LncRNATUG1 Facilitates Th2 Cell Differentiation by Targeting the miR-29c/B7-H3 Axis on Macrophages.
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ABSTRACT:
SUBMITTER: Sun H
PROVIDER: S-EPMC8322941 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Transforming growth factor-beta 1 (TGF-β1) suppresses T cell function, promoting tumor immune escape. Yet, whether the depression of TGF-β1 on T cell function is mediated by co-inhibitory molecules B7-H3 and B7-H4 remains largely unclear. Here, we demonstrated that TGF-β1 elevated the expression of miR-155 in colorectal cancer cells through SMAD3 and SMAD4. The upregulated miR-155 attenuated miR-143 by inhibiting its direct target, the transcription factor CEBPB. Consequently, the direct target genes of miR-143, B7-H3 and B7-H4, were augmented in the cytoplasm and membrane of tumor cells. Over-expression of B7-H3 and B7-H4 in HCT-116 cells induced T cells to secrete TGF-β1 and the immunosuppressive cytokines IL-2, IL-6, and IL-17. Restoration of miR-143 inhibited the growth of HCT-116 xenograft tumors in mice, and also repressed the expression of B7-H3 and B7-H4 in the tumors. Thus, this study reveals the mechanism by which TGF-β1 leads to T cell-mediated tumor evasion through an increase in B7-H3 and B7-H4 expression.
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Project description:BackgroundB7-H3, an immunoregulatory protein, is overexpressed in several cancers and is often associated with metastasis and poor prognosis. Here, our aim was to identify microRNAs (miRNAs) regulating B7-H3 and assess their potential prognostic implications in breast cancer.MethodsMicroRNAs targeting B7-H3 were identified by transfecting two breast cancer cell lines with a library of 810 miRNA mimics and quantifying changes of B7-H3 protein levels using protein lysate microarrays. For validations we used western immunoblotting and 3'-UTR luciferase assays. Clinical significance of the miRNAs was assayed by analysing whether their expression levels correlated with outcome in two cohorts of breast cancer patients (142 and 81 patients).ResultsWe identified nearly 50 miRNAs that downregulated B7-H3 protein levels. Western immunoblotting validated the impact of the 20 most effective miRNAs. Thirteen miRNAs (miR-214, miR-363*, miR-326, miR-940, miR-29c, miR-665, miR-34b*, miR-708, miR-601, miR-124a, miR-380-5p, miR-885-3p, and miR-593) targeted B7-H3 directly by binding to its 3'-UTR region. Finally, high expression of miR-29c was associated with a significant reduced risk of dying from breast cancer in both cohorts.ConclusionsWe identified miRNAs efficiently downregulating B7-H3 expression. The expression of miR-29c correlated with survival in breast cancer patients, suggesting a tumour suppressive role for this miRNA.
| S-EPMC3992492 | biostudies-literature
Project description:B7-H3 (CD276) is an important immune checkpoint member of the B7 and CD28 families. Induced on antigen-presenting cells, B7-H3 plays an important role in the inhibition of T-cell function. Importantly, B7-H3 is highly overexpressed on a wide range of human solid cancers and often correlates with both negative prognosis and poor clinical outcome in patients. Challenges remain to identify the receptor(s) of B7-H3 and thus better elucidate the role of the B7-H3 pathway in immune responses and tumor evasion. With a preferential expression on tumor cells, B7-H3 is an attractive target for cancer immunotherapy. Based on the clinical success of inhibitory immune checkpoint blockade (CTLA-4, PD-1, and PD-L1), mAbs against B7-H3 appear to be a promising therapeutic strategy worthy of development. An unconventional mAb against B7-H3 with antibody-dependent cell-mediated cytotoxicity is currently being evaluated in a phase I clinical trial and has shown encouraging preliminary results. Additional therapeutic approaches in targeting B7-H3, such as blocking mAbs, bispecific mAbs, chimeric antigen receptor T cells, small-molecule inhibitors, and combination therapies, should be evaluated, as these technologies have already shown positive results in various cancer settings. A better understanding of the B7-H3 pathway in humans will surely help to further optimize associated cancer immunotherapies. Clin Cancer Res; 22(14); 3425-31. ©2016 AACR.
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Project description:Medulloblastoma (MB) is the most common embryonal neuroepithelial tumor, with poor patient outcomes and secondary complications. In this study, we investigated the role of the B7 family of immune checkpoint homolog 3 (B7-H3) expression in MB angiogenesis. B7-H3, a co-inhibitory immune checkpoint, is highly expressed and is associated with lower overall survival in MYC+ MB's. Evidence for a direct transcriptional role of MYC on the B7-H3 gene promoter was confirmed by MYC inhibition and anti-MYC antibody ChIP analysis. Interestingly, MYC inhibition not only downregulated the B7-H3 protein expression, but also rescued miR-29 expression, thus indicating a triangular regulatory relationship between MYC, miR-29, and B7-H3 in Group 3 MB cells. From RNA seq and IPAD assay, we observed a negative feedback loop between miR-29 and MYC that may control B7-H3 expression levels in MB cells. Our studies show that B7-H3 expression levels play a crucial role in promoting MB angiogenesis which can be inhibited by miR-29 overexpression via miR-29-mediated B7-H3 downregulation. The tumor suppressor role of miR-29 is mediated by the activation of JAK/STAT1 signaling that further plays a role in MYC-B7-H3 downregulation in MB. This study highlights B7-H3 as a viable target in MB angiogenesis, and that the expression of miR-29 can inhibit B7-H3 and sensitize MB cells to treatment with MYC-inhibiting drugs.
| S-EPMC6723910 | biostudies-literature
Project description:While their function, as immune checkpoint molecules, is well known, B7-family proteins also function as regulatory molecules in bone remodeling. B7-H3 is a receptor ligand of the B7 family that functions primarily as a negative immune checkpoint. While the regulatory function of B7-H3 in osteoblast differentiation has been established, its role in osteoclast differentiation remains unclear. Here we show that B7-H3 is highly expressed in mature osteoclasts and that B7-H3 deficiency leads to the inhibition of osteoclastogenesis in human osteoclast precursors (OCPs). High-throughput transcriptomic analyses reveal that B7-H3 inhibition upregulates IFN signaling as well as IFN-inducible genes, including IDO. Pharmacological inhibition of type-I IFN and IDO knockdown leads to reversal of B7-H3-deficiency-mediated osteoclastogenesis suppression. Although synovial-fluid macrophages from rheumatoid-arthritis patients express B7-H3, inhibition of B7-H3 does not affect their osteoclastogenesis. Thus, our findings highlight B7-H3 as a physiologic positive regulator of osteoclast differentiation and implicate type-I IFN-IDO signaling as its downstream mechanism.
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Project description:BackgroundWith the broadened application of gene expression profiles analysis, the role of miRNA and circRNA are of increasing concern in recent years, especially during the pathogenesis of cancer. However, to date, the reported on this area in cervical cancer are limited.MethodIn this study, Weighted Gene Co-Expression Network Analysis (WGCNA) and differential gene expression analysis were utilized to screen out differentially expressed (DE) circular RNAs in cervical cancer, and then we predicted and screened the combined microRNAs (miRNA) and downstream mRNAs to construct circular (circ)RNA-miRNA-mRNA network.ResultAs a result, a regulatory circular (circ)RNA-miRNA-mRNA with 1 circRNA node, 4 miRNA nodes, 135 mRNA nodes were constructed in an attempt to provide novel biomarkers for the pathogenesis of cervical cancer. In addition, enrichment analysis including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) were performed on mRNAs in the network. After further screening of mRNAs by two online databases of GEPIA2 and RNAyhrid, precise target genes were obtained. Next, we screened out four target genes (CXCL16, IRF4, OAS3 and PTGER3) by constructing the protein-protein interaction (PPI) network, and mapped them to the initial network to reconstruct the circRNA-miRNA-mRNA network. Notably, the low expression of IRF4 was demonstrated to be associated with a significantly poorer overall survival in the GEPIA2 database, which was also verified by the immunofluorescence of the sections in Human Protein Atlas (HPA). The upstream miRNA corresponding to IRF4 is hsa-miR-1228-3p.ConclusionFrom above concern, it can conclude that hsa_circ_0000301/hsa-miR-1228-3p/IRF4 may be involved in the occurrence and development of cervical cancer. However, the specific mechanism should be further studied and confirmed.
| S-EPMC8140416 | biostudies-literature
Project description:Background In recent years, the incidence and mortality of colorectal cancer (CRC) have increased year by year among young people. Increased levels of Girdin expression predict a poor prognosis of CRC, which presents a serious threat to human health globally. Herein, we investigated the role of Girdin in CRC and explored the underlying mechanisms in CRC. Methods The expression of Girdin was detected in human specimens. HCT116 cells with stably expressing or knock-out Girdin protein were successfully constructed to observe the biological function of gene. Protein expression was determined by immunohistochemistry, immunofluorescence and western blot. Results Clinically, overexpression of Girdin was observed in the tumor tissue and poor prognosis of CRC patients. Gain-of-function and loss-of-function assays showed that Girdin promoted CRC cell proliferation in vitro. Mechanistically, Girdin knock-down significantly enhanced apoptosis, the mitochondrial membrane potential dropped, and the reactive oxygen species increased greatly. Last but not least, we analyzed the TargetScan dataset and found that Girdin was a regulated target of hsa-miR-29c-3p in CRC. Luciferase reporter assay was used to verify the interaction between hsa-miR-29c-3p and the 3’UTR of Girdin. Conclusions Our findings suggest that Girdin has a crucial role in CRC progression via miR-29c-3p/Girdin axis, highlighting Girdin as a therapeutic target for CRC.
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Project description:Increasing evidence has indicated that long non-coding RNAs (lncRNAs) play significant roles in various diseases; however, their roles in age-related macular degeneration (AMD) remain unclear. Dedifferentiation and dysfunction of retinal pigment epithelium (RPE) cells have been shown to contribute to AMD etiology in several studies. Herein, we found that lncRNA LINC00167 was downregulated in RPE-choroid samples of AMD patients and dysfunctional RPE cells, and it was consistently upregulated along with RPE differentiation. In vitro study indicated that reduced endogenous LINC00167 expression resulted in RPE dedifferentiation, which was typified by attenuated expression of RPE markers, reduced vascular endothelial growth factor A secretion, accumulation of mitochondrial reactive oxygen species, and interrupted phagocytic ability. Mechanistically, LINC00167 functioned as a sponge for microRNA miR-203a-3p to restore the expression of the suppressor of cytokine signaling 3 (SOCS3), which further inhibited the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. Taken together, our study demonstrated that LINC00167 showed a protective role in AMD by maintaining RPE differentiation through the LINC00167/miR-203a-3p/SOCS3 axis and might be a potential therapeutic target for AMD.
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Project description:Radiotherapy (RT) is a key treatment for prostate cancer. However, RT resistance can contribute to treatment failure. Prostate cancer stem cells (PCSCs) are radioresistant. We recently found that fractionated irradiation (FIR) upregulates expression of the immune checkpoint B7-H3 (CD276) on PCSCs and bulk cells in each prostate cancer cell line tested. These findings prompted us to investigate whether B7-H3 targeting chimeric antigen receptor (CAR) T cells, which may abrogate function of an immune checkpoint and mediate lysis of targeted cells, can target RT-resistant PCSCs in vitro and in vivo. B7-H3 expression is naturally higher on PCSCs than bulk prostate cancer cells and cytotoxicity of B7-H3 CAR T cells to PCSCs is more potent than to bulk prostate cancer cells. Furthermore, FIR significantly upregulates B7-H3 expression on PCSCs and bulk prostate cancer cells. The duration of FIR or single-dose irradiation-induced further upregulation of B7-H3 on bulk prostate cancer cells and PCSCs lasts for up to 3 days. B7-H3 CAR T-cell cytotoxicity against FIR-resistant PCSCs at a low effector to target ratio of 1:1 was assessed by flow cytometry and sphere formation assays. Further upregulation of B7-H3 expression by FIR made PCSCs even more sensitive to B7-H3 CAR T-cell-mediated killing. Consequently, the FIR and B7-H3 CAR T-cell therapy combination is much more effective than FIR or CAR T cells alone in growth inhibition of hormone-insensitive prostate cancer xenografts in immunodeficient mice. Our work provides a sound basis for further development of this unique combinatorial model of RT and B7-H3 CAR T-cell therapy for prostate cancer. SIGNIFICANCE: We demonstrate that FIR significantly upregulates B7-H3 expression by RT-resistant PCSCs and bulk cells; cytotoxicity of B7-H3 CAR T cells to FIR-treated PCSCs is potent and results in significantly improved antitumor efficacy in mice.
| S-EPMC7952034 | biostudies-literature
Project description:BackgroundLung adenocarcinoma (LUAD) is a common subtype of lung cancer with high recurrence rate and fatality. Circ_0001361 has been recognized as key regulators in various malignancies, but its roles in LUAD remain ambiguous.MethodsCirc_0001361, miR-525-5p, and VMA21 levels were assessed by RT-qPCR. The growth and metastasis of LUAD cells were detected by MTT, colony formation, wound scratch, and transwell assays, respectively. The interaction between circ_0001361/VMA21 and miR-525-5p was detected by dual luciferase, RNA immunoprecipitation, and RNA pull-down assays. VMA21 protein level was detected by Western blotting. Nude mouse xenograft model was established to determine the role of circ_0001361 in tumor growth in vivo.ResultsCirc_0001361 was up-regulated, while miR-525-5p was down-regulated in LUAD tissues and cells. Functional experiments demonstrated that circ_0001361 drove LUAD cell growth and metastasis. Mechanistically, circ_0001361 functioned as a sponge of miR-525-5p to up-regulate downstream target VMA21 level. MiR-525-5p/VMA21 axis was involved in circ_0001361-mediated malignant phenotypes of LUAD cells. Finally, inhibition of circ_0001361 restrained in vivo xenograft tumor growth via regulating miR-525-5p/VMA21 axis.ConclusionOur findings elucidate that circ_0001361 facilitates the tumorigenesis and development of LUAD through miR-525-5p/VMA21 axis, providing evidence for circ_0001361 as a potential prognosis biomarker and therapeutic target for clinical treatment of LUAD.
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