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ORIGINAL ARTICLE
Year : 2018  |  Volume : 131  |  Issue : 16  |  Page : 1944-1950

MicroRNA-375 Suppresses the Tumor Aggressive Phenotypes of Clear Cell Renal Cell Carcinomas through Regulating YWHAZ


1 Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
2 Teaching and Research Institute of Urology, School of Medicine, Shandong University, Jinan, Shandong 250012, China
3 Department of Urology, Qilu Hospital of Shandong University, Jinan, Shandong 250012; Department of Urology, Qingyun People's Hospital, Dezhou, Shandong 253700, China
4 Department of the First Operation Room, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China
5 Central Laboratory, The Second Hospital of Shandong University, Jinan, Shandong 250012, China
6 Department of Urology, Qilu Hospital of Shandong University; Medicaid and Health Care Service Office, Qilu Hospital of Shandong University, Jinan, Shandong 250012, China

Correspondence Address:
Dr. Jie Song
Department of Urology, Qilu Hospital of Shandong University, Wenhua West Road 44#, Jinan, Shandong 250012
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0366-6999.238153

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Background: MicroRNAs (miRNAs) are key regulators during tumor initiation and progression. MicroRNA-375 (MiR-375) has been proven to play a tumor-suppressive role in various types of human malignancies; however, its biological role in clear cell renal cell carcinoma (ccRCC) remains unclear. The purpose of this study was to explore the biologic role as well as the underlying mechanism of miR-375 in ccRCC progression. Methods: Quantitative polymerase chain reaction (qPCR) was applied to test the expression of miR-375 in tissues and cell lines by t-test. Functional experiments were used to investigate the biological role of miR-375 utilizing a gain-of-function strategy. The target of miR-375 was investigated by bioinformatic analysis and further verified by luciferase reporter assay, qPCR, Western blotting, and functional experiments in vitro. Results: Our study demonstrated that miR-375 was significantly downregulated in ccRCC tissues (cancer vs. normal, 0.804 ± 0.079 vs. 1.784 ± 0.200, t = 5.531 P < 0.0001) and cell lines, and loss of miR-375 expression significantly associated with advanced Fuhrman nuclear grades (Grade III and IV vs. Grade I and II, 1.000 ± 0.099 vs. 1.731 ± 0.189, t = 3.262 P = 0.003). Functional studies demonstrated that miR-375 suppressed ccRCC cell proliferation, migration, and invasion (all P < 0.05 in both 786-O and A498 cell lines). Multiple miRNA target prediction algorithms indicated the well-studied oncogene YWHAZ as a direct target of miR-375, which was further confirmed by the luciferase reporter assay, qPCR, and Western blotting. Moreover, restoration of YWHAZ could rescue the antiproliferation effect of miR-375. Conclusions: The data provide the solid evidence that miR-375 plays a tumor-suppressive role in ccRCC progression, partially through regulating YWHAZ. This study expands the antitumor profile of miR-375, and supports its role as a potential therapeutic target in ccRCC treatment.

 

 Abstract in Chinese

miR-375 通过调控YWHAZ抑制肾透明细胞癌的恶性侵袭性生物学行为

摘要

背景: 微小RNA(miR-375)在肿瘤的发生与发展中发挥了重要的生物学作用。研究表明miR-375在多种恶性肿瘤发生过程中发挥了重要的抑癌作用,然而,其在肾透明细胞癌(ccRCC)中的生物学作用尚不明确。本研究旨在研究ccRCC中miR-375的生物学作用及其潜在机制。

方法:应用定量PCR(qPCR)检测肾癌临床组织和细胞系中miR-375的表达水平。采取过表达策略应用多种细胞功能学实验研究miR-375在肾癌细胞中的生物学功能。应用生物信息学软件预测miR-375的潜在作用靶点,并应用荧光素酶报告实验、qPCR、蛋白印迹实验及细胞功能学实验验证。

结果:本实验证实miR-375在肾癌临床标本(肾癌组织 比 正常肾组织, 0.804 ± 0.079 比1.784 ± 0.200, P <0.0001) 和细胞系中均显著表达下调,且miR-375的低表达与更高的肾癌Fuhrman细胞核分级显著相关(高核分级 vs. 低核分级, 1.000±0.099 比 1.731±0.189, P =0.003)。功能学实验证实miR-375过表达可显著抑制ccRCC细胞增殖、迁移和侵袭(所有P<0.05)。多种miRNA靶点预测软件提示原癌基因YWHAZ是miR-375的靶基因,我们进一步应用荧光素酶报告实验、qPCR和蛋白印迹实验证实miR-375对YWHAZ的调控。并且,挽救实验证实YWHAZ再表达可逆转miR-375抑制细胞增殖的作用。

结论:本实验证实miR-375在ccRCC的恶性进展过程中发挥了重要的抑癌作用,其抑癌作用部分是通过对YWHAZ的调控来实现的。本实验进一步扩展了miR-375的抑癌谱,为研究其药用价值提供了理论依据。



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