MiR‐1253 exerts tumor‐suppressive effects in medulloblastoma via inhibition of CDK6 and CD276 (B7‐H3)

Abstract

Of the four primary subgroups of medulloblastoma, the most frequent cytogenetic abnormality, i17q, distinguishes Groups 3 and 4 which carry the highest mortality; haploinsufficiency of 17p13.3 is a marker for particularly poor prognosis. At the terminal end of this locus lies miR‐1253, a brain‐enriched microRNA that regulates bone morphogenic proteins during cerebellar development. We hypothesized miR‐1253 confers novel tumor‐suppressive properties in medulloblastoma. Using two different cohorts of medulloblastoma samples, we first studied the expression and methylation profiles of miR‐1253. We then explored the anti‐tumorigenic properties of miR‐1253, in parallel with a biochemical analysis of apoptosis and proliferation, and isolated oncogenic targets using high‐throughput screening. Deregulation of miR‐1253 expression was noted, both in medulloblastoma clinical samples and cell lines, by epigenetic silencing via hypermethylation; specific de‐methylation of miR‐1253 not only resulted in rapid recovery of expression but also a sharp decline in tumor cell proliferation and target gene expression. Expression restoration also led to a reduction in tumor cell virulence, concomitant with activation of apoptotic pathways, cell cycle arrest and reduction of markers of proliferation. We identified two oncogenic targets of miR‐1253, CDK6 and CD276, whose silencing replicated the negative trophic effects of miR‐1253. These data reveal novel tumor‐suppressive properties for miR‐1253, i.e., (i) loss of expression via epigenetic silencing; (ii) negative trophic effects on tumor aggressiveness; and (iii) downregulation of oncogenic targets.

The Regulatory Cross-Talk between microRNAs and Novel Members of the B7 Family in Human Diseases: A Scoping Review

“…The full-text assessment of the remaining 29 records was conducted, and two more records were excluded because they were not human studies [ 26 , 27 ]. Finally, a total of 27 eligible papers remained [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 ]. The characteristics of the included studies are summarized in Table 1 .…”

“…The included articles were published between 2009 and 2020. Twenty studies were performed in China [ 29 , 30 , 31 , 33 , 34 , 38 , 39 , 40 , 42 , 43 , 44 , 45 , 46 , 47 , 49 , 50 , 51 , 52 , 53 , 54 ], five in the United States [ 28 , 32 , 37 , 41 , 48 ], one in Canada [ 36 ], and one in Norway [ 35 ]. Clinical and experimental data from different human specimens, i.e., tissue, blood, serum, bone marrow, nasopharyngeal secretion, skin, and human cell lines, were evaluated.…”

“…Twenty-one papers studied B7-H3 regulatory axes [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 37 , 39 , 41 , 42 , 43 , 44 , 45 , 48 , 50 , 51 , 52 , 53 , 54 ]. Thirty-three miRs involved in the regulatory axes and diseases pathogenesis, including miR-29 (in Burkitt lymphoma, adenocarcinoma, brain tumor, hepatoblastoma, neuroblastoma, sarcomas, Wilms’ tumor, cutaneous melanoma, breast cancer, central nervous system (CNS) neuroblastoma, allergic asthma, diffuse brain glioma, colorectal cancer, medulloblastoma, Mycoplasma pneumoniae pneumonia), miR-539 (in glioma), miR-124 (in osteosarcoma), miR-187 (in psoriasis, colorectal cancer, and clear-cell renal cell carcinoma), miR-380–5p, miR-125b-2, miR-363, miR-940, miR-214, miR-34b, miR-665, miR-593, miR-555, miR-885–3p, miR-567, miR-297, miR-187–3p, miR-124a-1, miR-326, miR-601, miR-506 and miR-708 (in breast cancer), miR-155, miR-143, miR-192, miR-378, miR-1301–3p, miR-335–5p and miR-28–5p (in colorectal cancer), miR-506 (in mantle cell lymphoma), miR-214 (in multiple myeloma), miR-1253 (in medulloblastoma), miR-145 (in lung cancer and colorectal cancer), and miR-199a (in cervical cancer).…”

MicroRNA-1253 Regulation of WASF2 (WAVE2) and its Relevance to Racial Health Disparities

“…Previously, miR-1253 expression levels in plasma have been linked with glaucoma [59] and it is epigenetically silenced via hypermethylation in medulloblastoma tissues. [60]. miR-1253 regulates the expression of the long, non-coding RNA FOXC2-AS1 in prostate cancer cells [61] and WNT5A in lung carcinoma [62].…”

“…It is interesting to speculate how AA women with hypertension may have lost expression of miR-1253 in PBMCs. Considering that the miR-1253 loci is sensitive to hypermethylation in cancer [60], this could be a potential mechanism repressing miR-1253 expression levels in hypertensives. As well, ancestral polymorphisms can function as expression quantitative trait loci (eQTL) in macrophages and immune cells to influence differential gene expression and immune and metabolic function [3,65].…”