We here propose a novel concept of glial-mesenchymal transition after irradiation in which the sustained Snail expression plays an essential role.

Carbamylated erythropoietin (CEPO), a well characterized erythropoietin (EPO) derivative, does not bind to the classical EPO receptor and does not stimulate erythropoiesis. Using neural progenitor cells derived from the subventricular zone of the adult mouse, we investigated the effect of CEPO on neurogenesis and the associated signaling pathways in vitro. We found that CEPO significantly increased neural progenitor cell proliferation and promoted neural progenitor cell differentiation into neurons, which was associated with up-regulation of Sonic hedgehog (Shh), its receptor ptc, and mammalian achaete-scute homolog 1 (Mash1), a pro-neuron basic helix-loop-helix protein transcription factor. Blockage of the Shh signaling pathway with a pharmacological inhibitor, cyclopamine, abolished the CEPOinduced neurogenesis. Attenuation of endogenous Mash1 expression by short-interfering RNA blocked CEPO-promoted neuronal differentiation. In addition, recombinant mouse Shh up-regulated Mash1 expression in neural progenitor cells. These results demonstrate that the Shh signaling pathway mediates CEPO-enhanced neurogenesis and Mash1 is a downstream target of the Shh signaling pathway that regulates CEPO-enhanced neuronal differentiation.

SUMMARYWe have uncovered a role for Jumonji inhibitors in overcoming radioresistance through KDM5B inhibition. Pharmacological blockade of Jumonji demethy-lases with JIB-04 leads to specific accumulation of H3K4me3 at sites marked by γH2AX and impaired recruitment of DNA repair factors, preventing resolution of damage and resulting in robust sensitization to radiation therapy. In DNA-repair-proficient cancer cells, knockdown of the H3K4me3 demethylase KDM5B, but not other Jumonji enzymes, mimics pharmacological inhibition, and KDM5B overexpression rescues this phenotype and increases radioresistance. The H3K4me3 demethylase inhibitor PBIT also sensitizes cancer cells to radiation, while an H3K27me3 demethylase inhibitor does not. In vivo co-administration of radiation with JIB-04 significantly prolongs the survival of mice with tumors even long after cessation of treatment. In human patients, lung squamous cell carcinomas highly ex-pressing KDM5B respond poorly to radiation. Thus, we propose the use of Jumonji KDM inhibitors as potent radiosensitizers.

BackgroundResistance to humanized monoclonal erbB2/HER2 antibody, trastuzumab (Herceptin), has become a pivotal obstacle for targeted therapy of HER2-positive breast cancers. The activation of alternative growth factor receptors, in particular, the insulin-like growth factor 1 receptor (IGF1R), represents a common feature of trastuzumab-refractory cells; however, the underlying mechanism remains elusive.MethodsTrastuzumab-resistant breast cancer SKBr-3 cells were generated by long-term in vitro culture of SKBr-3 cells in the presence of trastuzumab. Among the differentially expressed microRNAs (miRNAs) screened by microarray analysis, candidate miRNA(s) predicted to target IGF1R was studied for its role in conferring trastuzumab resistance. The mechanism underlying decreased expression of IGF1R-targeted miRNA in refractory cells was also addressed.ResultsmiR-375, which was downregulated and predicted to target IGF1R in trastuzumab-resistant HER2-positive breast cancer cells, could indeed inhibit the cellular luciferase activity in a reporter construct containing the 3′-UTR of IGF1R. Overexpression of miR-375 restored the sensitivity of cells to trastuzumab, while inhibition of miR-375 conferred trastuzumab resistance on HER2-positive breast cancer cells. Blockade of DNA methylation and histone deacetylation restored the expression of miR-375 in trastuzumab-resistant cells. A reverse correlation between the levels of miR-375 and IGF1R was validated in clinical breast cancers.ConclusionsEpigenetic silencing of miR-375 causes the upregulation of IGF1R, which at least partially underlies trastuzumab resistance of breast cancer cells. Our study has implications for miR-375 as a potential target in combination with trastuzumab for treating HER2-positive breast cancers.

BackgroundThe RNA-seq FPKM data of 331 colorectal adenocarcinoma samples in The Cancer Genome Atlas database with matching clinical data were analyzed in order to reveal the prognostic value of m6A RNA methylation regulators in colon adenocarcinoma.Material/MethodsThe expression of 13 m6A RNA methylated regulators in samples were analyzed. The samples were classified into Cluster I and II by consistent clustering. The gene distribution was analyzed by principal component analysis. Further functional analysis of selected m6A RNA genes was performed and potential risk characteristics was developed using Lasso Cox regression algorithm. Using minimum criteria, the risk coefficients of YTHDF1 and HNRNPC were detected for Cluster II. Patients were divided into high-risk and low-risk subgroups based on the risk characteristics. The clinical data were analyzed by univariate and multivariate Cox regression analysis.ResultsExpression of the detected m6A RNA methylated regulators except YTHDC2 in tumors were significantly different from their adjacent mucosa. Among them, only ALKBH5 and METTL4 were downregulated in tumors. The gene distribution between the 2 subgroups were different. The expression of m6A RNA methylation regulators including YTHDF1, HNRNPC, YTHDC2, YTHDC1, ZC3H13, and RBM15 were different between the 2 groups (P<0.05). The prognostic characteristics between the high-risk and low-risk groups were significant different (P<0.05), which had a good predictive significance of prognosis area under the curve (AUC)=0.62). Risk scores were less than 0.05, suggesting risk score was an independent prognostic factor for colon adenocarcinoma.Conclusionsm6A RNA methylation regulators YTHDF1 and HNRNPC can be used as prognostic factors of colon cancer, which has potential value for colon cancer treatment.

Introduction: Myocardial infarction (MI) is the leading cause of congestive heart failure and mortality. Hypoxia is an important trigger in the cardiac remodeling of the myocardium in the development and progression of cardiac diseases. Objective: Thus, we aimed to investigate the effect of hypoxia-induced exosomes on cardiac fibroblasts (CFs) and its related mechanisms. Materials and Methods: In this study, we successfully isolated and identified the exosomes from hypoxic cardiomyocytes (CMs). Exosomes derived from hypoxic CMs promoted apoptosis and inhibited proliferation, migration, and invasion in CFs. RNA-Seq assay suggested that long noncoding RNA AK139128 (lncRNA AK139128) was found to overexpress in both hypoxic CMs and CMs-secreting exosomes. After coculturing with CFs, hypoxic exosomes increased the expression of AK139128 in recipient CFs. Moreover, exosomal AK139128 derived from hypoxic CMs stimulated CFs apoptosis and inhibited proliferation, migration, and invasion. Furthermore, the effect of exosomal AK139128 derived from hypoxic CMs could also exacerbate MI in the rat model. Conclusion: Taken together, hypoxia upregulated the level of AK139128 in CMs and exosomes and exosomal AK139128 derived from hypoxic CMs modulated cellular activities of CFs in vitro and in vivo. This study provides a new understanding of the mechanism underlying hypoxia-related cardiac diseases and insight into developing new therapeutic strategies.

MiR-211-5p affected the viability, proliferation and invasion of TC by negatively regulating SOX11 expression.

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