MiR-338-3p regulates neuronal maturation and suppresses glioblastoma proliferation

Abstract

Neurogenesis is a highly-regulated process occurring in the dentate gyrus that has been linked to learning, memory, and antidepressant efficacy. MicroRNAs (miRNAs) have been previously shown to play an important role in the regulation of neuronal development and neurogenesis in the dentate gyrus via modulation of gene expression. However, this mode of regulation is both incompletely described in the literature thus far and highly multifactorial. In this study, we designed sensors and detected relative levels of expression of 10 different miRNAs and found miR-338-3p was most highly expressed in the dentate gyrus. Comparison of miR-338-3p expression with neuronal markers of maturity indicates miR-338-3p is expressed most highly in the mature neuron. We also designed a viral “sponge” to knock down in vivo expression of miR-338-3p. When miR-338-3p is knocked down, neurons sprout multiple primary dendrites that branch off of the soma in a disorganized manner, cellular proliferation is upregulated, and neoplasms form spontaneously in vivo. Additionally, miR-338-3p overexpression in glioblastoma cell lines slows their proliferation in vitro. Further, low miR-338-3p expression is associated with increased mortality and disease progression in patients with glioblastoma. These data identify miR-338-3p as a clinically relevant tumor suppressor in glioblastoma.

miR‑338‑3p regulates the proliferation, apoptosis and migration of SW480 cells by targeting MACC1

“…miR-338-3p has been reported to be involved in the progression and development of various types of cancer (9)(10)(11)(12)(13)(14)17,18,21). However the cellular function of miR-338-3and its molecular mechanism in CRC remains unknown.…”

“…miRNAs are regulators of gene expression, which affect cell proliferation, differentiation and death (7,8). miR-338-3p is located on chromosome 17q25.3 within the 8th intron of the apoptosis-associated tyrosine kinase gene, which produces two forms: miR-338-3p and miR-338-5p (9)(10)(11)(12)(13)(14). It has been reported that chromosome 17q23-25 is a region associated with mutations in several malignant tumors (15,16).…”

“…In addition, this locus is associated with many malignant biological behaviors which include tumor vascular invasion and distant metastasis (13). Previous studies have demonstrated that miR-338-3p inhibits glioblastoma proliferation (9,12), renal carcinoma invasion (10), gastric cancer progression (11,17), ovarian epithelial carcinoma growth (18) and hepatocellular carcinoma proliferation (14). However, studies investigating the cellular function of miR-338-3p in CRC are lacking.…”

Circulating RNAs as Potential Biomarkers in Amyotrophic Lateral Sclerosis

“…Its role as a functional miRNA in controlling different molecular pathways has been reported. miR-338-3p is involved in neuronal proliferation, maturation and neurite outgrowth and in organization in the dentate gyrus, while also acting as a tumor suppressor in vivo [134][135][136][137]. miR-338-3p is also expressed in spinal cord oligodendrocytes, where it positively regulates oligodendrocyte differentiation from precursors into mature oligodendrocytes by repressing Sox5 and Hes6, two maturation-and differentiation-inhibiting transcription factors [138,139].…”

Epigenetic modulation during hippocampal development (Review)

“…miR-338-3p exerts a regulatory effect during the proliferation and development of DG neurons. With the maturation of DG neurons, the expression of miR-338-3p increases gradually and eventually reaches a peak in the NeuN + mature neurons (94). The knockdown of miR-338-3p results in decreased dendritic branching, abnormal distribution, and increased length of dendritic spines in the hippocampal neurons, leading to the abnormal proliferation of hippocampal cells and tumorigenesis (94).…”