miR-155 regulates IFN- production in natural killer cells
ABSTRACT MicroRNAs (miRs) are small, noncoding RNA molecules with important regulatory functions whose role in regulating natural killer (NK) cell biology is not well defined. Here, we show that miR-155 is synergistically induced in primary human NK cells after costimulation with IL-12 and IL-18, or with IL-12 and CD16 clustering. Over-expression of miR-155 enhanced induction of IFN-γ by IL-12 and IL-18 or CD16 stimulation, whereas knockdown of miR-155 or its disruption suppressed IFN-γ induction in monokine and/or CD16-stimulated NK cells. These effects on the regulation of NK cell IFN-γ expression were found to be mediated at least in part via miR-155's direct effects on the inositol phosphatase SHIP1. Consistent with this, we observed that modulation of miR-155 overrides IL-12 and IL-18-mediated regulation of SHIP1 expression in NK cells. Collectively, our data indicate that miR-155 expression is regulated by stimuli that strongly induce IFN-γ in NK cells such as IL-12, IL-18, and CD16 activation, and that miR-155 functions as a positive regulator of IFN-γ production in human NK cells, at least in part via down-regulating SHIP1. These findings may have clinical relevance for targeting miR-155 in neoplastic disease.
SourceAvailable from: Seyed Javad Mowla[Show abstract] [Hide abstract]
ABSTRACT: In the past decades, cancer medicine studies have mainly focused on tumor cell biology as the main promoter of solid tumor progression. However, tumor biology does not explain the intertwinement and ambiguity of the tumors' territory. Recently, the approach of understanding cancer has shifted from investigating the biology of tumor cells to studying the microenvironment surrounding them. MicroRNAs (miRNAs), which play a role in exploiting indigenous stromal cells and are components that cooperate and produce a favorable microenvironment for progressive tumor formation, have been implicated in numerous processes essential for tumor initiation and growth. Understanding the mechanisms underlying interactions between tumor cells and their adjacent environment holds many promises for the future of cancer-targeted therapies. Herein, we provide a step-by-step account of miRNA involvement in tumor-microenvironment interactions as the micromediators of tumor cell and stroma communications. We also focus on the clinical challenges in using miRNAs tof overcome therapy resistance mechanisms and tumor heterogeneity bias in cancer therapy. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.Genes Chromosomes and Cancer 03/2015; 54(6). DOI:10.1002/gcc.22244 · 3.84 Impact Factor
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ABSTRACT: Cancer cells and the immune system are closely related and thus influence each other. Although immune cells can suppress cancer cell growth, cancer cells can evade immune cell attack via immune escape mechanisms. Natural killer (NK) cells kill cancer cells by secreting perforins and granzymes. Upon contact with cancer cells, NK cells form immune synapses to deliver the lethal hit. Mature NK cells are differentiated from hematopoietic stem cells in the bone marrow. They move to lymph nodes, where they are activated through interactions with dendritic cells. Interleukin-15 (IL-15) is a key molecule that activates mature NK cells. The adoptive transfer of NK cells to treat incurable cancer is an attractive approach. A certain number of activated NK cells are required for adoptive NK cell therapy. To prepare these NK cells, mature NK cells can be amplified to obtain sufficient numbers of NK cells. Alternatively, NK cells can be differentiated and amplified from hematopoietic stem cells. In addition, the selection of donors is important to achieve maximal efficacy. In this review, we discuss the overall procedures and strategies of NK cell therapy against cancer.Experimental and Molecular Medicine 02/2015; 47(2):e141. DOI:10.1038/emm.2014.114 · 2.46 Impact Factor
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ABSTRACT: Human Papillomavirus cause a number of diseases most notably cervical cancer. K14-HPV16 transgenic mice expressing the HPV16 early genes in squamous epithelial cells provide a suitable experimental model for studying these diseases. MicroRNAs are small non-coding RNAs that play an important role in regulating gene expression and have been suggested to play an important role in cancer development. The role of miR-155 in cancer remains controversial and there is limited evidence linking this miRNA to HPV- associated diseases. We hypothesized that miR-155 expression modulates each tissue's susceptibility to develop HPV-associated carcinogenesis. In this study, we analyzed miR-155 expression in ear and chest skin samples from 22-26 weeks old, female K14-HPV16 transgenic (HPV16+/-) and wild-type (HPV-/-) mice. Among wild-type mice the expression of miR-155 was lower in ear skin compared with chest skin (p = 0.028). In transgenic animals, in situ carcinoma was present in all ear samples whereas chest tissues only showed epidermal hyperplasia. Furthermore, in hyperplastic chest skin samples, miR-155 expression was lower than in normal chest skin (p = 0,026). These results suggest that miR-155 expression may modulate the microenvironmental susceptibility to cancer development and that high miR155 levels may be protective against the carcinogenesis induced by HPV16.PLoS ONE 01/2015; 10(1):e0116868. DOI:10.1371/journal.pone.0116868 · 3.53 Impact Factor