Functional high-throughput screening reveals miR-323a-5p and miR-342-5p as new tumor-suppressive microRNA for neuroblastoma

Abstract

Current therapies for most non-infectious diseases are directed at or affect functionality of the human translated genome, barely 2% of all genetic information. By contrast, the therapeutic potential of targeting the transcriptome, ~ 70% of the genome, remains largely unexplored. RNA therapeutics is an emerging field that widens the range of druggable targets and includes elements such as microRNA. Here, we sought to screen for microRNA with tumor-suppressive functions in neuroblastoma, an aggressive pediatric tumor of the sympathetic nervous system that requires the development of new therapies. We found miR-323a-5p and miR-342-5p to be capable of reducing cell proliferation in multiple neuroblastoma cell lines in vitro and in vivo, thereby providing a proof of concept for miRNA-based therapies for neuroblastoma. Furthermore, the combined inhibition of the direct identified targets such as CCND1, CHAF1A, INCENP and BCL-XL could reveal new vulnerabilities of high-risk neuroblastoma. Electronic supplementary material The online version of this article (10.1007/s00018-019-03041-4) contains supplementary material, which is available to authorized users.

Hyperoxia‐induced miR‐342‐5p down‐regulation exacerbates neonatal bronchopulmonary dysplasia via the Raf1 regulator Spred3

“…Of note, decreased levels of miR‐342‐5p were also found in neonatal patients with moderate/severe BPD, highlighting its role in the human disease setting. As miR‐342‐5p has largely been associated with tumour suppression (Lindholm et al, 2019; Soriano et al, 2019) and is likely non‐oncogenic, miR‐342‐5p mimic therapy may show promise in treating or preventing BPD. Such a mimic therapy should be targeted at T2AECs in order to enhance the therapeutic effect.…”

A High-Throughput Screening Identifies MicroRNA Inhibitors That Influence Neuronal Maintenance and/or Response to Oxidative Stress

“…High-throughput functional screenings (HTFSs) have used miRNA-ASOs or RNA molecules designed to mimic endogenous mature miRNA (miRNA-mimics), to identify species with an effect in the expression of dosage-sensitive genes, in reporter assays 13, 14. In addition, most HTFS analyses have evaluated the effect of a moderate number of miRNA-mimics or -ASOs in tumorigenic outcomes, including cell invasiveness, 15 tumor cell death, 16 or cell growth 17, 18. HTFS studies to generally identify sncRNAs with a role in differentiated neuronal cell viability are missing.…”

Prognostic alternative splicing regulatory network of RBM25 in hepatocellular carcinoma

“…Another study showed that CDCA5, which is transcribed by E2F1, promotes oncogenesis by enhancing cell proliferation and inhibiting apoptosis via the AKT pathway in HCC [30]. In addition, INCENP dysregulation has also been confirmed to be related to the occurrence and development of a variety of tumors [31][32][33][34]. INCENP depletion can suppress neuroblastoma cell growth by inducing polyploidization, apoptosis, and senescence [31].…”