MiR-135a functions as a selective killer of malignant glioma.
ABSTRACT Glioma is the most common and fatal primary brain tumor. Thus far, therapeutic strategies to efficiently and specifically antagonize glioma are limited and poorly developed. Here we report that glia-enriched miR-135a, a microRNA that is dramatically downregulated in malignant glioma and correlated with the pathological grading, is capable of inducing mitochondria-dependent apoptosis of malignant glioma by regulating various genes including STAT6, SMAD5 and BMPR2, as well as affecting the signaling pathway downstream. Moreover, this lethal effect is selectively towards malignant glioma cells, but not neurons and glial cells, through a novel mechanism. Our findings suggest an important role of miR-135a in glioma etiology and provide a potential candidate for malignant glioma therapy.
SourceAvailable from: Ju Ming Wang[Show abstract] [Hide abstract]
ABSTRACT: In Alzheimer's disease (AD), large populations of endothelial cells undergo angiogenesis due to brain hypoxia and inflammation. Substantial evidence from epidemiologic, pathologic, and clinical reports suggests that vascular factors are critical for the pathogenesis of AD. However, the precise mechanistic correlation between inflammation and angiogenesis in AD has not been well elucidated. Prostaglandin E2 (PGE2), a key factor of the inflammatory response, has been known to promote angiogenesis. In this study, we demonstrated that PGE2 acts through EP4 receptor and protein kinase A to modulate CCAAT/enhancer-binding protein delta (CEBPD) abundance in astrocytes. Attenuated vessel formation was observed in the brains of AppTg/Cebpd(-/-) mice. We showed that miR135a was responsive to the induction of CEBPD and further negatively regulated thrombospondin 1 (THBS1) transcription by directly targeting its 3'-untranslated region (3'UTR) in astrocytes. Furthermore, conditioned media from astrocytes expressing miR135a promoted Human umbilical vein endothelial cells (HUVECs) tube-like formation, which correlated with the effects of PGE2 on angiogenesis. Our results indicated that CEBPD contributes to the repression of THBS1 transcription by activating the expression of miR135a in astrocytes following PGE2 treatment. We provided new evidence that astrocytic CEBPD increases angiogenesis during AD pathogenesis. This discovery supports the negative influence of CEBPD activation in astrocytes with respect to AD pathogenesis and implies that the CEBPD/miR135a/THBS1 axis could be a therapeutic target of AD. Copyright © 2015 Elsevier Inc. All rights reserved.Neurobiology of Aging 12/2014; 36(3). DOI:10.1016/j.neurobiolaging.2014.11.020 · 4.85 Impact Factor
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ABSTRACT: Though tumor necrosis factor related apoptosis inducing ligand (TRAIL) has been used as a potent anticancer agent, TRAIL resistance is a hot-issue in cancer therapy. We investigated the antitumor mechanism of Tanshinone I to sensitize prostate cancer cells to TRAIL. Comibination of Tanshinone I and TRAIL exerted synergistic cytotoxicity, increased cleaved PARP, sub G1 population, the number of TUNELpositive cells, activated caspase 8, 9 and ROS production in PC-3 and DU145 cells. Of note, combination of Tanshinone I and TRAIL enhanced the protein expression of death receptor 5 (DR5) and attenuated anti-apoptotic proteins. RT-PCR and RT-qPCR analyses confirmed that co-treatment of Tanshinone I and TRAIL up-regulated DR5 and microRNA 135a-3p at mRNA level or activity of DR5 promoter and attenuated phosphorylation of extracellular signal regulated kinases in PC-3. Conversely, the silencing of DR5 blocked the increased cytotoxicity, sub G1 population and PARP cleavages induced by co-treatment of Tanshinone I and TRAIL. Interestingly, miR135a-3p mimic enhanced DR5 at mRNA, increased PARP cleavage, Bax and the number of TUNEL positive cells in Tanshinone I and TRAIL cotreated PC-3. Overall, our findings suggest that Tanshinone I enhances TRAIL mediated apoptosis via upregulation of miR135a-3p mediated DR5 in prostate cancer cells as a potent TRAIL sensitizer.Oncotarget 06/2014; 5(14). · 6.63 Impact Factor
Article: MicroRNAs and cancer[Show abstract] [Hide abstract]
ABSTRACT: The review is devoted to analyzing the data on the role of microRNAs in human tumor progression. The following topics are thoroughly discussed in the review: (1) general characteristics of microRNAs; (2) their expression pattern in human tumors and specificity of this expression; (3) the possible role of microRNAs as oncogenes and tumor growth suppressors; and (4) their participation in the processes responsible for the transformed phenotype of tumor cells; and (5) the role of microRNAs in early diagnostics of the disease and its prognosis.Molecular Biology 03/2014; 48(2):197-206. DOI:10.1134/S0026893314020083 · 0.74 Impact Factor