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,West 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 ofmiR-375,which was further confirmed by the luciferase reporter assay,qPCR,and West blotting.Moreover,restoration of YWHAZ could rescue the antiproliferation effect ofmiR-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 ofmiR-375,and supports its role as a potential therapeutic target in ccRCC treatment.