BackgroundWith concerns about the disastrous health and economic consequences caused by the influenza pandemic, comprehensively understanding the global host response to influenza virus infection is urgent. The role of microRNA (miRNA) has recently been highlighted in pathogen-host interactions. However, the precise role of miRNAs in the pathogenesis of influenza virus infection in humans, especially in critically ill patients is still unclear.MethodsWe identified cellular miRNAs involved in the host response to influenza virus infection by performing comprehensive miRNA profiling in peripheral blood mononuclear cells (PBMCs) from critically ill patients with swine-origin influenza pandemic H1N1 (2009) virus infection via miRNA microarray and quantitative reverse-transcription polymerase chain reaction (qRT-PCR) assays. Receiver operator characteristic (ROC) curve analysis was conducted and area under the ROC curve (AUC) was calculated to evaluate the diagnostic accuracy of severe H1N1 influenza virus infection. Furthermore, an integrative network of miRNA-mediated host-influenza virus protein interactions was constructed by integrating the predicted and validated miRNA-gene interaction data with influenza virus and host-protein-protein interaction information using Cytoscape software. Moreover, several hub genes in the network were selected and validated by qRT-PCR.ResultsForty-one significantly differentially expressed miRNAs were found by miRNA microarray; nine were selected and validated by qRT-PCR. QRT-PCR assay and ROC curve analyses revealed that miR-31, miR-29a and miR-148a all had significant potential diagnostic value for critically ill patients infected with H1N1 influenza virus, which yielded AUC of 0.9510, 0.8951 and 0.8811, respectively. We subsequently constructed an integrative network of miRNA-mediated host-influenza virus protein interactions, wherein we found that miRNAs are involved in regulating important pathways, such as mitogen-activated protein kinase signaling pathway, epidermal growth factor receptor signaling pathway, and Toll-like receptor signaling pathway, during influenza virus infection. Some of differentially expressed miRNAs via in silico analysis targeted mRNAs of several key genes in these pathways. The mRNA expression level of tumor protein T53 and transforming growth factor beta receptor 1 were found significantly reduced in critically ill patients, whereas the expression of Janus kinase 2, caspase 3 apoptosis-related cysteine peptidase, interleukin 10, and myxovirus resistance 1 were extremely increased in critically ill patients.ConclusionsOur data suggest that the dysregulation of miRNAs in the PBMCs of H1N1 critically ill patients can regulate a number of key genes in the major signaling pathways associated with influenza virus infection. These differentially expressed miRNAs could be potential therapeutic targets or biomarkers for severe influenza virus infection.

Fibrodysplasia ossificans progressiva (FOP) is a rare congenital disorder of skeletal malformations and progressive extraskeletal ossification. There is still no effective treatment for FOP. All FOP individuals harbor conserved point mutations in ACVR1 gene that are thought to cause ACVR1 constitutive activation and activate BMP signal pathway. The constitutively active ACVR1 is also found to be able to cause endothelial-to-mesenchymal transition (EndMT) in endothelial cells, which may cause the formation of FOP lesions. MicroRNAs (miRNAs) play an essential role in regulating cell differentiation. Here, we verified that miR-148a directly targeted the 3′ UTR of ACVR1 mRNA by reporter gene assays and mutational analysis at the miRNA binding sites, and inhibited ACVR1 both at the protein level and mRNA level. Further, we verified that miR-148a could inhibit the mRNA expression of the Inhibitor of DNA binding (Id) gene family thereby suppressing the BMP signaling pathway. This study suggests miR-148a is an important mediator of ACVR1, thus offering a new potential target for the development of therapeutic agents against FOP.

FOSB protein is encoded by the FOSB gene in humans, which shares structural similarities with the prototype of the Fos family. FOSB plays a role by AP-1 complex which is composed of heterodimers of Jun and Fos members. Our experiment aimed to evaluate the effect of FOSB in gastric cancer (GC) patients and then probe its significance in prognosis. We detected the expression of FOSB in GC and adjacent non-cancerous tissues by western blot analysis and real-time quantitative PCR (qRT-PCR). Moreover, we analyzed FOSB expression in patients who underwent resection procedures using immunohistochemistry. The relationship between the expression of FOSB, the clinicopathological characteristics and the patients survival were also investigated. Furthermore, in vitro, we evaluated the effects of FOSB gene on gastric cancer cell viability, proliferation and migration by MTT, clone formation and transwell assays. Finally, the Kaplan-Meier method and log-rank test were used to compare the overall survival between high FOSB expression group and low FOSB expression group. Immunohistochemical staining data showed that FOSB expression was significantly decreased in gastric cancer cases. In addition, we confirmed FOSB downregulation in both mRNA and protein levels in GC tissues compared with matched adjacent non-cancerous tissues. Downregulated expression of FOSB was correlated with poor differentiation, lymph node metastasis and advanced TNM stage. Moreover, we found that low FOSB expression exhibited a significant correlation with poor prognosis for GC patients by Kaplan-Meier survival analysis. Overexpression of FOSB significantly suppressed cell proliferation, clone formation and migration in GC cell lines. In contrast, silencing of FOSB expression in GC cells promoted proliferation, clone formation and migration. Our results showed that FOSB plays a crucial role in the suppression of GC, and that it may be a useful biomarker in diagnosis and prognosis for GC patients.