CCAR1 5′ UTR as a natural miRancer of miR-1254 overrides tamoxifen resistance

Abstract

MicroRNAs (miRNAs) typically bind to unstructured miRNA-binding sites in target RNAs, leading to a mutual repression of expression. Here, we report that miR-1254 interacts with structured elements in cell cycle and apoptosis regulator 1 (CCAR1) 5′ untranslated region (UTR) and this interaction enhances the stability of both molecules. miR-1254 can also act as a repressor when binding to unstructured sites in its targets. Interestingly, structured miR-1254-targeting sites act as both a functional RNA motif-sensing unit, and an independent RNA functional unit that enhances miR-1254 expression. Artificially designed miRNA enhancers, termed “miRancers”, can stabilize and enhance the activity of miRNAs of interest. We further demonstrate that CCAR1 5′ UTR as a natural miRancer of endogenous miR-1254 re-sensitizes tamoxifen-resistant breast cancer cells to tamoxifen. Thus, our study presents a novel model of miRNA function, wherein highly structured miRancer-like motif-containing RNA fragments or miRancer molecules specifically interact with miRNAs, leading to reciprocal stabilization.

Variations in MicroRNA-25 Expression Influence the Severity of Diabetic Kidney Disease

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Targeting HSP90-HDAC6 Regulating Network Implicates Precision Treatment of Breast Cancer

“…The Tam-resistant cell line T47D-TAR cell line was generated by exposing T47D to tamoxifen (1μM) for > 12 months. ERα was significantly decreased in T47D-TAR cell line compared with its parental cells, indicating the loss of ERα function in T47D-TAR 14. T47D-TAR was then maintained in RMPI 1640 supplemented with 1μM tamoxifen.…”

MicroRNA‐1254 inhibits the migration of colon adenocarcinoma cells by targeting PSMD10

“…21 However, miR-1254 suppresses breast cancer cell migration and stem cell-like behavior. 11 These previous observations suggest that miR-1254 may function in a cell-specific or tissue-specific manner. Nevertheless, the role of this miRNA in CRC remains unknown and the detailed molecular pathways mediating the effect of miR-1254 on CRC migration is still elusive.…”

“…Serum concentration of miR‐1254 increases noticeably in patients with early‐stage non‐small cell lung cancer (NSCLC) . However, miR‐1254 suppresses breast cancer cell migration and stem cell‐like behavior . These previous observations suggest that miR‐1254 may function in a cell‐specific or tissue‐specific manner.…”