Mir-182 Is Involved In Sulindac Anticancer Activity In Colon Cancer

Abstract Nonsteroidal anti-inflammatory drugs (NSAIDs) display promising antineoplastic activity in many human solid tumors including colorectal cancer. Previous studies reported that sulindac sulfide (SS) can inhibit the growth of tumor cells through cyclooxygenase-2 (COX-2) dependent or independent pathways. Obviously, COX-2 independent pathway involves a low toxic property to support the clinical potential for using sulindac as a chemoprevention drug. However, the molecular mechanisms responsible for COX-2 independent pathway have not been completely elucidated. In this project, we employed two human colon cancer cell lines, referred to HCT116 and HT29. HCT116 cells are characterized for low COX-2 expression, while HT29 cells show relatively high COX-2 expression. We found that SS could unbiasedly inhibit the growth of HCT116 and HT29 cells by arresting cells in G1/G2 phases. CyclinG2 was found to be upregulated in response to SS treatment. FOXO3a has been reported to regulate CyclinG2 expression at the transcriptional level. Our results demonstrate that SS could also upregulate FOXO3a. By using the loss-of-function strategy, we found that SS could not efficiently upregulate CyclinG2 and lead to cell cycle arrest in cells with FOXO3a knockdown. In addition, we studied the mechanism that could be involved in SS regulation of FOXO3a. Our previous studies reported that a panel of miRNAs could be altered by SS treatment in both colon and breast cancer cells. In the downregulated miRNA list, we found that miR-182 could potentially target FOXO3a. By using luciferase assay, we validated the direct regulation of miR-182 on the expression of FOXO3a. When miR-182 was downregulated, SS could neither efficiently upregulate the expression of FOXO3a nor inhibit cell growth as it did in control cells. We gained highly consistent results in HT29 and HT29 cells with COX-2 knockdown. Therefore, our study demonstrates a pathway consisting of miR-182/ FOXO3a/ CyclinG2 as a novel mechanism responsible for SS anticancer activity in colon cancer, which may imply a COX-2 independent pathway. Citation Format: Hongyou Zhao, Bin Yi, Zhipin Liang, Ruixia Ma, Yaguang Xi. Mir-182 is involved in sulindac anticancer activity in colon cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1480. doi:10.1158/1538-7445.AM2017-1480