miR-19 promotes the proliferation of clear cell renal cell carcinoma by targeting the FRK–PTEN axis

Zhi-Fei Jing,1,2 Jian-Bin Bi,1,2 Ze-Liang Li,1,2 Xian-Kui Liu,1,2 Jun Li,1,2 Yu-Yan Zhu,1,2 Xiao-Tong Zhang,1,2 Zhe Zhang,1,2 Zhen-Hua Li,1,2 Chui-Ze Kong1,2 1Department of Urology, First Hospital of China Medical University, Shenyang, Liaoning 110001, People’s Republic of China; 2Institute of Urology, China Medical University, Shenyang 110001, People’s Republic of China Background: The non-receptor tyrosine kinase Fyn-related kinase (FRK) has been reported to affect cell proliferation in several cancer types. However, its effect on the proliferation of clear cell renal cell carcinoma (ccRCC) remains largely unknown.Purpose: The objective of this study was to investigate the expression pattern and function of FRK in ccRCC. We further determined how FRK interacted with other molecules to regulate ccRCC proliferation.Patients and methods: The expression of FRK in ccRCC samples and paired normal renal tissues from 30 patients were analyzed by immunoblotting, immunohistochemistry and quantitative PCR. Then the role of FRK in ccRCC proliferation was analyzed by Cell Counting Kit-8, colony formation assay and EdU incorporation assay. In addition, the miRNA targeting FRK was predicted through a bioinformatic approach and validated by quantitative PCR, immunoblotting and luciferase reporter assay. Finally, the underlying mechanism of FRK regulation of ccRCC proliferation was also determined.Results: Low expression of FRK was detected in ccRCC samples and predicted poor survival for ccRCC patients. FRK inhibited the proliferation of ccRCC cells via phosphorylating downstream PTEN. miR-19 was identified as a novel suppressor of FRK in renal cancer cells and it promoted the proliferation of ccRCC by inhibiting the FRK–PTEN axis.Conclusion: Our results unravel a new regulatory mechanism involved in ccRCC proliferation and may be useful in the identification of therapeutic targets for ccRCC. Keywords: clear cell renal cell carcinoma, miR-19, miR-17~92 cluster, FRK, PTEN, proliferation, oncomiR-1