Abstract
Gene associated with retinoid-interferon-induced mortality-19 (GRIM-19) has been recognized as a tumor suppressor protein, which regulates cell growth, apoptosis, and migration by signal transducer and activator of transcription 3 (STAT3) signaling pathway and non-STAT3 pathway in glioma cells. Here, we investigated the molecular mechanisms that regulated GRIM-19 expression in glioma cells. By the TargetScan algorithm, four miRNAs, hsa-miR-17-3p, hsa-miR-423-5p, hsa-miR-3184-5p, and hsa-miR-6743-5p, were identified with the potential to bind with 3′-UTR of GRIM-19. Further miRNA inhibitor transfection and luciferase assays revealed that miR-6743-5p was able to directly target the 3′-UTR of GRIM-19. Additionally, miR-6743-5p expression was inversely related with GRIM-19 expression in glioma specimens and cell lines. Moreover, the inhibition of miR-6743-5p caused a significant inhibition of cell proliferation and a marked promotion of cell apoptosis in glioma cells, and this phenotype was rescued by GRIM-19 knockdown. Finally, the inhibition of miR-6743-5p expression suppressed the phosphorylation of STAT3, and the mRNA expression of CyclinD1 and Bcl-2, two target genes of STAT3, while miR-6743-5p mimic had the inversed effects. Treatment with STAT3 inhibitor AG490 partially rescued the proliferation-promoting and anti-apoptosis effects of miR-6743-5p overexpression or GRIM-19 knockdown. Collectively, miR-6743-5p may act as an oncomiRNA in glioma by targetting GRIM-19 and STAT3.
Highlights
Glioma is the most frequent type of primary malignant brain tumor, arising from the brain or spinal cord tissues [1]
We found that hsa-miR-17-3p, hsa-miR-423-5p, hsa-miR-3184-5p, and hsa-miR-6743-5p had the potential to bind with Gene associated with retinoid-interferon-induced mortality-19 (GRIM-19)
To clarify whether these miRNAs could regulate GRIM-19 mRNA expression in glioma, we knocked down the expression of these miRNAs in a glioma cell line, U251, and assessed GRIM-19 expression levels
Summary
Glioma is the most frequent type of primary malignant brain tumor, arising from the brain or spinal cord tissues [1]. Glioblastoma multiforme (GBM, grade IV) is the most malignant and frequent type, accounting for approximately 70% of all diagnosed gliomas [3]. The prognosis of glioma remains poor because of the characteristic malignant proliferation and diffuse invasion [4]. Subsequent studies showed that GRIM-19 plays essential role in normal embryonic development, cell apoptosis, and cell growth [6-10]. Loss of expression of GRIM-19 has been reported in renal cell carcinoma [12], cervical cancer [13], colon cancer [14], and glioma [15].
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