Downregulation of the long noncoding RNA DSCR9 (Down syndrome critical region 9) delays breast cancer progression by modulating microRNA-504-5p-dependent G protein-coupled receptor 65.

Abstract

Possible roles of long noncoding RNAs (lncRNAs) in cancer stem cells (CSCs) have often been reported. Here, we focused on the regulatory function of the lncRNA Down syndrome critical region 9 (DSCR9) in breast cancer stem cells (BCSCs). Through bioinformatics analysis, DSCR9, microRNA-504-5p (miR-504-5p), and G protein-coupled receptor 65 (GPR65) were identified as targets implicated in breast cancer development. Then, clinical tissue samples, breast cancer cells, and isolated BCSCs were used to determine the expression of DSCR9, miR-504-5p, and GPR65. The results confirmed the overexpression of DSCR9 and GPR65 but low expression of miR-504-5p in breast cancer tissues and cells as well as in BCSCs. Following mechanistic investigation, it was found that DSCR9 targeted miR-504-5p, and that silencing DSCR9 inhibited the proliferation of BCSCs by elevating the expression of miR-504-5p. Additionally, miR-504-5p targeted GPR65 and inhibited its expression. Moreover, GPR65 activated the MEK/ERK signaling pathway to regulate BCSC proliferation. Finally, animal study verified that depletion of DSCR9 inhibited the proliferation of BCSCs in vivo and that BCSC proliferation was restored by overexpression of GPR65. Altogether, our findings revealed that DSCR9 elevated GPR65 expression by targeting miR-504-5p to exacerbate breast cancer, highlighting a new treatment modality for breast cancer.