Cyclin G2, a novel target of sulindac to inhibit cell cycle progression in colorectal cancer

Abstract 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, particularly via G1-arrest, in human colorectal cancer cells. To understand the underlying mechanisms involved in the inhibitory activity of sulindac, we have demonstrated that the up-regulation of the Cyclin G2 gene following 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, was also involved in the suppressive effect of SS on cell cycle progression. This process begins with the downregulation of miR-182, enhanced FOXO3a transcriptional activity, and 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 is there a significant difference 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.