MicroRNA (miR)-597-5p Inhibits Colon Cancer Cell Migration and Invasion by Targeting FOS-Like Antigen 2 (FOSL2)

Our previous work had shown that FOS-like antigen 2 (FOSL2) is regulated by miR-143-5p in colorectal cancer (CRC). Given that it has been shown by others that FOSL2 is also a target of miR-597-5p in breast adenocarcinoma, the objective of the current work was to determine whether FOSL2 is regulated by miR-597-5p in CRC and the role of miR-597-5p in CRC. MiR-597-5p expression was determined in RNA obtained from 30 paired samples of colon cancer and tumor adjacent normal tissue, as well as in the LoVo (CRC cell line) and FHC (normal colonic epithelial cells) by quantitative real time polymerase chain reaction (qRT-PCR). MiR-597-5p expression was significantly downregulated in both CRC tissue and LoVo cells. Reporter assays using wild-type and miR-597-5p seed mutant FOSL2 confirmed that FOSL2 is a bona fide target of miR-597-5p. Modulating miR-597-5p expression levels in FHC and LoVo cells using antagomir and mimic, respectively, impacted expression of epithelial and mesenchymal cell markers as well as in vitro migration and invasion, without any effect on cell proliferation, showing that miR-597-5p functions as a suppressor of epithelial to mesenchymal transition. Restoration of FOSL2 expression rescued pro-metastatic functional properties of LoVo cells conforming that effect of miR-597-5p was being mediated by targeting FOSL2. Xenograft assays in athymic nude mice showed that miR-597-5p mimic did not reduce tumor incidence or growth in LoVo cells. However, using a hepatic metastasis model showed that miR-597-5p mimic can significantly prevent hepatic metastatic nodule formation as well as FOSL2 expression in these metastatic nodules. Importantly, FOSL2 mRNA and miR-597-5p expression was found to be inversely correlated in an independent cohort of 21 CRC patients Cumulatively our results show that miR-597-5p functions as a suppressor of metastatic progression in CRC by targeting FOSL2. Replenishment of miR-597-5p can be a potential therapeutic target where its expression along with FOSL2 can serve as potential diagnostic markers in CRC.