No abstract

MicroRNAs (miRNAs), which are endogenous about 20–23 nucleotides non-coding RNAs, have been acted as post-transcriptional regulators of gene expression. Current studies demonstrated that miRNAs are promising candidates for tumor gene therapy because of their important biological functions in tumor cell proliferation, metastasis, apoptosis, and drug resistance. As an important delivery system, nanostructured lipid carriers (NLCs) have great potential in tumor gene therapy, particularly for miRNA delivery, due to low toxicity, low immunogenicity, long metabolic cycles, and easy modification. This article reviews recent research progress on NLCs for miRNA delivery in tumor gene therapy and prospective applications.

BaCKgRoUND aND aIMS:Increasing evidence in recent years has suggested that microRNA-7 (miR-7) is an important gene implicated in the development of various diseases including HCC. However, the role of miR-7 in autoimmune hepatitis (AIH) is unknown. appRoaCH aND ReSUltS: Herein, we showed that miR-7 deficiency led to exacerbated pathology in Concanavalin-A-induced murine acute autoimmune liver injury (ALI) model, accompanied by hyperactivation state of CD4 + T cells. Depletion of CD4 + T cells reduced the effect of miR-7 deficiency on the pathology of ALI. Interestingly, miR-7 deficiency elevated CD4 + T-cell activation, proliferation, and cytokine production in vitro. Adoptive cell transfer experiments showed that miR-7 def CD4 + T cells could exacerbate the pathology of ALI. Further analysis showed that miR-7 expression was up-regulated in activated CD4 + T cells. Importantly, the transcription of pre-miR-7b, a major resource of mature miR-7 in CD4 + T cells, was dominantly dependent on transcription factor CCAAT enhancer binding protein alpha (C/ EBPα), which binds to the core promoter region of the miR-7b gene. Global gene analysis showed that mitogen-activated protein kinase 4 (MAPK4) is a target of miR-7 in CD4 + T cells. Finally, the loss of MAPK4 could ameliorate the activation state of CD4 + T cells with or without miR-7 deficiency.Our studies document the important role of miR-7 in the setting of AIH induced by Concanavalin-A. Specifically, we provide evidence that the C/EBPα/miR-7 axis negatively controls CD4 + T-cell activation and function through MAPK4, thereby orchestrating experimental AIH in mice.CoNClUSIoNS: This study expands on the important role of miR-7 in liver-related diseases and reveals the value of the C/EBPα/miR-7 axis in CD4 + T-cell biological function for the pathogenesis of immune-mediated liver diseases.

Recent evidence has shown that microRNA-126 (miR-126) has been involved in the development and function of immune cells, which contributed to the pathogenesis of related clinical diseases. However, the potential role of miR-126 in the development and function of CD4 T cells remains largely unknown. Here we first found that the activation and proliferation, as well as the expression of interferon (IFN)-γ, of CD4 T cells from miR-126 knock-down (KD) mice using the miRNA-sponge technique were enhanced significantly in vitro, compared with those in CD4 T cells from wild-type (WT) mice. To monitor further the possible effect of miR-126 deficiency on the function of CD4 T cells in vivo, we used dextran sulphate sodium (DSS)-induced murine model of acute autoimmune colitis and found that miR-126 deficiency could elevate the pathology of colitis. Importantly, the proportion of CD4 T cells in splenocytes increased significantly in miR-126KD mice. Moreover, the expression levels of CD69 and CD44 on CD4 T cells increased significantly and the expression level of CD62L decreased significantly. Of note, adoptive cell transfer assay showed that the pathology of colitis was more serious in carboxyfluorescein succinimidyl ester (CFSE)-labelled miR-126KD CD4 T cell-transferred group, compared with that in the CFSE-labelled WT CD4 T cells transferred group. Consistently, the expression levels of CD69 and CD44 on CFSE cells increased significantly. Furthermore, both the proliferation and IFN-γ secretion of CFSE cells also increased significantly in the CFSE-labelled miR-126KD CD4 T cell-transferred group. Mechanistic evidence showed that the expression of insulin receptor substrate 1 (IRS-1), as a functional target of miR-126, was elevated in CD4 T cells from miR-126KD mice, accompanied by altered transduction of the extracellular regulated kinase, protein B (AKT) and nuclear factor kappa B (NF-κB) pathway. Our data revealed a novel role in which miR-126 was an intrinsic regulator in the function of CD4 T cells, which provided preliminary basis for exploring further the role of miR-126 in the development, function of CD4 T cells and related clinical diseases.