Sulindac has shown significant clinical benefit in preventing colorectal cancer progression, but its mechanism of action has not been fully elucidated. We have found that sulindac sulfide (SS) is able to inhibit cell cycle progression in human colorectal cancer cells, particularly through G1 arrest. To understand the underlying mechanisms of sulindac inhibitory activity, we have demonstrated that Cyclin G2 up-regulation upon SS treatment can substantially delay cell cycle progression by enhancing the transcriptional activity of FOXO3a in human colorectal tumor cells. MiR-182, an oncogenic microRNA known to inhibit FOXO3a gene expression, is also involved in the suppressive effect of SS on cell cycle progression. This process begins with the down-regulation of miR-182, followed by the enhancement of FOXO3a transcriptional activity and the up-regulation of Cyclin G2. To further determine the clinical utility of this axis, we analyzed the expression of miR-182/FOXO3a/Cyclin G2 in human colorectal tumor samples. Our results show not only that there are significant differences in miR-182/FOXO3a/Cyclin G2 between tumors and normal tissues, but also that the synergetic effect of miR-182 and FOXO3a is associated with predicting tumor progression. Our study demonstrates a novel mechanistic axis consisting of miR-182/FOXO3a/Cyclin G2 that mediates sulindac inhibition of cell cycle progression.

舒林酸在预防结直肠癌进展方面显示出显着的临床益处，但其作用机制尚未完全阐明。我们发现舒林酸硫化物 (SS) 能够抑制人结直肠癌细胞的细胞周期进程，特别是通过 G1 期阻滞。为了了解舒林酸抑制活性的潜在机制，我们证明了 SS 处理后 Cyclin G2 的上调可以通过增强人结直肠肿瘤细胞中 FOXO3a 的转录活性来显着延迟细胞周期进程。MiR-182 是一种致癌 microRNA，已知可抑制 FOXO3a 基因表达，也参与 SS 对细胞周期进程的抑制作用。这个过程首先是 miR-182 的下调，然后是 FOXO3a 转录活性的增强和 Cyclin G2 的上调。为了进一步确定该轴的临床实用性，我们分析了人类结直肠肿瘤样本中 miR-182/FOXO3a/Cyclin G2 的表达。我们的结果不仅表明miR-182/FOXO3a/Cyclin G2在肿瘤和正常组织之间存在显着差异，而且miR-182和FOXO3a的协同作用与预测肿瘤进展相关。我们的研究证明了由 miR-182/FOXO3a/Cyclin G2 组成的新机制轴，介导舒林酸对细胞周期进展的抑制。