CD24 Induces Expression of the Oncomir miR-21 via Src, and CD24 and Src Are Both Post-Transcriptionally Downregulated by the Tumor Suppressor miR-34a

Cancer is a complex disease process that evolves as a consequence of multiple malfunctions in key regulatory molecular networks. Understanding these networks will be essential to combat cancer. In this study, we focussed on central players in such networks. In a series of colon and breast cancer cell lines, we found that CD24 activates Src, and induces the activation of c-Jun and expression of c-Jun and c-Fos. Thereby CD24 increases the promoter activity and expression of miR-21, which in turn suppresses expression of Pdcd4 and PTEN. Co-transfection of a CD24 expression construct and an siRNA that silences Src showed that CD24-dependent upregulation of miR-21 is mediated by Src. Additionally, we found that miR-34a post-transcriptionally downregulates CD24 and Src expression, leading to the deactivation of c-Jun, reduced expression of c-Jun and c-Fos, inhibition of miR-21, and upregulation of Pdcd4 and PTEN. Furthermore, miR-34a-mediated inhibition of Src expression reduced migration and invasion of colorectal cancer cells. Resected tumor tissues from 26 colorectal patients showed significantly lower expression of Pdcd4 and miR-34a, and higher expression of CD24, Src and miR-21 compared to the corresponding normal tissues. Moreover, CD24 positively correlated with the amount of Src protein in tumor tissues, and a trend towards an inverse correlation between miR-34a and Src protein levels was also observed. Our results reveal essential players in the complex networks that regulate the progression of solid tumors such as colorectal cancer. These findings therefore identify novel therapeutic approaches for combating tumor growth and progression.

癌症是一类复杂的疾病进程，其发生发展源于关键调控分子网络的多重功能异常。解析此类网络对于对抗癌症至关重要。本研究聚焦于此类调控网络中的核心因子。在一系列结肠与乳腺癌细胞系中，本研究发现CD24可激活Src，并诱导c-Jun的活化以及c-Jun与c-Fos的表达。借此CD24可增强miR-21的启动子活性并提升其表达水平，而miR-21又会抑制Pdcd4与PTEN的表达。将CD24表达载体与靶向沉默Src的小干扰RNA（siRNA）共转染后，实验证实CD24依赖的miR-21上调作用由Src介导。此外，本研究发现miR-34a可在转录后水平下调CD24与Src的表达，进而导致c-Jun失活、c-Jun与c-Fos表达水平降低、miR-21的表达受到抑制，同时上调Pdcd4与PTEN的表达。进一步研究显示，miR-34a介导的Src表达抑制可降低结直肠癌细胞的迁移与侵袭能力。对26名结直肠癌患者的手术切除肿瘤组织与配对正常组织进行检测后发现，肿瘤组织中Pdcd4与miR-34a的表达水平显著降低，而CD24、Src与miR-21的表达水平则显著升高。此外，肿瘤组织中CD24的表达水平与Src蛋白含量呈正相关，同时miR-34a与Src蛋白水平也呈现出负相关趋势。本研究结果揭示了调控结直肠癌等实体瘤进展的复杂分子网络中的核心调控因子，为对抗肿瘤生长与进展提供了全新的治疗策略。