The Central Laboratory of Sanming First Hospital Affiliated to Fujian Medical University, Sanming City, 365000, China.
Department of Clinical Medical Oncology, Qingyuan People's Hospital, The Six Affiliated Hosptial of Guangzhou Medical University, Qingyuan City, 511518, China.
Exp Cell Res. 2019 Jul 1;380(1):80-89. doi: 10.1016/j.yexcr.2019.04.019. Epub 2019 Apr 16.
CSTP1, a recently identified protein phosphotase, is frequently repressed in bladder cancers. Previous results showed that CSTP1 over-expression inhibited cell cycle progression and promoted apoptosis through dephosphorylating Akt kinase at Ser473 site in bladder cancer cells, but the mechanisms how CSTP1 exerted tumor suppressive activity remains unclear. In this study, we analyzed the gene expression profile changes that affected by CSTP1 overexpression by microarray, and reported that CSTP1 decreased IL-6 expression/secretion in bladder cancer cells and re-expression of IL-6 abrogated CSTP1's tumor suppressive activity. We also found that FoxO3a occupy IL-6 gene promoter and repressed IL mRNA transcription. Further results showed that decreased expression of IL-6 in CSTP1-overexpressing cells inactivated Stat3 transcriptional factor, which resulted in the down-regulation of cyclin D1, Bcl-xl expression. Spearman correlation analysis revealed that the mRNA level of CSTP1 correlated inversely with that of IL-6 in bladder cancer tissues. In conclusion, our studies revealed that protein phosphotase CSTP1 inhibited IL-6 expression through targeting Akt/FoxO3a signaling pathway and IL-6 inactivated Stat3 was necessary for CSTP1's tumor suppressive function.
CSTP1 是一种新鉴定的蛋白磷酸酶，在膀胱癌中经常受到抑制。先前的研究结果表明，CSTP1 过表达通过使膀胱癌细胞中 Akt 激酶在 Ser473 位点去磷酸化来抑制细胞周期进程并促进细胞凋亡，但 CSTP1 发挥肿瘤抑制活性的机制尚不清楚。在这项研究中，我们通过微阵列分析了受 CSTP1 过表达影响的基因表达谱变化，并报告 CSTP1 降低了膀胱癌细胞中 IL-6 的表达/分泌，并且重新表达 IL-6 可消除 CSTP1 的肿瘤抑制活性。我们还发现 FoxO3a 占据了 IL-6 基因启动子并抑制了 IL mRNA 的转录。进一步的结果表明，在 CSTP1 过表达细胞中 IL-6 的表达降低使 Stat3 转录因子失活，从而导致细胞周期蛋白 D1、Bcl-xl 表达下调。Spearman 相关分析显示，膀胱癌细胞中 CSTP1 的 mRNA 水平与 IL-6 的 mRNA 水平呈负相关。总之，我们的研究表明，蛋白磷酸酶 CSTP1 通过靶向 Akt/FoxO3a 信号通路抑制 IL-6 的表达，而 IL-6 使 Stat3 失活是 CSTP1 肿瘤抑制功能所必需的。
