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Investigation of the potential theranostic role of KDM5B/miR-29c signaling axis in paclitaxel resistant endometrial carcinoma

Li, Lijie, Shou, Huafeng, Wang, Qianqian, Liu, Suxiao
Gene 2019 v.694 pp. 76-82
3' untranslated regions, binding sites, carcinoma, cell lines, endometrium, enzymes, gene silencing, genes, histones, paclitaxel, patients, uterine neoplasms
Endometrial cancer (EC) is one of the most common female reproductive system tumors. In this study, we explored the clinical significance of Histone demethylase KDM5B gene and its effects on paclitaxel (PTX) sensitivity in EC.First, we found that KDM5B expression significantly higher in EC tissues and cell lines. The elevated KDM5B expression was associated with high pathological grade and low PTX sensitivity. The functional role of KDM5B in PTX-resistant Ishikawa-R and HEC1A-R cells were examined by gene silencing experiments.Knockdown of KDM5B resulted in the re-sensitization towards paclitaxel in both resistant cell lines. In addition, we also identified that microRNA-29c-3p (a tumor suppressor) was significantly lower in the EC cells and linked to the low PTX sensitivity of EC. The up-regulation of miR-29c-3p using exogenous mimic molecules markedly increased PTX sensitivity in both cell lines and reduced expression of KDM5B while the inhibitor of miR-29-3p resulted in the opposite effects. Notably, we also demonstrated that the level of miR-29c-3p was inversely correlated to the invasive, colony-forming abilities and PTX resistance in both cell lines. We also identified that miR-29c-3p has a binding site in the 3′UTR of the KDM5B gene, establishing a link of this signaling axis. In conclusion, high-expression of KDM5B is associated with the poor response to PTX in EC patients. Silencing of KDM5B led to the reversal of PTX resistance through miR-29c-3p/KDM5B pathway in EC.Our findings provide new insights into the mechanism by which EC cells acquire paclitaxel resistance and potential this signaling as a theronostic marker for this malignancy.