BTG2 is a tumor suppressor gene upregulated by p53 and PTEN in human bladder carcinoma cells

摘要

Although widely deemed as a tumor suppressor gene, the role of B‐cell translocation gene 2 (BTG2) in bladder cancer is still inconclusive. We investigated the role and regulatory mechanism of BTG2 in bladder cancer. BTG2 expression in human bladder tissues was determined by RT‐qPCR and immunoblotting assays. Expressions of BTG2 and PTEN in bladder carcinoma cells were determined by immunoblotting, RT‐qPCR, or reporter assays. The ³H‐thymidine incorporation assay, flow cytometry, and the xenograft animal model were used to determine the cell growth. BTG2 expression was lower in human bladder cancer tissues than normal bladder tissues. Highly differentiated bladder cancer cells, RT4, expressed higher BTG2 than the less‐differentiated bladder cancer cells, HT1376 and T24. Overexpression of BTG2 in T24 cells inhibited cell growth in vitro and in vivo. Camptothecin and doxorubicin treatments in RT‐4 cells or transient overexpression of p53 into p53‐mutant HT1376 cells induced p53 and style="fixed-case">BTG2 expression. Further reporter assays with site‐mutation of p53 response element from style="fixed-case">GGGAAAGTCC to style="fixed-case">GGAGTCC within style="fixed-case">BTG2 promoter area showed that p53‐induced style="fixed-case">BTG2 gene expression was dependent on the p53 response element. Ectopic style="fixed-case">PTEN overexpression in T24 cells blocked the Akt signal pathway which attenuated cell growth via upregualtion of style="fixed-case">BTG2 gene expression, while reverse effect was found in style="fixed-case">PTEN‐knockdown style="fixed-case">RT‐4 cells. style="fixed-case">PTEN activity inhibitor ( style="fixed-case">VO‐ style="fixed-case">OHpic) treatment decreased style="fixed-case">BTG2 expression in style="fixed-case">RT‐4 and style="fixed-case">PTEN‐overexpressed T24 cells. Our results suggested that style="fixed-case">BTG2 functioned as a bladder cancer tumor suppressor gene, and was induced by p53 and style="fixed-case">PTEN. Modulation of style="fixed-case">BTG2 expression seems a promising way to treat human bladder cancer.