Wilms' tumor 1-associating protein promotes renal cell carcinoma proliferation by regulating CDK2 mRNA stability.
Wilms' tumor 1-associating protein promotes renal cell carcinoma proliferation by regulating CDK2 mRNA stability.
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DOI：
10.1186/s13046-018-0706-6
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发表时间：
2018-02-27
期刊：
影响因子：
--
通讯作者：
Yang H
中科院分区：
文献类型：
--
作者：
Tang J;Wang F;Cheng G;Si S;Sun X;Han J;Yu H;Zhang W;Lv Q;Wei JF;Yang H
肾母细胞瘤相关蛋白1（Wilms' tumor 1-associated protein，WTAP）在细胞周期调控等生理过程和肿瘤发生发展中起重要作用。细胞周期的调控主要依赖于细胞周期蛋白和细胞周期蛋白依赖性蛋白激酶（cyclin-dependent protein kinases，CDKs）。近年来的研究表明，CDKs与肿瘤的诊断、进展和治疗反应密切相关。然而，它们在肾细胞癌（RCC）中的具体生物学作用及其相关机制尚不清楚。采用实时荧光定量PCR、免疫印迹和免疫组化方法检测WTAP和CDK 2的表达。采用生存分析方法探讨WTAP表达与肾癌预后的关系。采用慢病毒法稳定转染肾癌细胞，通过观察细胞增殖、细胞周期及裸鼠成瘤情况，评价WTAP对肾癌的治疗作用。采用RNA免疫沉淀、荧光素酶报告基因分析和siRNA技术鉴定WTAP与CDK 2转录本的直接结合位点。通过集落形成试验来证实CDK 2在WTAP诱导的生长促进中的功能。在肾细胞癌细胞系和组织中，WTAP显著过表达。与WTAP低表达患者相比，WTAP高表达患者的总生存率较低。细胞功能检测显示，WTAP过表达组细胞增殖能力增强，而WTAP敲低组则相反。皮下移植瘤模型显示，敲低WTAP可抑制体内肿瘤的发生。机制研究表明，CDK 2表达与WTAP表达呈正相关。WTAP通过与CDK 2转录本的3′-UTR结合，稳定CDK 2转录本，提高CDK 2的表达。此外，CDK 2活性的特异性抑制剂和CDK 2表达的小干扰RNA（siRNA）抑制WTAP介导的增殖促进。这些结果表明，WTAP可能通过与CDK 2转录本物理结合并增强其转录本的稳定性而在RCC中发挥致癌作用，这可能为RCC治疗提供新的见解。本文的在线版本（10.1186/s13046-018-0706-6）包含补充材料，可供授权用户使用。
Wilms’ tumor 1-associating protein (WTAP) plays an important role in physiological processes and the development of tumor such as cell cycle regulation. The regulation of cell cycle is mainly dependent on cyclins and cyclin-dependent protein kinases (CDKs). Recent studies have shown that CDKs are closely related to the tumor diagnosis, progression and response to treatment. However, their specific biological roles and related mechanism in renal cell carcinoma (RCC) remain unknown. Quantitative real-time PCR, western blotting and immunohistochemistry were used to detect the expression of WTAP and CDK2. The survival analysis was adopted to explore the association between WTAP expression and the prognosis of RCC. Cells were stably transfected with lentivirus approach and cell proliferation and cell cycle, as well as tumorigenesis in nude mice were performed to assess the effect of WTAP in RCC. RNA immunoprecipitation, Luciferase reporter assay and siRNA were employed to identify the direct binding sites of WTAP with CDK2 transcript. Colony formation assay was conducted to confirm the function of CDK2 in WTAP-induced growth promoting. In RCC cell lines and tissues, WTAP was significantly over-expressed. Compared with patients with low expression of WTAP, patients with high expression of WTAP had lower overall survival rate. Additionally, cell function test indicated that cell proliferation abilities in WTAP over-expressed group were enhanced, while WTAP knockdown showed the opposite results. Subcutaneous xenograft tumor model displayed that knockdown of WTAP could impede tumorigenesis in vivo. Mechanism study exhibited that CDK2 expression was positively associated with the expression of WTAP. Moreover, WTAP stabilized CDK2 transcript to enhance CDK2 expression via binding to 3′-UTR of CDK2 transcript. Additionally, specific inhibitors of CDK2 activity and small interfering RNA (siRNA) of CDK2 expression inhibited WTAP-mediated promotion of proliferation. These findings suggest that WTAP may have an oncogenic role in RCC through physically binding to CDK2 transcript and enhancing its transcript stability which might provide new insights into RCC therapy. The online version of this article (10.1186/s13046-018-0706-6) contains supplementary material, which is available to authorized users.
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