The poliovirus receptor (PVR) gene is closely related to tumorogenesis and development, while the regulatory roles and mechanisms of PVR in tumor immunity are not fully elucidated. This study analyzed the expression of PVR in different types of tumor tissues from a pan-cancer perspective and its correlation with patients prognosis and immunity. The analysis of the expression differences of PVR between cancerous and normal tissues was based on The Cancer Genome Atlas (TCGA) and TIMER database, and the correlation between PVR and the prognosis of cancer patients was assessed using survival analysis tools. Expression analyses of PVR in various with immune cells infiltration, immune checkpoint (ICP) genes expression and stromal/immune scoring were evaluated by the TIMER database and R software. To further understand the potential biological mechanisms of PVR in various cancers, single-cell level sequencing and Gene Set Enrichment Analysis (GSEA) were performed. The expression of PVR was verified by qRT-PCR in a variety of cancer cell lines. The results showed that, compared to that of normal tissues, PVR was significantly differentially expressed in tumor tissues like bladder urothelial carcinoma, cholangiocarcinoma, colon adenocarcinoma, esophageal carcinoma, and head & neck squamous cell carcinoma, etc. Aberrant expression of PVR was associated with poor prognosis for multiple cancers including adrenocortical cancer, bladder urothelial carcinoma, breast invasive carcinoma, and cervical carcinoma, etc. PVR expression was significantly correlated with immune cells infiltration, stromal/immune scoring and the regulation of ICP genes expression on pan-cancer level (all with P<0.05). Single-cell sequencing outcomes showed that PVR was associated with tumor cells multiple cytobiological functions and phenotypes, including cell differentiation, gene silencing and DNA repairing. GSEA revealed that PVR was engaged in immune-related functions and signaling pathways in multiple tumor cells. The qRT-PCR results showed that PVR was highly expressed in stomach, colon and hepatocellular carcinoma cell lines compared to healthy cells. This comprehensive pan-cancer analysis suggests that PVR is an oncogene highly expressed in tumor tissues and leads to poor prognosis. Therefore, PVR may be a new immune-dependent prognosis-predicting marker that may provide new directions for targeted oncotherapy.
This study aimed to investigate the effect and mechanism of silencing DNA methyltransferase 1 (DNMT1) on the killing effect of NK-92 on Jurkat cells. The DNMT1 expression in the bone marrow of 35 patients with acute lymphocyte leukemia (ALL) from January 2020 to December 2021 were measured. The si-RNA-DNMT1 was transfected into NK-92 cells and co-cultured with Jurkat cells. The killing effect on Jurkat cells was detected by lactate dehydrogenase (LDH) method, and the apoptosis and membrane NKG2D of Jurkat cells were detected by flow cytometry. The levels of IFN-γ were estimated by ELISA. The expressions of Syk, ZAP70, p-Syk, p-ZAP70, perforin and granzyme B in NK-92 cells were measured by Western blotting. The results showed that the level of DNMT1 was increased in patients with ALL compared to the control group (P<0.05), and it was of diagnostic value for ALL (AUC: 0.692, 95% CI: 0.533-0.851, P=0.033). The progression free survival of patients with high DNMT1 was significantly lower than those with low DNMT1 (P<0.05). NK-92 transfected with si-RNA-DNMT1 showed a higher killing rate and cell apoptosis compared to those of the si-NC group (P<0.05), along with the enhanced ability to secrete NKG2D and express perforin and granzyme B (P<0.05). The IFN-γ level of NK-92 transfected with si-RNA-DNMT1 was significantly higher than that in the si-NC group (P<0.05). The p-Syk and p-ZAP70 protein levels of si-RNA-DNMT1 transfected NK-92 were also significantly higher than those in the si-NC group (P<0.05). In conclusion, DNMT1 expression increases in ALL and silencing DNMT1 promotes the killing ability of NK-92 cells on Jurkat cells. The mechanism may be related to enhanced function of NK-92 cells and activation of Syk/ZAP70 pathway.
To investigate the effect of circular RNA 0000885 (circ_0000885) on theproliferation, apoptosis and migration of glioma cells, and further to explore its potential mechanism,circ_0000885 and miR-186 expression in normal brain tissues and glioma tissues was analyzed using qRT-PCR. Dual luciferase reporter experiment verified the targeting relationship between circ_0000885 and miR-186. Small interfering RNA negative control (si-NC), circ_0000885 small interfering RNA (si-circ_0000885), miRNA mimic negative control (miR-NC), miR-186 mimic, miRNA inhibitor negative control (anti-miR-NC), miR-186 inhibitor (anti-miR-186), and si-circ_0000885 +anti-miR-186 were transfected into glioma cell line LN229. The effects of circ_0000885 and miR-186 expression on cell viability, colony formation, apoptosis and migration of LN229 cells was evaluated by cell counting kit (CCK-8), plate cloning experiment, flow cytometry, and Transwell experiment, respectively. The transplanted tumor volume was detected by the nude mouse xenograft experiment. The results showed that compared to that of the normal brain tissue, circ_0000885 expression in glioma tissue was significantly increased (P<0.05), while miR-186 expression was significantly decreased (P<0.05). Interfering with the expression of circ_0000885 or overexpressing miR-186 significantly decreased the viability, colony formation number, and migration number of LN229 cells (P<0.05), increased cell apoptosis rate and miR-186 expression level (P<0.05), while inhibiting the expression of miR-186 had the opposite effect. Inhibition of miR-186 expression significantly attenuated the effects of JP2interfering circ_0000885 expression on LN229 cell viability, colony formation, migration, apoptosis and xenograft growth. This study suggests that interfering with circ_0000885 inhibits the tumor proliferation and migration, and induces cell apoptosis of glioma cells by targeting and up-regulating miR-186.
The study aims to explore the correlation between the dynamic changes in antigen-specific T cell function and the protection duration of Bacillus Calmette-Guérin (BCG) vaccine. Enzyme-linked immunospot assay (ELISPOT) and flow cytometry were used to assess the response level of peripheral antigen-specific CD4+ T cells in healthy volunteers in Shanghai. The results showed that the levels of IFN-γ increased with the age of individual (P<0.05). In population aged 30 and above, the percentage of IFN-γ-secreting antigen-specific CD4+ effector T cells (Teff) significantly increased (P<0.01). At the same time, the percentage of IFN-γ-producing CD4+ memory T cells (TM) in the population aged 18 and above significantly decreased (P<0.05). Both IL-17α+ CD4+ T cells and CD4+ Teff were significantly higher in adults than adolescents (P<0.01). Additionally, in the 18-29 age group, peripheral CD4+ naive T cells (TN) and CD4+ Teff primarily secreted IL-17α, whereas in the population over 30, the percentages of CD4+ TM secreting IFN-γ decreased (P<0.000 1), and the two subsets were in balance. These findings suggest that following BCG vaccination, the peripheral antigen-specific Th1, Th17 Teff, and TM response profiles change with individual age and may play a protective role against Mycobacterium tuberculosis (Mtb) infection. Therefore, the design of specific tuberculosis subunit vaccines to enhance the protective long-term TM response may be critical for tuberculosis prevention and control.
The aim of this study was to investigate the effect of suppressor of cytokine signaling 3 (SOCS3) on the high glucose(HG)-induced inflammatory factors expression in rat glomerular mesangial cell (RMC) and the related mechanism. For this purpose, RMCs were divided into six groups: normal control (NC) group, osmotic control (OSM) group, HG group, HG+TAK-242 (TLR4 inhibitor) group, HG+sh-SOCS3 group, and HG+sh-SOCS3+TAK-242 group. Cell viability was detected by CCK-8 assay and cell apoptosis was detected by FACS. The levels of inflammatory factors TNF-α, IL-1β, IL-6, and COX2 in cell culture supernatant were detected by ELISA. The mRNA expressions of TLR4, NF-κB p65, and IκB-α in RMC were detected by qPCR. The protein expressions of TLR4, NF-κB p65, p-p65, IκB-α, and p-IκB-α were detected by western blotting. The results showed that compared to those of NC group, the cell survival rate of the HG group was significantly decreased (P<0.01), while the cell apoptosis rate, the levels of TNF-α, IL-1β, IL-6 and COX2 in cell culture supernatant, the mRNA expression of TLR4, p65 and IκB-α and the protein expression of TLR4、p-p65 and p-IκB-α were significantly increased (all with P<0.01). Compared to those of HG group, the cell survival rates of the HG+TAK-242 group and the HG+sh-SOCS3 group were significantly increased (both P<0.05) while the apoptosis rate, the levels of TNF-α, IL-1β, IL-6 and COX2 in the cell culture supernatant, the mRNA expression of TLR4, p65, and IκB-α, and the protein expression of TLR4, p-p65, and p-IκB-α were significantly decreased (all with P<0.05). The above changes were more significant in the HG+sh-SOCS3+TAK-242 group than the HG+TAK-242 group (all with P<0.05). Taken together, SOCS3 up-regulates the expression of inflammatory factors in RMCs cultured with HG by activating the TLR4/NF-κB signaling pathway, thus aggravates the inflammatory responses.
This study aims to explore the effects and regulatory mechanism of parthenolide (PTL) on LPS-induced acute lung injury (ALI). C57BL/6 mice were used to establish the ALI model by a single intratracheal administration of LPS (4 mg/kg). For in vitro LPS-induced cell injury, MLE-12 cells were treated with 1 μg/mL LPS. Mice were randomly divided into four groups: control group, LPS group, LPS+5 mg/kg PTL doses group, and LPS+10 mg/kg PTL doses group, with 10 mice in each group. H-E staining was used to examine the pathological changes of lung tissue. Lung tissues were collected and the ratio of wet weight(W)to dry weight (D) was measured. IL-1β, IL-6, and TNF-α content in alveolar lavage fluid and cells was measured by ELISA. The levels of miR-141-3p and programmed cell death 4(PDCD4)were measured by qRT-PCR and Western blotting, respectively. Cell viability and apoptosis were determined by CCK-8 method and FACS, respectively. The results showed that compared to those of the control group, the lung tissue W/D ratio, TNF-α, IL-1β, IL-6, and PDCD4 expression levels were significantly increased (P<0.05). Alveolar wall thickening, diffuse pulmonary interstitial hemorrhage, and inflammatory infiltration were increased and the pathological score of lung tissue was also increased (P<0.05), while the expression of miR-141-3p was decreased in the LPS group (P<0.05). Compared to those of the LPS group, the W/D ratio, TNF-α, IL-1β, IL-6, and PDCD4 levels were decreased (P<0.05), alveolar wall thickening was alleviated, diffuse pulmonary interstitial hemorrhage and inflammatory infiltration were reduced, pathological scores of lung tissue were decreased (P<0.05), and the expression of miR-141-3p was increased in LPS+5 mg/kg PTL doses group and LPS+10 mg/kg PTL doses group (P<0.05) in a dose-dependent manner. Compared to those of the control group, the cell viability and miR-141-3p expression were decreased (P<0.05), while the apoptosis rate and the levels of TNF-α, IL-1β, IL-6, and PDCD4 were increased in the LPS group (P<0.05). The cell viability and miR-141-3p expression were increased (P<0.05), while the apoptosis rate and the levels of TNF-α, IL-1β, IL-6, and PDCD4 were decreased after 5 or 10 μmol/L doses of PTL treatment (P<0.05) in a dose-dependent manner. Furthermore, PDCD4 was shown to target miR-141-3p. The study suggests that PTL inhibits inflammation to alleviate LPS-induced ALI by upregulating the miR-141-3p/PDCD4 axis.
The purpose of this study was to investigate the expressions and clinical significance of the innate immune associated molecule nucleotide binding oligomerization domain-like receptor family caspase recruitment domain containing 3 (NLRC3) and the homeostatic basic transcription factor forkhead box protein 3 (FOXP3) in endometriosis (EMT) patients. Immunohistochemistry, western blotting and qRT-PCR were used to detect the expression levels of NLRC3 and FOXP3 in 22 cases of stage III and 18 cases of stage IV of ovarian endometriosis patients and 25 cases of healthy women to analyze the correlation between the expressions of NLRC3, FOXP3 and the clinical pathological characteristics of EMT. The results showed that compared to the normal endometrium group, the expression levels of NLRC3 were decreased in both the stage III and IV EMT groups, while expressions of FOXP3 in both groups increased. The expressions of NLRC3 and FOXP3 in stage III and IV EMT patients showed no significant difference. Analysis of pathological sections revealed that foci with higher CA125 levels correlated with lower positive rate of NLRC3 and higher number of infiltrated FOXP3+ cells (P<0.05). There was a negative correlation between the expressions of NLRC3 and numbers of infiltrated FOXP3+ cells (P<0.05). In addition, among EMT patients with different ages, lesion sizes and dysmenorrhea degrees, the expression levels of NLRC3 and FOXP3 showed no statistical significance (P>0.05). This study indicates that the pathogenesis of endometriosis is associated with immune imbalance in the abdominal microenvironment. Targeting the unbalanced immune microenvironment of EMT by interfering with the expression of NLRC3 and FOXP3 might be a potential treatment for EMT.
This study aims to investigate the influence of jaceosidin on inflammatory response in diabetic nephropathy (DN) rats. Male SD rats were randomly divided into control group, model group, low (10 mg/kg) and high (20 mg/kg) dose jaceosidin groups, positive control group (500 mg/kg metformin), and inhibitor group (20 mg/kg jaceosidin+5 mg/kg silent mating-type information regulation 2 homolog 1 [SIRT1] inhibitor EX-527), with 12 animals in each group. Except for the control group, all rats were fed with high-fat diet combined with chemical induction to establish the rat DN model. After the model was successfully established, animals were treated with drugs by gavage, once a day for four weeks. Kidney function changes were detected by microplate reader and the expressions of inflammatory factors were detected by ELISA. The pathological changes of the kidney were examined by H-E staining and the expressions of nephrin and podocin in renal tissues were detected by immunohistochemistry. The expressions of SIRT1/forkhead box protein O3(FoxO3) signaling pathway-related proteins in renal tissues were detected by Western blotting. The results showed that compared to the control group, the model group showed obvious interstitial inflammatory infiltration, glomerular hypertrophy, and vacuolar degeneration of renal tubular cells, impaired kidney functions, serum inflammatory factors and FoxO3 expression were significantly increased, while the nephrin, podocin, and phosphorylated SIRT1 (p-SIRT1)/SIRT1 expression levels were significantly decreased (P<0.05). Compared to that of the model group, the pathological injury of the renal tissues in the low-dose and high-dose jaceosidin groups and the positive control group was significantly improved, and kidney functions were restored, while serum inflammatory factors and FoxO3 expression were significantly decreased, while the expressions of nephrin, podocin, and p-SIRT1/SIRT1 were significantly increased (P<0.05). Adding SIRT1 inhibitor EX-527 attenuated the anti-inflammatory effect of jaceosidin. The study suggests that jaceosidin can alleviate inflammatory response in DN rats by regulating the SIRT1/FoxO3 signaling pathway.
This study aims to investigate the effect of silencing cyclic ribonucleic acid MET (circMET) on inhibiting the invasion and migration of human rectal cancer cell by targeting miR-30a-5p/integrin β3 (ITGβ3). Human rectal cancer cell line SW1463 were divided into si-NC group, si-circMET group, miR-NC group, miR-30a-5p group, si-circMET+anti-miR-NC group, and si-circMET+anti-miR-30a-5p group, with 6 replicates in each group. Transwell assays were used to detect cell invasion and migration. The expressions of circMET, miR-30a-5p, ITGβ3, matrix metalloproteinase 2 (MMP-2), and matrix metalloproteinase 9 (MMP-9) were determined by qRT-PCR and Western blotting. Dual luciferase reporter gene assays were used to verify the targeting of circMET to miR-30a-5p and miR-30a-5p to ITGβ3, respectively. The results showed that compared to those of the si-NC group, the number of invasive and migrating cells, the expression of circMET, and the mRNA and protein expressions of ITGβ3, MMP-2, and MMP-9 in the si-circMET group were decreased, whereas the expression of miR-30a-5p was increased (P<0.05). Compared to those of the miR-NC group, the number of invasive and migrating cells, the expression of circMET, and the mRNA and protein levels of ITGβ3, MMP-2, and MMP-9 in the miR-30a-5p group were decreased, while the expression of miR-30a-5p was increased (P<0.05). Compared to those of the si-circMET+anti-miR-NC group, the number of invasive and migrating cells, the expression of circMET, and the mRNA and protein levels of ITGβ3, MMP-2, and MMP-9 in the si-circMET+anti-miR-30a-5p group were increased, while the expression of miR-30a-5p was decreased (P<0.05). In addition, Dual luciferase reporter gene assays confirmed the targeted regulatory relationship between circMET and miR-30a-5p as well as miR-30a-5p and ITGβ3. In summary, silencing circMET can inhibit the invasion and migration of human rectal cancer cell line SW1463, which may be achieved by targeting miR-30a-5p to inhibit the expressions of ITGβ3, MMP-2, and MMP-9.
Protein kinase CK2 is a highly conserved and ubiquitous protein kinase which phosphorylates a variety of protein substrates, and is involved in the regulation of several signaling pathways. Abnormal CK2 expression can lead to dysregulation of various signaling pathways, which is closely related to tumorigenesis and progression. This review summarizes the composition, structure and regulatory role of CK2 in important tumor-related signaling pathways and provides foundation to further explore CK2-targeted therapeutic strategies in cancer.
B cells are the major component in the tumor microenvironment and play key roles in tumor immunity. Previous studies have suggested that B cells promote tumor progression via secreting immune-inhibitory cytokines or activating the complement system through B cell-secreted antibodies. However, recent studies have revealed an important role of B cells in anti-tumor immune responses. This review summarizes the multiple functions of B cells in tumor immunity and discusses the underlying mechanisms and the effects on patients prognosis.
Sex hormones are steroid hormones secreted by gonads and adrenal glands or converted from other substances. Sjogren's syndrome (SS) is a chronic progressive systemic autoimmune disease mediated by lymphocytes, mainly affecting exocrine glands. Due to the complex etiology, its pathogenesis has not been fully elucidated. The fact that the incidence of SS is higher in women than in men suggests a relationship between sex hormones and the development of SS. This review discusses the mechanism and influence of estrogen, androgen, and prolactin on SS to provide reference to understand the pathogenesis of SS and explore the therapeutic strategies.