Summary The neuroinflammation following traumatic spinal cord injury (SCI) is a critical process that impacts both the injury and the recovery of spinal cord parenchyma. Infiltrating regulatory T (Treg) cells are potent anti‐inflammatory cells that restrain post‐SCI neuroinflammation. To understand the molecular mechanisms underlying the activity of infiltrating Treg cells, we used a mouse spinal cord compression injury model to analyze the role of Sirtuins (SIRTs) in the modulation of infiltrating Treg cell functions. We found that the expressions of SIRT4 and SIRT6 were up‐regulated in infiltrating Treg cells. Using lentivirus‐mediated gene expression or RNA interference, we revealed that SIRT4 substantially inhibited the expression of Foxp3, interleukin‐10, and transforming growth factor‐β in Treg cells, whereas SIRT6 had little effect on Treg cells. Consistently, SIRT4 overexpression weakened the suppressive effect of Treg cells on lipopolysaccharide‐stimulated spinal cord CD11b+ myeloid cells. Knock‐down of SIRT4 enhanced the anti‐inflammatory activity of infiltrating Treg cells in the parenchyma of injured spinal cords. Additionally, SIRT4 overexpression blocked in vitro Treg cell generation from conventional T cells. Furthermore, SIRT4 down‐regulated 5′ AMP‐activated protein kinase (AMPK) signaling in Treg cells, whereas the AMPK agonist AICAR restored the expression of Foxp3 and interleukin‐10 in SIRT4‐overexpressing Treg cells. In conclusion, our research unveils a new mechanism by which the post‐SCI neuroinflammation is regulated.
Figure S1. Overexpression of miR-1287-5p induces ferroptosis and inhibition of human osteosarcoma cells. (A) Relative LPO and MDA levels at 96 h after the miR-1287-5p mimic (100 nmol/L) transfection (n=6). (B-C) The releases of 5-HETE and 15-HETE to the medium from the miR-1287-5p mimic (100 nmol/L)transfected cell (n=6). (D) Intracellular GSH levels (n=6). (E) Quantification of cystine uptake levels (n=6). (F) Relative protein level of GPX4 in human osteosarcoma cell lines treated with the miR-1287-5p mimic or control for 96 h at indicating doses (n=6). (G) Relative level of intracellular ROS was determined by DCFH-DA staining at 96 h after the miR-1287-5p mimic transfection with indicating doses (n=6). (H) Cell death ratio at 96 h after the miR-1287-5p mimic transfection with indicating doses (n=6). The data are expressed as the mean ± SD and a P value < 0.05 was regarded as statistical significance. n.s. indicates no statistical significance.
Increased expressions of VEGF and VEGF-C were closely associated with progression of PCa. The main contribution of increased VEGF expression for PCa progression was to upregulate MVD, which maintained the growth advantage of tumor tissue. However, the chief role of increased expressions of VEGF-C and VEGFR-3 was to enhance lymphangiogenesis and provide a main pathway for cancer cells to disseminate.
Wip1 has been shown to correlate with the metastasis/invasion of several tumors. This study was designed to investigate the clinical significance and biological function of Wip1 in intrahepatic cholangiocarcinoma (ICC). The expression of Wip1 was investigated in sixty human ICC biopsy samples by immunohistochemistry. Transient and stable knockdown of Wip1 in two human ICC cells (ICC-9810 and SSP25) were established using short hairpin RNA expression vector. Immunohistochemistry revealed that Wip1 was up-regulated in human ICC tissues (47/60, 78.3%). High levels of Wip1 in human ICC correlated with metastasis to the lymph metastasis (P=0.022). Genetic depletion of Wip1 in ICC cells resulted in significantly inhibited proliferation and invasion compared with controls. Most importantly, Wip1 down-regulation impaired tumor migration capacity of ICC cells in vivo. Subsequent investigations revealed that matrix metalloproteinase-2 (MMP-2) is an important target of Wip1. Consistently, in human ICC tissues, Wip1 level was positively correlated with MMP-2 expression. Taken together, our founding indicates that Wip1 may be a crucial regulator in the tumorigenicity and invasion of human ICC, Wip1 exerts its pro-invasion function at least in part through the MMP-2 signaling pathway, suggesting Wip1 as a potential therapeutic target for ICC.
Aim : To investigate the association among the polymorphisms of the cytochrome P450 1A1 and 2E1 genes, smoking, drinking and the risk of prostate cancer (PCa) in a Han nationality population in Southern China. Methods : A case-control study including 225 PCa patients and 250 age-matched controls was conducted. The six polymorphic sites of the CYP 1A1 and CYP2E1 genes were analysed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) or allele-specific PCR technique using genomic DNA isolated from peripheral blood lymphocytes. Results : We found that the CYP1A1 Val/Val genotype significantly increased the risk for PCa (OR, 2.26; 95% CI, 1.09-4.68). In contrast, the CYP2E1 C1/C2 (OR, 0.67; 95% CI, 0.46-0.99) or C2/C2 genotype (OR, 0.31; 95% CI, 0.10-1.00) significantly decreased the risk. Furthermore, the individuals carrying the CYP1A1 Val allele and the CYP2E1 C1/C1 genotype showed the highest risk (OR, 2.50; 95% CI, 1.45-4.29). Though there was no significant difference with smoking history ( P = 0.237) or drinking habit ( P = 0.499) between cases and controls, a deep smoking habit (OR, 2.02; 95% CI, 1.28-3.17) and heavy smoking history (OR, 1.61; 95% CI, 1.04-2.50) significantly increased the susceptibility of PCa after stratification by smoking method and accumulative smoking amount. Moreover, both the CYP1A1 Val allele (OR, 2.82; 95% CI, 1.49-5.35) and CYP2E1 C1/C1 genotype (OR, 2.57; 95% CI, 1.31-5.02) had obvious interaction with heavy smoking history that significantly raised the risk. We also discovered a significant interaction between the CYP2E1 C1/C1 genotype and drinking (OR, 1.85; 95% CI, 1.04-3.28). Conclusions : Individuals carrying the CYP1A1 Val allele or the CYP2E1 C1/C1 genotype with a smoking or drinking habit were at increased risk of PCa, which also showed a positive correlation with exposure dose of tobacco.
ABSTRACT. This study aimed to determine the expression of integrin β1 and vascular endothelial growth factor (VEGF) and microvascular density (MVD) by CD105 staining in hypopharyngeal squamous cell carcinoma to determine their association with clinicopathologic characteristics, and to determine their role and the effects of their interactions in the development and progression of hypopharyngeal squamous cell carcinomas. The expression of integrin β1 and VEGF and MVD in hypopharyngeal squamous cell carcinomas and normal hypopharyngeal tissues were evaluated using immunohistochemistry. The Image-Pro Plus software was used to determine the mean optical density of the immunohistochemical images. Integrin β1 expression was significantly higher in hypopharyngeal squamous cell carcinoma tissues (78.00%) than in normal hypopharyngeal tissues (35.00%; P = 0.001) and significantly differed across pathologic grades and different T stages, and regarding the presence of cervical lymph node metastasis (P < 0.05). VEGF expression was significantly higher in hypopharyngeal squamous cell carcinoma tissues (74.00%) than in normal hypopharyngeal tissues (30.00%; P = 0.002), VEGF overexpression differed significantly across different pathologic grades and different T stages, and regarding the presence of cervical lymph node metastasis (P < 0.05). The MVD count was significantly higher in hypopharyngeal squamous cell carcinoma tissues (37.10 ± 5.95) than in normal hypopharyngeal tissues (8.70 ± 3.34; P = 0.000). MVD differed significantly across different pathologic grades and different T stages, and regarding the presence of cervical lymph node metastasis (P < 0.05). The expression of integrin β1 and VEGF and the MVD count exhibited no significant differences in terms of age, gender, history of smoking, and clinical stages (P > 0.05). VEGF expression was positively associated with the MVD count of hypopharyngeal squamous cell carcinomas (r = 0.582, P = 0.000); however, integrin β1 was not associated with VEGF or MVD (P > 0.05). Integrin β1 and VEGF are overexpressed and MVD increased in hypopharyngeal squamous cell carcinomas. VEGF is positively correlated with MVD.
Metastatic castration-resistant prostate cancer (mCRPC) is the lethal stage and the leading cause of death in prostate cancer patients, among which bone metastasis is the most common site. Here in this article, we downloaded the gene expression data and clinical information from online dataset. We found that prostate cancer metastasis in bone is prone to have higher prostate-specific antigen (PSA) and longer time on first-line androgen receptor signaling inhibitors (ARSI). A total of 1,263 differentially expressed genes (DEGs) were identified and results of functional enrichment analysis indicated the enrichment in categories related to cell migration, cancer related pathways and metabolism. We identified the top 20 hub genes from the PPI network and analyzed the clinical characteristics correlated with these hub genes. Finally, we analyzed the immune cell abundance ratio of each sample in different groups. Our results reveal the different clinical characteristics, the immune cell infiltration pattern in different sites of mCRPC, and identify multiple critical related genes and pathways, which provides basis for individualized treatment.
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