Abstract MicroRNAs (miRNAs) are noncoding single‐stranded RNAs, approximately 20‐24 nucleotides in length, known as powerful posttranscriptional regulators. miRNAs play important regulatory roles in cellular processes by changing messenger RNA expression and are widely involved in human diseases, including tumors. It has been reported in the literature that miRNAs have a precise role in cell proliferation, programmed cell death, differentiation, and expression of coding genes. MicroRNA‐124 (miR‐124) has reduced exparession in various human neoplasms and is believed to be related to the occurrence, development, and prognosis of malignant tumors. In our review, we focus on the specific molecular functions of miR‐124 and the downstream gene targets in major cancers, which provide preclinical evidence for the treatment of human cancer. Although some obstacles exist, miR‐124 is still attracting intensive research focus as a promising and effective anticancer weapon.
Abstract Objective Increasing research have focused on the potential therapeutic value of tolerogenic DC (tol-DC) in clinical organ transplantation. However, the role of long non-coding RNA (lncRNA) in tol-DC remains to be elucidated. Our report aims to illuminate the relationship between lncRNA NEAT1 and DC function in inmune tolerance of heart transplantation. Methods and Results We identified lncRNA NEAT1 was upregulated in cardiac allografts of mice by microarray. Applying Flow Cytometry, we found that LPS-dependent maturation of DC was inhibited after siNEAT1 characterizing the low expression of costimulatory molecular CD80, CD86 and MHCII. A mixed lymphocytere action (MLR) was performed to dectect the function of DC in simulating T cells. CD4+CD25+FoxP3+T cells were significantly increased in siNEAT1-DC, however, the proliferation of T cells was suppressed. Bioinformatic databases and dual-luciferase reporter gene assay confirmed that Neat1 can regulate mircoRNA let-7i. In addition, BALB/c recipients transfused with siNEAT1-DC had significantly prolonged allograft survival. Histological examination of cardiac allografts showd slight cell infiltration in recipients transfused with siNEAT1-DC. Conclusion LncRNA NEAT1 can regulate DC maturation and function, and transfusion of LPS-induced DC transfected with siNEAT1 prolonged allograft survival, besides, we identified that NEAT1 can regulate mircoRNA let-7i. This study enriched the network of interaction between lncRNA and mircoRNA and may provide a new therapeutic target in heart transplantation.
Abstract During melanoma progression, tumor cells come into direct contact with subcutaneous tissues and these advanced lesions portend a poor prognosis. Despite the fact that subcutaneous tissues are largely composed of adipocytes, little is known about the mechanisms by which adipocytes influence melanoma. Using both in vitro and in vivo models, we find that adipocytes increase proliferation and invasion of adjacent melanoma cells. This is accompanied by direct transfer of fatty acids from adipocytes to melanoma cells, which increases tumor cell metabolism and invasion programs. These adipocyte-derived lipids are transferred to melanoma cells through the FATP/SLC27A family of lipid transporters expressed on the tumor cell surface. Among the six related FATP/SLC27A family members, melanomas significantly overexpress FATP1/SLC27A1. Melanocyte-specific FATP1 expression cooperates with BRAFV600E in transgenic zebrafish to accelerate melanoma development, an effect that is similarly seen in mouse xenograft studies. These data demonstrate that adipocytes in the tumor microenvironment can drive melanoma progression through FATP lipid transporters, and represents a new target aimed at interrupting adipocyte-melanoma crosstalk. Citation Format: Maomao Zhang. Adipocyte-derived lipids mediate melanoma progression via FATP proteins [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5120.
Dendritic cells (DCs) can initiate immune responses or confer immune tolerance depending on functional status. Lipopolysaccharide (LPS) induced DC maturation as defined by enhanced surface expression of CD80 and CD86. MicroRNAs (miRNAs) are critical for the regulation of DC function and immunity, and the miRNA let-7i was up-regulated during LPS-induced DC maturation. Down-regulation of let-7i significantly impeded DC maturation as evidenced by reduced CD80 and CD86 expression. DCs stimulated by LPS (LPS-DCs) promoted T-cell proliferation in co-culture, while LPS-stimulated DCs with down-regulated let-7i were not effective at stimulating T cell proliferation but promoted expansion of the regulatory T cell (Treg) population. There were two subpopulations of LPS-stimulated DCs with down-regulated let-7i, CD86- and CD86+, and it was the CD86- DCs that were more effective in inducing T cell hyporesponsiveness and enhancing Treg numbers, indicating that this DC population had tolerogenic properties. Furthermore, Treg with up-regulated IL-10 underscored the tolerogenic effect of CD86- DCs. Suppressor of cytokine signalling 1 (SOCS1), a crucial mediator of DC maturation, was confirmed as a let-7i target gene by luciferase construct assay. Suppression or overexpression of let-7i caused reciprocal alterations in SOCS1 protein expression, but had no significant effects on SOCS1 mRNA levels, indicating that let-7i regulated SOCS1 expression by translational suppression. The modulation of SOCS1 protein by let-7i was mainly restricted to CD86- DCs. Our study demonstrates that let-7i regulation of SOCS1 is critical for LPS-induced DC maturation and immune function. Dynamic regulation of let-7i may fine tune immune responses by inducing antigen-specific immune tolerance.
<p>Supplementary Figure S1: RNA-seq analysis of human A375 melanoma cells in co-culture with adipocytes compared to monoculture controls Supplementary Figure S2: Lipid transfer and melanoma cell uptake of long chain fatty acids Supplementary Figure S3: Adipocytes do not increase glycolysis in melanoma cells Supplementary Figure S4: Endogenous FATP expression in control tissues and patient-derived xenografts Supplementary Figure S5: Absence of lipid-laden tumor cells in in vivo setting devoid of adipocytes Supplementary Figure S6: Lipidomics reveals specific lipid species transferred from adipocytes to melanoma cells Supplementary Figure S7: FATP1 expression and survival Supplementary Figure S8: Validation of FATP1 knockdown Supplementary Figure S9: Lipofermata targets FATP1 Supplementary Figure S10: Compounds that are structurally similar to Lipofermata do not cause decreases in lipid uptake or increased cell death Supplementary Figure S11: Measurement of apoptosis in Lipofermata-treated cells</p>
Dendritic cells (DCs) can initiate immune responses or confer immune tolerance depending on functional status. MicroRNAs (miRNAs) are critical for the regulation of DC function and immunity. Therefore, we try to find some miRNAs that can dynamic regulate DC maturation so as to further modulate specify antigen-specific immune responses.
Methods
Bone marrow-derived DCs were generated and stimulated by LPS. To manipulate let-7i in DCs before LPS stimulation, cultured DCs were transfected with let-7i mimic or inhibitor. The maturation and functional state of DCs were assessed by Flow cytometry, MLR assay and ELISA. The subpopulation of DCs were separated by MACS. The target gene of let-7i was proved by luciferase assay, western blots, immunofluorescence and qRT-PCR.
Results
We found that the miRNA let-7i was up-regulated during LPS-induced DC maturation. Down-regulation of let-7i significantly impeded DC maturation as evidenced by reduced CD80 and CD86 expression. DCs stimulated by LPS (LPS-DCs) promoted T-cell proliferation in co-culture, while LPS-stimulated DCs with down-regulated let-7i were not effective at stimulating T cell proliferation but promoted expansion of the regulatory T cell (Treg) population. There were two subpopulations of LPS-stimulated DCs with down-regulated let-7i, CD86− and CD86+, and it was the CD86− DCs that were more effective in inducing T cell hyporesponsiveness and enhancing Treg numbers, indicating that this DC population had tolerogenic properties. Furthermore, Treg with up-regulated IL-10 underscored the tolerogenic effect of CD86− DCs. Suppressor of cytokine signalling 1 (SOCS1), a crucial mediator of DC maturation, was confirmed as a let-7i target gene by luciferase construct assay. Suppression or overexpression of let-7i caused reciprocal alterations in SOCS1 protein expression, but had no significant effects on SOCS1 mRNA levels, indicating that let-7i regulated SOCS1 expression by translational suppression. The modulation of SOCS1 protein by let-7i was mainly restricted to CD86− DCs.
Conclusions
Our study demonstrates that let-7i regulation of SOCS1 is critical for LPS-induced DC maturation and immune function. Dynamic regulation of let-7i may fine tune immune responses by inducing antigen-specific immune tolerance.
By synergistically integrating mobile networks and embodied artificial intelligence (AI), Mobile Embodied AI Networks (MEANETs) represent an advanced paradigm that facilitates autonomous, context-aware, and interactive behaviors within dynamic environments. Nevertheless, the rapid development of MEANETs is accompanied by challenges in trustworthiness and operational efficiency. Fortunately, blockchain technology, with its decentralized and immutable characteristics, offers promising solutions for MEANETs. However, existing block propagation mechanisms suffer from challenges such as low propagation efficiency and weak security for block propagation, which results in delayed transmission of vehicular messages or vulnerability to malicious tampering, potentially causing severe traffic accidents in blockchain-enabled MEANETs. Moreover, current block propagation strategies cannot effectively adapt to real-time changes of dynamic topology in MEANETs. Therefore, in this paper, we propose a graph Resfusion model-based trustworthy block propagation optimization framework for consortium blockchain-enabled MEANETs. Specifically, we propose an innovative trust calculation mechanism based on the trust cloud model, which comprehensively accounts for randomness and fuzziness in the miner trust evaluation. Furthermore, by leveraging the strengths of graph neural networks and diffusion models, we develop a graph Resfusion model to effectively and adaptively generate the optimal block propagation trajectory. Simulation results demonstrate that the proposed model outperforms other routing mechanisms in terms of block propagation efficiency and trustworthiness. Additionally, the results highlight its strong adaptability to dynamic environments, making it particularly suitable for rapidly changing MEANETs.
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