Sulindac has shown significant clinical benefit in preventing colorectal cancer pro-gression,but its mechanism of action has not been fully elucidated.We have found that sulin-dac sulfide(SS)is able to inhibit cell cy...Sulindac has shown significant clinical benefit in preventing colorectal cancer pro-gression,but its mechanism of action has not been fully elucidated.We have found that sulin-dac 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 substan-tially 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 expres-sion,is also involved in the suppressive effect of SS on cell cycle progression.This process be-gins 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 colo-rectal tumor samples.Our results show not only that there are significant dfferences 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 dem-onstrates a novel mechanistic axis consisting of miR-182/FOXO3a/Cyclin G2 that mediates su-lindac inhibition of cell cycle progression.展开更多
文摘Sulindac has shown significant clinical benefit in preventing colorectal cancer pro-gression,but its mechanism of action has not been fully elucidated.We have found that sulin-dac 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 substan-tially 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 expres-sion,is also involved in the suppressive effect of SS on cell cycle progression.This process be-gins 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 colo-rectal tumor samples.Our results show not only that there are significant dfferences 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 dem-onstrates a novel mechanistic axis consisting of miR-182/FOXO3a/Cyclin G2 that mediates su-lindac inhibition of cell cycle progression.
