MicroRNAs (miRNAs) have been demonstrated to participate in many important cellular processes including radiosensitization. VEGF family, an important regulator of angiogenesis, also plays a crucial role in the regulation of cancer cell radiosensitivity. VEGFR2 mediates the major growth and permeability actions of VEGF in a paracrine/autocrine manner. MiR-200c, at the nexus of epithelial-mesenchymal transition (EMT), is predicted to target VEGFR2. The purpose of this study is to test the hypothesis that regulation of VEGFR2 pathway by miR-200c could modulate the radiosensitivity of cancer cells. Bioinformatic analysis, luciferase reporter assays and biochemical assays were carried out to validate VEGFR2 as a direct target of miR-200c. The radiosensitizing effects of miR-200c on A549 cells were determined by clonogenic assays. The downstream regulating mechanism of miR-200c was explored with western blotting assays, FCM, tube formation assays and migration assays. We identified VEGFR2 as a novel target of miR-200c. The ectopic miR-200c increased the radiosensitivity of A549 while miR-200c down-regulation decreased it. Besides, we proved that miR-200c radiosensitized A549 cells by targeting VEGF-VEGFR2 pathway specifically, thus leading to inhibition of its downstream pro-survival signaling transduction and angiogenesis, and serves as a potential target for radiosensitizition research.
Depression is a serious psychiatric disorder that easily causes physical impairment and a high suicide rate.1) Current treatment mainly depends on the traditional therapeutic strategy that affecting serotonin and/or norepinephrine system, but roughly half of affected individuals are inadequately treated by available medications and psychotherapeutic approaches.2,3) Despite tremendous effort, the field has not yet succeeded in developing fundamentally new antidepressants with distinct mechanisms of action. 4)It has been demonstrated that adult neurogenesis in the dentate gyrus (DG) plays a critical role in depression and the therapeutic effects of antidepressants appear to be neurogenesis-dependent. 5) Neurotrophic factors such as brain-derived neurotrophic factor (BDNF), which act as critical regulator of memory and synaptic plasticity, produce the up-regulation of neurogenesis.6) It is well known that BDNF has been shown to enhance neurogenesis. In addition, BDNF initiates TrkB receptor-dependent activation of extracellular signalregulated kinases (ERKs) and exhibits beneficial effect for the treatment of depression. 7) ERKs is the well-studied member of the mitogen-activated protein kinase (MAPK) family and ERK pathway is the major convergence point involved in neurotrophic and other signal pathways that regulates cellular differentiation and neuronal plasticity. [8][9][10] It has been demonstrated that ERK activation can further trigger neurotrophic effects, including neurite growth, neuronal survival and hippocampal neurogenesis.11) Thus, much attention has turned to the role of ERKs in depression. Actually, many classic antidepressant drugs, such as fluoxetine, can reverse the decreased ERK1/2 phosphorylation (p-ERK1/2) induced by depression in the hippocampus.12) By the fact that the therapeutic effects of antidepressants appear to be ERK-related, we postulate that agents that can reverse the decrease in BDNF and p-ERK1/2 caused by depression may produce antidepressant effects.Accumulated evidence has shown that plant-derived flavonoids can produce wide effects including neuroprotection, antioxidant, and regulation of synaptic plasticity and memory enhancement. [13][14][15][16] Recently, it is demonstrated that some flavonoids such as hypericum perforatum and quercetin, display antidepressant effects and attenuate the cognitive deficits caused by major depression. [17][18][19] Baicalein (Bai) is one of the most active flavonoids found in the dry roots of Scutellaria baicalensis Georgi. It is documented that Bai can get across blood-brain barrier (BBB). 13,20) In our previous study, it is shown that Bai protects neurons from free radical-induced damage in vitro and alleviates ischemic brain injury in vivo. 13,21) More importantly, several reports have revealed that Bai stimulates the expression levels of pERK and BDNF in the hippocampus of normal rats. 22) Considering this neurotrophic effect, we postulate that Bai may have an antidepressant-like effect. Thus, the therapeutic role of Bai in animals of depre...
Mounting evidences indicated that long non-coding RNA is dysregulated and involved in the pathology of tumors. However, the role of lncRNAs in colorectal cancer (CRC) progression is not fully determined. Differentially expressed lncRNA profile in CRC was conducted by lncRNA microarray in 15 pairs of CRC tissues and adjacent normal tissues, and validated by real-time PCR analysis in another 106 pairs of tissues. The biological effect of lncRNA ZNFX1-AS1 was evaluated by in vitro and in vivo assays. The regulation between lncRNA ZNFX1-AS1 and miR-144 was evaluated by a series of experiments. We found that lncRNA ZNFX1-AS1 expression was significantly upregulated in CRC tissues and cell lines, and the expression of lncRNA ZNFX1-AS1 was associated with aggressive tumor phenotype and poor prognosis in CRC. Functionally, knockdown of lncRNA ZNFX1-AS1 inhibited cell proliferation, invasion, in vitro and tumorigenesis and metastasis in vivo. Further investigation demonstrated that lncRNA ZNFX1-AS1 functioned as a competing endogenous RNA (ceRNA) for miR-144, thereby leading to the depression of its endogenous target gene Polycomb group protein enhancer of zeste homolog 2 (EZH2). We found that lncRNA ZNFX1-AS1 is significantly upregulated in CRC, and the newly identified lncRNA ZNFX1-AS1-miR-144-EZH2 axis is involved in the regulation of CRC progression, which might be used as potential therapeutic targets for CRC patients.
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