RESUMEN
NCAPG2 has been reported to be associated with tumorigenesis in various types of cancer. However, data on the pathological mechanisms of NCAPG2 in pan-cancers remain lacking. Therefore, the study aimed to comprehensively elucidate the immune characteristics and prognostic of NCAPG2 in tumor microenvironments (TMEs). NCAPG2 was overexpressed in many tumor types, and this overexpression is related to poor clinical stages and prognosis. Furthermore, elevated NCAPG2 expression was strongly associated with TMEs. Moreover, gene set enrichment analysis was performed to investigate the pathways associated with NCAPG2, revealing its involvement in several immune-related pathways. Finally, we predicted the immunotherapeutic value and sensitivity to drugs based on NCAPG2 expression. Our study revealed that NCAPG2 could be utilized as an immune-related biomarker for both diagnosing and predicting the prognosis of multiple cancer types. Therefore, our findings suggest that targeting NCAPG2 in TMEs could be a promising therapeutic strategy.
RESUMEN
Group A streptococcus (GAS), a common pathogen, is able to escape host immune attack and thus survive for longer periods of time. One of the mechanisms used by GAS is the upregulated expression of immunosuppressive molecules, which leads to a reduction in the production of inflammatory cytokines in immune cells. In the present study, we found that macrophages produced lower levels of proinflammatory cytokines (IL-1ß, TNF-α, IL-6) when challenged with GAS than they did when challenged with Escherichia coli (E. coli). Simultaneously, in a mouse model of lung infection, GAS appeared to induce a weaker inflammatory response compared to E. coli. Our data also indicated that the expression of the A20 transcriptional regulator was higher in GAS-infected macrophages than that in macrophages infected with E. coli, and that high expression of A20 correlated with a reduction in the production of TRAF6. SiRNA targeting of A20 led to the increased production of TRAF6, IL-1ß, TNF-α, and IL-6, suggesting that A20 inhibits synthesis of these key proinflammatory cytokines. We also investigated the pathway underlying A20 production and found that the synthesis of A20 depends on My88, and to a lower extent on TNFR1. Finally, we showed a significant reduction in the expression of A20 in macrophages stimulated by M protein-mutant GAS, however, a speB-GAS mutant, which is unable to degrade M protein, induced a greater level of A20 production than wild type GAS. Collectively, our data suggested that M protein of GAS was responsible for inducing A20 expression in macrophages, which in turn down-regulates the inflammatory cytokine response in order to facilitate GAS in evading immune surveillance and thus prolong survival in the host.
Asunto(s)
Antígenos Bacterianos/metabolismo , Proteínas de la Membrana Bacteriana Externa/metabolismo , Proteínas Portadoras/metabolismo , Pulmón/inmunología , Macrófagos/inmunología , Neumonía Neumocócica/metabolismo , Streptococcus pyogenes/inmunología , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/metabolismo , Animales , Antígenos Bacterianos/genética , Proteínas de la Membrana Bacteriana Externa/genética , Proteínas Portadoras/genética , Modelos Animales de Enfermedad , Escherichia coli/genética , Escherichia coli/inmunología , Femenino , Humanos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Pulmón/microbiología , Pulmón/patología , Macrófagos/microbiología , Ratones , Ratones Endogámicos C57BL , Neumonía Neumocócica/microbiología , Células RAW 264.7 , Streptococcus pyogenes/genética , Proteína 3 Inducida por el Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Some microbial pathogens utilize human complement regulatory proteins, such as factor H (FH) and factor H-like protein 1 (FHL-1), for immune evasion. FbaA is an FHL-1 and FH binding protein expressed on the surface of group A streptococcus (GAS), a common agent of pharyngeal, skin, and soft tissue infections. In this study, we prepared monoclonal antibodies (MAbs) against FbaA, assayed them for specificity, and located their binding domains in FbaA. We found an MAb called FbaA MAb2, which demonstrated the highest affinity to GAS among all of the MAbs. Based on the binding with component peptides, the detected epitope, which was specific for FbaA MAb2, was the amino acid residues 95 to 118 of FbaA; on the other hand, it did not bind with the truncated protein of the internally deleted residues of the segment from 95 to 118 of FbaA. Furthermore, the predominant amino acids specific for FbaA MAb2 screened by phage display epitope library were I, T, P, D, and L, corresponding to the amino acid residues 101, 103, 105, 106, and 110 of FbaA, respectively. The binding location of FbaA with FH and FHL-1 was a 16-amino-acid region corresponding to amino acid residues 97 to 112 of FbaA, which overlapped the FbaA MAb2 binding domain, as confirmed by competitive inhibition enzyme-linked immunosorbent assay and immunofluorescence microscopy. Based on the results of the invasion assay, FbaA MAb2 can inhibit the binding of FH to GAS.
Asunto(s)
Adhesinas Bacterianas/inmunología , Anticuerpos Antibacterianos/inmunología , Anticuerpos Monoclonales/inmunología , Proteínas Portadoras/inmunología , Factor H de Complemento/antagonistas & inhibidores , Streptococcus pyogenes/inmunología , Animales , Sitios de Unión , Factor H de Complemento/metabolismo , Mapeo Epitopo , Femenino , Humanos , Ratones , Ratones Endogámicos BALB C , Unión Proteica , Mapeo de Interacción de ProteínasRESUMEN
BACKGROUND: To study the correlation among the number of tumor-infiltrating dendritic cells (TIDC) in cancer tissues and biological behavior and prognosis in lung cancer patients. METHODS: S-100 protein expression level was determined in 39 patients with lung cancer by immunohistochemistry technique. The number of S-100 + TIDC and DNA ploidy were measured by means of flow cytometry. RESULTS: The rate of positive S-100 protein expression was 100% in 39 patients, S-100 + cells showed typical morphology of dendritic cells. The percentage of S-100 +TIDC in patients with heteroploid (21.81%±8.18%) was significantly higher than those with diploid (16.03%±4.75%) (P=0.006). There was no statistical difference between lymph node metastasis group (20.43%±7.74%) and no lymph node metastasis group ( 19.41% ±7.76%), between tumor size greater than 3cm group ( 20.90% ±8.65%) and less than 3cm group ( 19.70% ±7.61%), between non-small cell lung cancer group (19.48%±7.98%) and small cell lung cancer group (21.74%±6.17%). No correlation was found between survival time ( 1 year , 1-3 years, greater than 3 years, respectively) and percentage of S-100 +TIDC (21.96%±8.05%, 19.47%±6.18%, 19.14%±8.76%, respectively). CONCLUSIONS: The number of TIDC should not be chosen as an independent prognostic criterion in human lung cancer.