Novel internal regulators and candidate miRNAs within miR-379/miR-656 miRNA cluster can alter cellular phenotype of human glioblastoma

Nayak, S; Aich, M; Kumar, A; Sengupta, S; Bajad, P; Dhapola, P; Paul, D; Narta, K; Purkrait, S; Mehani, B; Suri, A; Chakraborty, D; Mukhopadhyay, A; Sarkar, C

Abstract

Clustered miRNAs can affect functioning of downstream pathways due to possible coordinated function. We
observed 78-88% of the miR-379/miR-656 cluster (C14MC) miRNAs were downregulated in three sub-types
of diffuse gliomas, which was also corroborated with analysis from The Cancer Genome Atlas (TCGA)
datasets. The miRNA expression levels decreased with increasing tumor grade, indicating this
downregulation as an early event in gliomagenesis. Higher expression of the C14MC miRNAs significantly
improved glioblastioma prognosis (Pearson’s r=0.62; p<3.08e-22). ENCODE meta-data analysis, followed by
reporter assays validated existence of two novel internal regulators within C14MC. CRISPR activation of the
most efficient internal regulator specifically induced members of the downstream miRNA sub-cluster and
apoptosis in glioblastoma cells. Luciferase assays validated novel targets for miR-134 and miR-485-5p, two
miRNAs from C14MC with the most number of target genes relevant for glioma. Overexpression of miR-134
and miR-485-5p in human glioblastoma cells suppressed invasion and proliferation, respectively.
Furthermore, apoptosis was induced by both miRs, individually and in combination. The results emphasize
the tumor suppressive role of C14MC in diffuse gliomas, and identifies two specific miRNAs with potential
therapeutic value and towards better disease management and therapy.

Citation

Nayak, S., Aich, M., Kumar, A., Sengupta, S., Bajad, P., Dhapola, P., …Sarkar, C. (2018). Novel internal regulators and candidate miRNAs within miR-379/miR-656 miRNA cluster can alter cellular phenotype of human glioblastoma. Scientific reports, 8(2018), #7673. https://doi.org/10.1038/s41598-018-26000-8

• Journal Article Type: Article
• Acceptance Date: Apr 17, 2018
• Online Publication Date: May 16, 2018
• Publication Date: May 16, 2018
• Deposit Date: Apr 24, 2018
• Publicly Available Date: May 18, 2018
• Journal: Scientific Reports
• Print ISSN: 2045-2322
• Publisher: Nature Publishing Group
• Volume: 8
• Issue: 2018
• Pages: #7673
• DOI: https://doi.org/10.1038/s41598-018-26000-8
• Publisher URL: https://doi.org/10.1038/s41598-018-26000-8
• Related Public URLs: http://www.nature.com/srep/
• Additional Information: Funders : Department of Biotechnology (DBT), Government of India;Council of Scientific and Industrial Research (CSIR), Government of India;Cardio-Neurosciences Centre (AIIMS, New Delhi); Grant Number: GAP-0094; Grant Number: BSC-0123