MicroRNA128-1 (miR128-1), as a brain-specific miRNA, is downregulated in glioblastoma multiforme (GBM) and closely associated with the progression of GBM. However, the underlying molecular mechanism of the downregulation and its role in the regulation of tumorigenesis and anticancer drug resistance in GBM remains largely unknown. In the current study,we found that miR128-1 was downregulated in GBM and glioma stem-like cells (GSCs). Intriguingly, treatment with the DNA methylation inhibitors 5-Aza-CdR (Aza) and 4-phenylbutyric acid (PBA) resulted in miR128-1 upregulation in both GBM cells and GSCs. Either forced expression of miR128-1 or Aza/PBA treatment inhibited tumor cell proliferation, migration and invasion in vitro. Moreover, overexpression of miR128-1 inhibited the growth of transplant tumor in vivo. BMI1 and E2F3 were found to be direct targets of miR128-1 and downregulated by miR128-1 in vitro and in vivo. Our results revealed a mechanism of methylation that controls miR128-1 expression in GBM cells and GSCs and indicate miR128-1 could function as a tumor suppressor in GBM by negatively regulating tumor cell proliferation, invasion and self-renewal through direct targeting BMI1 and E2F3. Our findings suggest that DNA methylation inhibitors are potential agents for GBM treatment by upregulating miR-128-1.
Abstract. In the present study, we investigated the prognostic roles of the O 6 -methylguanine-DNA methyltransferase (MGMT) gene methylation status, the protein profiles of MGMT, and the glioma stem cell (GSC) marker CD133 in malignant glioma resistance to radiotherapy. The proliferation of glioma cells was assessed using a clonogenic survival assay and flow cytometry. CD133 expression was assessed in SHG-44-GSCs using RT-PCR and flow cytometry. MGMT exhibited resistance to radiation in the SHG-44-GSCs using siRNA transfection. The effects of the siRNA on mRNA and protein expression of MGMT in SHG-44-GSCs were detected using semi-quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting. MGMT methylation status, MGMT and CD133 expression profiles were assessed in 59 malignant glioma patients using methylation-specific polymerase chain reaction (MSP), and immunohistochemistry. In vitro, SHG-44-GSCs exhibited a characteristic resistance to radiation that was not observed in SHG-44 cells. This resistance was attributed to the unmethylated status of the MGMT promoter and to high expression levels of MGMT mRNA in the glioma cells. In these patients, the CD133 marker, but not MGMT promoter methylation or MGMT protein level, was associated with resistance to radiotherapy (n=59; hazard ratio=2.838; 95% CI, 1.725-7.597; p=0.001). The median progression-free survival (PFS) among patients with the CD133 marker was 14 months, whereas it was 35 months in patients without CD133 (p= 0.001). Notably, co-expression of the methylated MGMT promoter and the CD133 marker was associated with the poorest outcome in patients with gliomas treated by radiotherapy; in these patients, PFS was 7 months. These results suggest that assessment of GSC MGMT and CD133 levels will guide future clinical targeted therapies and stratify glioma patient treatment regimens. High expression levels of the CD133 protein could be used as a predictor for poor survival in patients treated with radiotherapy.
Curcumin (CUR), a natural polyphenolic compound, is considered as one of the most potential candidates against Alzheimer disease (AD) by targeting multiple pathologies such as amyloid-beta, tau phosphorylation, and oxidative stress. Poor physicochemical profile and oral bioavailability (BA) are the major contributors to its failure in clinical trials. Lack of success in numerous drug clinical trials for the treatment of AD urges the need of repositioning of CUR. To overcome its limitation and enhance oral BA, Novel CUR Formulation (NCF) was developed using self-nanomicellizing solid dispersion strategy which displayed 117-fold enhancement in oral BA of CUR. NCF was tested using SH-SY5Y695 APP human neuroblastoma cell line against the cytotoxicity induced by copper metal ion, HO, and Aβ42 oligomer and compared with CUR control. The safety and efficacy of NCF on mice AD-like behavioral deficits (open field, novel objective recognition, Y-maze, and Morris water maze tests) were assessed in transgenic AD (APPSwe/PS1deE9) mice model. In SH-SY5Y695 APP human neuroblastoma cell line, NCF showed better safety and efficacy against the cytotoxicity due to the significantly enhancement of cellular uptake. It not only prevents the deterioration of cognitive functions of the aged APPSwe/PS1deE9 mice during aging but also reverses the cognitive functions to their much younger age which is also better than the currently available approved options. Moreover, NCF was proved as well tolerated with no appearance of any significant toxicity via oral administration. The results of the study demonstrated the potential of NCF to improve the efficacy of CUR without compromising its safety profile, and pave the way for clinical development for AD.
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