Project description:The colonization of distant organs by metastatic carcinoma cells underpins most human cancer-related deaths, including those from head and neck squamous cell carcinoma (HNSCC). We report that miR-203, a miRNA that promotes keratinocyte differentiation, is necessary and sufficient to inhibit multiple post-extravasation events during HNSCC lung metastasis, including initial survival/engraftment, escape from metastatic dormancy, and overt colonization in vivo. Restoration of miR-203 expression in established lung metastases reduces overall metastatic burden. Instead of promoting differentiation, miR-203 controls lung metastasis through direct targeting of genes involved in cytoskeletal dynamics (LASP1), ECM remodeling (SPARC), and cell metabolism (NUAK1). Expression of miR-203 and its downstream targets correlates with HNSCC overall survival outcomes, suggesting the therapeutic potential of targeting this signaling axis. Total RNA (including small RNAs) was isolated from cultured cells stably infected in biological duplicate with either a scrambled control hairpin or miR-203. Samples were harvested in technical duplicate.
Project description:Endotoxin/LPS tolerance is a tightly regulated phenomenon, which, during infection, prevents systemic hyper-inflammation. Here we report for the first time that morphine reversal of endotoxin tolerance resulting in persistent inflammation thus contributing to septicemia and septic shock. We further report that this regulation is mediated by LPS-induced down-regulation of microRNAs 146a and 155. However, only over-expression of miR-146a, but not miR-155 abrogates morphine mediated hyper-inflammation, while antagonizing miR-146a (but not miR-155) augments morphine mediated hyper-inflammation. Hence, miR-146a could be the potential therapeutic target for morphine-mediated abrogation of endotoxin tolerance. All treatments done in vivo. Morphine implanted subcuteniously, LPS administered as intraperitoneal injection.
Project description:MircoRNAs are small RNAs which regulate a pleiotropy of cellular processes and are also involved in tumorigenesis, cancer progression and therapy resistance. We investigated the influence of miRNA-200c on chemoresistance of tumor cells. A proteomic approach identified glutathione S-transferases to be differentially expressed when miR-200c was knocked out and cells were treated with the chemotherapeutic drug doxorubicin.
Project description:In this study, we defined a novel miRNA, hsa-miR-12462, through small RNA sequencing of the bone marrow (BM) cells from 128 newly diagnosed subjects with AML
Project description:Endotoxin/LPS tolerance is a tightly regulated phenomenon, which, during infection, prevents systemic hyper-inflammation. Here we report for the first time that morphine reversal of endotoxin tolerance resulting in persistent inflammation thus contributing to septicemia and septic shock. We further report that this regulation is mediated by LPS-induced down-regulation of microRNAs 146a and 155. However, only over-expression of miR-146a, but not miR-155 abrogates morphine mediated hyper-inflammation, while antagonizing miR-146a (but not miR-155) augments morphine mediated hyper-inflammation. Hence, miR-146a could be the potential therapeutic target for morphine-mediated abrogation of endotoxin tolerance.
Project description:Extracellular pH (pHe) is lower in many tumors than in the corresponding normal tissue. Acidic tumor microenvironment has been shown to facilitate epithelial mesenchymal transition (EMT) and tumor metastasis, while the mechanisms underlying tumor acidic microenvironment-induced tumor cell metastasis remain undefined. Here, we aimed to investigate the tumor metastasis and the EMT by acidic microenvironment and to explore their mechanisms and clinical significance in lung cancer. Results showed that acidic pHe remarkably enhanced invasion ability of lung cells accompanying with increased mesenchymal and decreased epithelial markers. Moreover, acidic pHe triggered the inhibition of microRNA-7 (miR-7) expression and activation of TGF-β2/SMAD signaling. Mechanistic studies showed that TGF-β2 is a direct potential target gene of miR-7, and acidity-induced metastasis could be abolished by treatment with a TGFβRI inhibitor, anti-TGF-β2 antibody and miR-7 mimic, respectively. The clinical samples further revealed that miR-7 was decreased in lung tissues and antagonistically correlated with TGF-β2 expression, associating with overall survival and metastasis. In conclusion, our study indicated that acidic pHe showed enhanced invasive potential, and enhanced potential to develop experimental metastases by a novel mechanism involving tumor acidic microenvironment-induced regulation of miR-7/TGF-β2/SMAD axis. Our findings suggest that the possibility that pHe of the primary tumor may be an important prognostic parameter for lung cancer patients merit clinical investigation. Moreover, miR-7 may serve as prognostic molecular marker and a novel therapeutic target for lung cancer.
Project description:MicroRNAs (miRNAs) are small non-coding RNAs that modulate gene expression by negatively regulating translation of target genes. miRNAs involvement in vascular smooth muscle cell (VSMC) biology has been deeply investigated, nevertheless the role of miR-128 in such context has not been yet explored. We aimed to evaluate whether this miR-128 might modulate VSMC phenotype similarly to what was previously observed for other type of contractile cells, such as cardiomyocytes (CM) and skeletal muscle cells. To this end, we compared the expression profiles of miR-128 overexpression in Primary mouse VSMCs and control groups (treated with scrambled miRNA). The expression profiles were defined by Illumina arrays.
Project description:MiR-200c is a well-studied miRNA that is involved in stemness, the epithelial-mesenchymal transition, chemoresistance, radioresistance, and invasion/metastasis of various cancer cells. To obtain an overview of the lncRNA/mRNA regulated by miR-200c signaling in breast-cancer cell lines, we performed global lncRNA/mRNA-expression profiling on MDA-MB-231-pGIPZ and MDA-MB-231-miR-200c cells.
