）的重要介质，并且该分子已被报道是人类癌症中的肿瘤抑制剂。然而，NUDT 21在膀胱癌（BC）中的作用及其机制尚不清楚。方法：采用实时荧光定量PCR、免疫印迹和免疫组化方法检测NUDT 21在BC中的表达水平。进行体外和体内测定以研究NUDT 21在膀胱癌细胞中的肿瘤发生中的功能。结果：NUDT 21在BC组织和细胞中的表达降低，NUDT 21低表达的BC患者的总生存期和无复发生存期均短于NUDT 21高表达的患者。NUDT 21的异位表达或敲低分别显著抑制或促进BC细胞的增殖、迁移和侵袭能力。我们还通过调节NUDT 21表达鉴定了许多具有缩短的3 'UTR的基因，并进一步表征了NUDT 21调节的基因ANXA 2和LIMK 2。我们发现NUDT 21在Wnt/beta-catenin和NF-κ B B信号通路中调节ANXA 2和LIMK 2的表达。NUDT 21因此可能具有作为治疗BC的诊断和治疗靶点的潜力。
Purpose: Nudix Hydrolase 21 (NUDT21) is a crucial mediator involved in alternative polyadenylation (APA), and this molecule has been reported to be a tumor suppressor in human cancers. However, neither the role NUDT21 plays in bladder cancer (BC) nor the mechanisms which are involved have been investigated.Methods: Expression levels of NUDT21 in BC were evaluated with real-time PCR, western blotting, and immunohistochemistry (IHC). In vitro and in vivo assays were performed to investigate the function of NUDT21 in tumorigenesis in bladder cancer cells. The TOP/FOP flash reporter assay, western blot, and global APA site profiling analysis were used to identify the pathway which mediates the biologic roles of NUDT21 in BC.Results: NUDT21 expression is reduced in BC tissue and cells, and BC patients with lower NUDT21 expression have shorter overall and recurrent-free survival than patients with higher NUDT21 expression. NUDT21 ectopic expression or knockdown respectively profoundly inhibited or promoted the capacity of BC cells for proliferation, migration and invasion. We also identified a number of genes with shortened 3'UTRs through modulation of NUDT21 expression, and further characterized the NUDT21-regulated genes ANXA2 and LIMK2. We found NUDT21 modulates the expression of ANXA2 and LIMK2 in the Wnt/beta-catenin and NF-kappa B signaling pathways.Conclusions: These findings show NUDT21 plays a crucial role in BC progression, at least in part through ANXA2 and LIMK2 which act by alternative polyadenylation. NUDT21 may thus have potential as a diagnostic and therapeutic target in treatment of BC.