RESUMO
BACKGROUND: The occurrence of chronic inflammation resulting from infection with human papillomaviruses is an important factor in the development of cervical cancer (CC); thus, deciphering the crosstalk between the tumor microenvironment and innate immune cells during the establishment of immune tolerance is vital for identifying potential treatment strategies. METHODS: Single-cell RNA sequencing data and primary tumor samples from patients with CC were used to evaluate the functional role of Siglec-10 on dendritic cells (DCs). Patient-derived tumor fragment platforms were used to examine the ability of Siglec-10 blockade to reinvigorate DC-mediate T-cell activation and tumor clearance. RESULTS: Here, we demonstrated that Siglec-10 is a prominent inhibitory checkpoint for DCs infiltrated in CC. CC epithelial cells use their aberrant surface sialylated structures to induce the transformation of conventional DCs into phenotypes characterized by low immunogenicity and high immunotolerance. Additionally, Siglec-10+ DCs suppress the function of adaptive T cells via galectin-9 signaling to strengthen the immunosuppressive CC microenvironment. Disturbance of Siglec-10 signaling restored the DC-mediated tumoricidal response and increased adaptive T cells sensitivity to programmed cell death protein 1 inhibition. CONCLUSION: Our study confirms the checkpoint role of Siglec-10 on DCs and proposes that targeting Siglec-10 may be a promising avenue for immunotherapy against CC.
Assuntos
Células Dendríticas , Imunoterapia , Neoplasias do Colo do Útero , Humanos , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Feminino , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/terapia , Imunoterapia/métodos , Lectinas/metabolismo , Lectinas/imunologia , Microambiente Tumoral/imunologia , Receptores de Superfície CelularRESUMO
Objective: Non-small cell lung cancer (NSCLC) explains about 80 percent of whole lung cancers, and its 5-year survival rate is impoverished, as when people are first diagnosed, 68% of whom are identified at a dangerous stage. The molecular mechanisms of NSCLC are still being explored. Methods: GSE18842 and GSE19804 were exerted to scan for diversely expressed genes (DEGs) in NSCLC, and then we used GEPIA for the validation of DEGs expression. The prognostic values were determined through Kaplan-Meier analysis. Three target prediction databases indicated potential microRNAs (miRNAs), while miRNet predicted hsa-miR-1-3p's upstream long non-coding RNAs (lncRNAs) and pseudogenes. UALCAN was utilized to identify the co-expressed genes of PAICS, while enrichment analysis on them was managed with Enrichr. Results: We initially found that the gene expression level of cyclin B1 (CCNB1), cyclin-dependent kinases1 (CDK1), and phosphoribosylaminoimidazole succinocarboxamide synthetase (PAICS) had a notable increase in NSCLC. We predicted 6, 10, and 7 microRNAs to target CCNB1, CDK1, and PAICS, respectively. Among miRNA-mRNA (microRNA-messenger RNA) pairs, we deduced that the hsa-miR-1-PAICS axis was the most potential one to inhibit the occurrence of NSCLC. We also noted that the hsa-miR-1-3p-PAICS axis participated in regulating the process of mitosis with mechanical functions. Moreover, we identified 5 pseudogenes and 33 long non-coding RNAs (lncRNAs) that might inhibit the hsa-miR-1-3p-PAICS axis in NSCLC. Conclusions: The pseudogene/lncRNA-hsa-miR-1-3p-PAICS is very important in NSCLC on the basis of this study, thus providing us with effective treatments and promising biomarkers for the diagnosis of NSCLC.
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This study was conducted to evaluate the prognostic value of receptor-interacting protein kinase 4 (RIPK4) in ovarian cancer (OC) and its role in tumorigenesis. RNA expression and the corresponding clinical data were obtained from The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. The relationship between clinical-pathological characteristics and RIPK4 expression was analyzed using the Wilcoxon signed-rank test and logistic regression. The Cox regression and the Kaplan-Meier method were used to evaluate the relationship between clinicopathological features and overall survival (OS). Gene set enrichment analysis (GSEA) was performed using Molecular Signatures Database. Scratch assay, transwell assay, and cell transfection were used to verify the function of RIPK4. Overexpression of RIPK4 was associated with the stage of OC and distant metastasis. Survival analysis revealed that patients with OC and higher expression of RIPK4 had a poorer prognosis. Univariate and multivariate analyses indicated that high expression of RIPK4 was associated with poor OS, as well as age and stage of OC. The areas under the curve (AUC) at 1, 4, and 8 years were 0.737, 0.634, and 0.669, respectively, according to the established OS prediction model. GSEA revealed that adherens junction, cadherin binding, and Wnt signaling pathway were enriched in the high RIPK4 expression group. Cell transfection confirmed RIPK4 was involved in the Wnt signaling pathway. RIPK4 can act as a potential prognostic molecular marker for poor survival in OC. Moreover, RIPK4 is associated with tumor metastasis and implicated in the regulation of the Wnt signaling pathway.
Assuntos
Bases de Dados de Ácidos Nucleicos , Regulação Enzimológica da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias , Neoplasias Ovarianas , Proteínas Serina-Treonina Quinases , Via de Sinalização Wnt/genética , Linhagem Celular Tumoral , Intervalo Livre de Doença , Feminino , Humanos , Metástase Neoplásica , Proteínas de Neoplasias/biossíntese , Proteínas de Neoplasias/genética , Neoplasias Ovarianas/enzimologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/mortalidade , Proteínas Serina-Treonina Quinases/biossíntese , Proteínas Serina-Treonina Quinases/genética , Taxa de SobrevidaRESUMO
Chronic obstructive pulmonary disease (COPD) and obstructive sleep apnea (OSA) are highly prevalent potential risk factors for systemic disease. Previous studies have reported that COPD and OSA are major independent risk factors for cardio or cerebrovascular diseases. The present study aimed to investigate the role of bone marrow mesenchymal stem cells (BMSCs) on vascular injury in a COPDOSA overlap syndrome (OS) rat model. Rats were randomly divided into three groups: Sham, OS model and BMSC. BMSC localization in major organs was detected via confocal laser fluorescence microscopy, and the aortic tissue pathological changes and related genes were measured using hematoxylin & eosin and Masson staining. Genes associated with vascular endothelial cell injury, including endothelin 1, vascular cell adhesion molecule 1 and endothelial nitric oxide synthase, were detected via reverse transcriptionquantitative PCR and western blotting. Apoptosis of vascular endothelial cells was detected using TUNEL and immunofluorescence assays. The endothelial cell marker CD31 in injured vessels was analyzed via immunohistochemistry. BMSCs migrated into the heart, liver, spleen, lung, kidney, brain and aorta in the OS model. The green fluorescence expression of BMSCs demonstrated the highest level in the lung, followed by the aorta. Aortic tissue had a more severe vascular injury and increased apoptosis in the model group compared with the BMSC group. Vascular endothelial cell apoptosis was decreased in the BMSC group compared with the model group. The findings suggested that BMSCs could repair vascular injury by inhibiting endothelial cell damage and apoptosis. These data provide a theoretical basis for the treatment of cardiovascular diseases caused by OS with BMSCs.
Assuntos
Células da Medula Óssea/metabolismo , Transplante de Células-Tronco Mesenquimais , Doença Pulmonar Obstrutiva Crônica/terapia , Apneia Obstrutiva do Sono/terapia , Lesões do Sistema Vascular/terapia , Aloenxertos , Animais , Células da Medula Óssea/patologia , Modelos Animais de Doenças , Feminino , Células-Tronco Mesenquimais , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Ratos , Ratos Sprague-Dawley , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/patologia , Síndrome , Lesões do Sistema Vascular/metabolismo , Lesões do Sistema Vascular/patologiaRESUMO
Bone marrowderived mesenchymal stem cells (BMSCs) possess potential therapeutic properties for treating patients with chronic obstructive pulmonary disease (COPD), which is characterized by emphysema and obstructive sleep apnea (OSA). However, their effects on overlap syndrome (OS) remain unclear. We investigated the potential therapeutic effects and possible mechanisms of BMSC transplantation in OS rats. To generate the OS model in rats, the animals underwent daily exposure to cigarette smoke and intermittent hypoxia. BMSCs were intravenously injected into rats. At 4 weeks posttransplantation, the severity of emphysema was assessed by lung hematoxylin and eosin (H&E) staining. The levels of oxidative stress and the malondialdehyde (MDA) and superoxide dismutase (SOD) contents in serum and lung were detected. The apoptosis of alveolar septal cells was also detected by TUNEL assay. Finally, we determined the expression of CD31 and VWF in lung tissues by an immunohistochemical (IHC) assay. It was found that BMSCs were able to migrate to the injured lung and aorta tissues. In lung tissues, transplanted BMSCs, some of which had differentiated into endotheliocytes, were found in the alveolar walls. The mean linear intercept (MLI) and pathological scores were higher and the mean alveolar number (MAN) was lower in the OS group than these parameters in the control group. These values were significantly reduced in the OS+BMSC group compared to those in the OS group. The MDA content was decreased and SOD activity was increased in the OS+BMSC group compared to those in the OS group. The apoptotic index of alveolar wall cells in the OS group was higher than that in the OS+BMSC group. The expression levels of CD31 and VWF in alveolar wall cells in the OS group were lower than those in the OS+BMSC group. These results indicate that BMSCs may inhibit the progression of emphysema in the OS model by differentiating into endotheliocytes and suppressing the apoptosis of endotheliocytes and oxidative stress. There is a possibility that the release of growth factors and structural support may be a determinant for the regenerative effects observed following treatment with BMSCs.
Assuntos
Células da Medula Óssea/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Doença Pulmonar Obstrutiva Crônica , Apneia Obstrutiva do Sono , Aloenxertos , Animais , Células da Medula Óssea/patologia , Modelos Animais de Doenças , Células-Tronco Mesenquimais/patologia , Doença Pulmonar Obstrutiva Crônica/metabolismo , Doença Pulmonar Obstrutiva Crônica/patologia , Doença Pulmonar Obstrutiva Crônica/terapia , Ratos , Ratos Sprague-Dawley , Apneia Obstrutiva do Sono/metabolismo , Apneia Obstrutiva do Sono/patologia , Apneia Obstrutiva do Sono/terapiaRESUMO
OBJECTIVE: To explore the effects of transplanting bone marrow mesenehymal stem cells (MSCs) on emphysema in rats and elucidate the possible mechanisms. METHODS: A total of 24 female Sprague-Dawley rats were randomly divided randomly into 3 groups of control, emphysema and MSCs transplantation (n=8 each). The rat model of emphysema was established by 14-week exposure to cigarette smoking and then MSCs labeled with 4, 6-diamidino-2-phenylindole (DAPI) were injected into recipient rats of MSCs transplantation group via tail veins. At 2 and 4 weeks post-transplantation, engraftment and differentiation of MSCs was determined. At 8 weeks post-transplantation, lung fissure sections were prepared for examining the morphological alterations. The apoptosis of alveolar septal cells was assessed. And the levels of oxidative stress in sera and lung were detected. RESULTS: At 2 and 4 weeks post-transplantation, MSCs labeled with DAPI could be found in recipient lungs, some of which differentiated into type II alveolar epithelial cells. Mean linear intercept was higher in emphysema and MSCs transplantation groups than control group [(111 ± 23) and (90 ± 15) vs (74 ± 10) µm], mean alveolar numbers were lower than control group [(94 ± 22) and (125 ± 15) vs (159 ± 22)/mm²] (all P<0.05); mean linear intercept was higher and mean alveolar numbers were lower in emphysema group than MSCs transplantation group (both P<0.05). The apoptotic index of alveolar wall cells in emphysema group was higher than MSCs transplantation group [(13.5 ± 2.5)% vs (4.8 ± 0.7)%, P<0.05]. Malondialdehyde of sera and lung in emphysema and MSCs transplantation groups was higher than control group [(4.3 ± 0.8), (3.7 ± 0.4) vs (3.0 ± 0.4) nmol/ml, (5.4 ± 0.5), (4.8 ± 0.4) vs (4.2 ± 0.6) nmol/mg, all P<0.05]; malondialdehyde of sera and lung in emphysema group was higher than MSCs transplantation group (both P<0.05). Superoxide dismutase (SOD) of sera and lung in emphysema and MSCs transplantation groups was lower than control group [(8.7 ± 0.8), (9.6 ± 0.7) vs (10.5 ± 0.9) U/ml and (56.3 ± 13.4), (70.2 ± 11.0) vs (84.9 ± 13.0) U/mg, all P<0.05]; SOD of sera and lung in emphysema group was lower than MSCs transplantation group (both P<0.05). CONCLUSION: MSCs transplantation via tail vein may arrest the progression of emphysema in a cigarette-smoke-induced rat model of emphysema through a differentiation of injected MSCs into type II alveolar epithelial cells and down-regulations of apoptosis and oxidative stress.