IMP3 accelerates the progression of prostate cancer through inhibiting PTEN expression in a SMURF1-dependent way

Journal of Experimental & Clinical Cancer Research

Xingwei Jin¹  Xiang Zhang¹  Xianjin Wang¹  Weichao Tu¹  Yuan Shao¹  Dawei Wang¹  Junwei Pan¹  Boke Liu¹ 

[1] Department of Urology, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, No. 197, 2nd Ruijin Road, 200025, Shanghai, PR China;Department of Urology, Ruijin Hospital North, Shanghai Jiaotong University School of Medicine, No. 999, Xiwang Road, 201801, Shanghai, China;

关键词: Prostate cancer;    IMP3;    PTEN;    PI3K/AKT/mTOR;    SMURF1;    Ubiquitination;   

DOI  :  10.1186/s13046-020-01657-0

来源: Springer

【 摘 要 】

BackgroundInsulin-like growth factor 2 (IGF2) messenger RNA binding protein 3 (IMP3) has been testified to be overexpressed in prostate cancer and strongly related to patients’ poor prognosis. However, the functions of IMP3 and the underlying mechanisms in prostate cancer still remain unknown. Therefore, the current study was carried out to reveal the role and molecular mechanism of IMP3 in prostate cancer progression.MethodsThe expression levels of IMP3 in prostate cancer tissues and cells were detected by immunohistochemistry (IHC), western blotting and RT-PCR. CCK-8, clone formation, flow cytometry and in vivo tumor formation assays were used to determine cell growth, clone formation apoptosis and tumorigenesis, respectively. The effect of IMP3 on the expression levels of the key proteins in PI3K/AKT/mTOR signaling pathway, including PIP2, PIP3, p-AKT, AKT, p-mTOR, mTOR, PTEN and BAD activation of was determined by western blotting. IP (Immunoprecipitation) assay was used to evaluate the effects of IMP3 and SMURF1 (SMAD specific E3 ubiquitin protein ligase 1) on the ubiquitination of PTEN protein.ResultsIMP3 expression level was significantly increased in prostate cancer tissues and cell lines (LNCap, PC3 and DU145) as compared with the paracancerous normal tissues and cells (RWPE-1), respectively. High expression of IMP3 apparently promoted cell viability, tumorigenesis and inhibited cell apoptosis in prostate cancer LNCap, DU145 and PC3 cell lines. In mechanism, IMP3 upregulation significantly increased the phosphorylation levels of AKT and mTOR, and elevated PIP3 expression level, while induced significant reductions in the expression levels of BAD, PTEN and PIP2. And, IMP3 overexpression increased SMURF1 expression, which facilitated PTEN ubiquitination. In addition, SMURF1 overexpression enhanced prostate cancer cell viability and inhibited cell apoptosis. Silence of SMURF1 rescued the enhancements in cell proliferation and tumorigenesis and the inhibition in cell apoptosis rates induced by IMP3 in prostate cancer DU145 and LNCap cells.ConclusionThis study reveals that IMP3 is overdressed in prostate cancer, which accelerates the progression of prostate cancer through activating PI3K/AKT/mTOR signaling pathway via increasing SMURF1-mediated PTEN ubiquitination.

【 授权许可】

CC BY