Aberrant expression of protein arginine methyltransferases (PRMTs) has been implicated in a number of cancers, making PRMTs potential therapeutic targets. But it remains not well understood how PRMTs impact specific oncogenic pathways. We previously identified PRMTs as important regulators of cell growth in neuroblastoma, a deadly childhood tumor of the sympathetic nervous system. Here, we demonstrate a critical role for PRMT1 in neuroblastoma cell survival. PRMT1 depletion decreased the ability of murine neuroblastoma sphere cells to grow and form spheres, and suppressed proliferation and induced apoptosis of human neuroblastoma cells. Mechanistic studies reveal the prosurvival factor, activating transcription factor 5 (ATF5) as a downstream effector of PRMT1-mediated survival signaling. Furthermore, a diamidine class of PRMT1 inhibitors exhibited anti-neuroblastoma efficacy both in vitro and in vivo. Importantly, overexpression of ATF5 rescued cell apoptosis triggered by PRMT1 inhibition genetically or pharmacologically. Taken together, our findings shed new insights into PRMT1 signaling pathway, and provide evidence for PRMT1 as an actionable therapeutic target in neuroblastoma.
Background/Aims: Recently, the insulin-like growth factor mRNA-binding protein 3 (IMP3) has been reported to be involved in tumorigenesis. We aimed to study the expression and role of IMP3 in human glioblastoma. Methods: We analyzed the expression of IMP3 in 70 cases of glioma tissues, normal brain tissues and 5 kinds of cell lines using western blot. Immunohistochemistry (IHC) was used to evaluate the expression and distribution of IMP3 in glioma tissues. Colony formation, wound healing, migration and invasion assays and tumorigenesis in nude mice were used to explore the function of IMP3 in vitro and in vivo. The epithelial-mesenchymal transition (EMT)-related biomarkers were detected by western blot. Results: We found that the expression level of IMP3 was obviously higher in glioma tissues than that in normal brain tissues, and associated with glioma grade. In-vitro assays revealed that IMP3 overexpression significantly induced cell proliferation, migration, and invasion. Mechanically, IMP3 over-expression downregulated the expression of E-cadherin, but upregulated the expressions of N-cadherin, vimentin, snail, slug and MMP9. However, the inhibition of IMP3 impaired these oncogenic effects. In vivo assay also demonstrated that silencing of IMP3 inhibited tumor growth and improved survival of tumor-bearing xenograft nude mice. Conclusion: IMP3 can promote cell proliferation, migration and invasion by inducing EMT in glioblastoma. Thus, targeting IMP3 pathway may be a novel way to treat patients with glioblastoma.
To date, miR-148-3p and DNMT1‐recombinant human runt-related transcription factor 3 (RUNX3) axis have been linked to cell proliferation, migration, and invasion; however, their roles and relationships in human glioblastoma multiforme (GBM) are still not clear. Here we found that the expression of miR-148-3p in glioma tissues was decreased compared with adjacent nontumor tissues and correlated with WHO grade, tumor size, and prognosis as well as DNMT1 and RUNX3 expressions. Compared with NHA cells, the expression of miR-148-3p in U87 and U251 cells was also downregulated and accompanied with upregulation of DNMT1 and hypermethylation level of RUNX3 promoter region. miR-148-3p overexpression induced apoptosis and cell cycle arrest of U87 and U251 cells, and affected cell migration and invasion. miR-148-3p mimics effectively suppressed the expression of DNMT1 and methylation of RUNX3 promoter, finally upregulating RUNX3 expression. Mechanistically, the 3′-untranslated region (3′-UTR) of DNMT1 was a direct target of miR-148-3p. Overexpression of miR-148-3p or inhibition of DNMT1 induced the expression of E-cadherin and reduced the expressions of N-cadherin, vimentin, MMP-2, and MMP-9. In conclusion, miR-148-3p directly repressed the expression of DNMT1 and inhibited proliferation, migration, and invasion by regulating DNMT1‐RUNX3 axis and the epithelial‐mesenchymal transition in GBM. Our findings provide a new foundation for treatment of patients with GBM.
These findings indicated that high glucose induced cell apoptosis by causing the loss of MMP, the overproduction of ROS and mtDNA damage. Targeting DNA repair enzymes hOGG1 in mitochondria partly mitigated the high glucose-induced consequences, which shed new light for DR therapy.
PURPOSE. Retinoblastoma is a malignant tumor of the developing retina that mostly occurs in children. Our study aimed to investigate the effect of tripartite motif-containing protein 59 (TRIM59) on retinoblastoma growth and the underlying mechanisms. METHODS. We performed bioinformatic analysis of three datasets (GSE24673, GSE97508, and GSE110811) from the Gene Expression Omnibus database. Quantitative reversetranscription PCR and immunoblotting of three retinoblastoma cell lines were conducted to verify TRIM59 as a differentially expressed gene. Specific siRNAs were used to inhibit TRIM59 expression in the HXO-Rb44 cell line. A lentiviral vector was transfected into the Y79 cell line to overexpress TRIM59. The effects of TRIM59 on retinoblastoma cell proliferation, cell cycling, and apoptosis were explored in vitro using the abovementioned cell lines. The effect of TRIM59 expression on retinoblastoma cell proliferation was evaluated in a mouse xenograft tumor model. RESULTS. TRIM59 expression in three retinoblastoma cell lines was remarkably elevated compared with normal control. Knocking down TRIM59 expression remarkably suppressed cell proliferation and growth and promoted cell apoptosis in HXO-Rb44 cells, whereas TRIM59 overexpression promoted tumor progression in Y79 cells. Silencing TRIM59 also markedly inhibited in vivo tumor growth in the xenograft model. Mechanistic studies revealed that TRIM59 upregulated phosphorylated p38, p-JNK1/2, p-ERK1/2, and p-c-JUN expression in retinoblastoma cells. Notably, the p38 inhibitor SB203580 attenuated the effects of TRIM59 on cell proliferation, apoptosis, and the G 1 /S phase transition. CONCLUSIONS. TRIM59 plays an oncogenic role in retinoblastoma and exerts its tumorpromotive function by activating the p38-mitogen-activated protein kinase pathway.
Objective. To explore the role of LncHOTAIR in apoptosis and autophagy in lymphoma. Methods. The interaction between LncHOTAIR and miR-6511b-5p, as well as between miR-6511b-5p and ATG7, was verified by a dual luciferase assay. LncHOTAIR overexpression lentivirus was transducted and siATG7s were transfected into Raji and BJAB lymphoma cells, and the efficiency was verified by qPCR. Lymphocyte proliferation was detected by the cell counting kit-8 (CCK8) test, and autophagy was detected by transmission electron microscopy. The protein expressions of ULK1, Beclin1, ATG7, LC3, Bax, cleaved-caspase 3, and Bcl-2 were detected using Western blots. Results. There was a targeting relationship between LncHOTAIR and miR-6511b-5p and between miR-6511b-5p and ATG7. LncHOTAIR overexpression promoted the proliferation and autophagy of Raji and BJAB cells, significantly upregulated ATG7, Beclin1, ULK1, Bcl-2, and LC3-II/LC3-I levels, and downregulated Bax and cleaved-caspase3 levels. siATG7 significantly inhibited the proliferation and autophagy of Raji and BJAB cells and promoted their apoptosis. Conclusion. LncHOTAIR/hsa-miR-6511b-5p/ATG7 could regulate the proliferation, apoptosis, and autophagy of Raji and BJAB lymphoma cells.
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