Background: Cutaneous melanoma is a highly malignant skin tumor, and most patients have a poor prognosis. In recent years, immunotherapy has assumed an important role in the treatment of advanced cutaneous melanoma, but only a small percentage of patients benefit from immunotherapy. A growing number of studies have demonstrated that the prognosis of patients with cutaneous melanoma is closely related to long non-coding RNA and the tumor immune microenvironment. Methods: We downloaded RNA expression data and immune-related gene lists of cutaneous melanoma patients separately from The Cancer Genome Atlas database and ImmPort website and identified immune-related lncRNAs by co-expression analysis. The prognostic model was constructed by applying least absolute shrinkage and selection operator regression, and all patients were classified into high-and low-risk groups according to the risk score of the model. We evaluated the differences between the two groups in terms of survival outcomes, immune infiltration, pathway enrichment, chemotherapeutic drug sensitivity and immune checkpoint gene expression to verify the impact of lncRNA signature on clinical prognosis and immunotherapy efficacy. Results: By correlation analysis and LASSO regression analysis, we constructed an immune-related lncRNA prognostic model based on five lncRNA: HLA-DQB1-AS1, MIR205HG, RP11-643G5.6, USP30-AS1 and RP11-415F23.4. Based on this model, we plotted Kaplan-Meier survival curves and time-dependent ROC curves and analyzed its ability as an independent prognostic factor for cutaneous melanoma in combination with clinicopathological features. The results showed that these lncRNA signature was an independent prognostic factor of cutaneous melanoma with favorable prognostic ability. Our results also show a higher degree of immune infiltration, higher expression of immune checkpoint-associated genes, and better outcome of immunotherapy in the low-risk group of the lncRNA signature. Conclusion:The 5 immune-related lncRNA signatures constructed in our study can predict the prognosis of cutaneous melanoma and contribute to the selection of immunotherapy.
Introduction. In our previous study, it has been confirmed that formaldehyde (FA) not only inhibits the proliferative activity, but also causes DNA-protein crosslinks (DPCs) formation in bone marrow mesenchymal stem cells (BMSCs). The purpose of this study was to detect the protective effect of astragalus polysaccharide (APS) against the cytotoxicity and genotoxicity of BMSCs exposed to FA, and to explore potential molecular mechanisms of APS activity.Material and methods. Human BMSCs were cultured in vitro and randomly divided into control cells (Ctrl group), FA-treated cells (FA group, 120 μmol/L), and cells incubated with FA and increasing concentrations (40, 100, or 400 μg/mL) of APS (FA + APS groups). Cytotoxicity was measured by MTT assay. DNA strand breakage, DNA-protein crosslinks (DPCs), and micronucleus formation were respectively detected by comet assay, KCl-SDS precipitation assay, and micronucleus assay. The mRNA and protein expression level of xeroderma pigmentosum group A (XPA),xeroderma pigmentosum group C (XPC), excision repair cross-complementation group 1 (ERCC1), replication protein A1 (RPA1), and replication protein A2 (RPA2) were all detected by qRT-PCR and Western Blot.Results. Compared with the FA group, the cytotoxicity, DNA strand breakage, DPCs, and micronucleus levels were decreased significantly in FA + APS groups (P < 0.01). Meanwhile, the mRNA and protein expression of XPA, XPC, ERCC1, RPA1, and RPA2 were up-regulated significantly in the FA + APS groups (P < 0.05) with the most prominent effect of the 100 μg/mL APS. Conclusions.Our results suggest that APS can protect the cytotoxicity and genotoxicity of human BMSCs induced by FA. The mechanism may be associated with up-regulated expression of XPA, XPC, ERCC1, RPA1, and RPA2 in the nucleotide excision repair (NER) pathway which promotes DNA damage repair.
In this study, we assessed the toxic effects of formaldehyde (FA) on mouse bone marrow mesenchymal stem cells (BMMSCs). Cytotoxicity was measured by using MTT assay. DNA strand breakage was detected by standard alkaline comet assay and comet assay modified with proteinase K (PK). DNA -protein crosslinks (DPCs) were detected by KCl-SDS precipitation assay. We found that FA at a concentration from 75 to 200 mM inhibited cell survival and induced DPCs over 125 mM. The PK-modified comet assay showed that FA-induced DNA strand breakage was increased in a dose-dependent manner from 75 to 200 mM. On the other hand, standard alkaline comet assay showed that DNA strand breakage was decreased with FA concentration over 125 mM. We confirmed by using Pearson correlation that there was a negative linear correlation between DPCs and survival rate (r 5 20.987, P < 0.01) and positive linear relationships between DPCs and (i) sister chromatid exchange and (ii) micronucleus (r 5 0.995, P < 0.01; r 5 0.968, P < 0.01). DNA damage RT 2 profiler polymerase chain reaction array was used to investigate the changes in the expression of damage response genes. Xpa and Xpc of the nucleotide excision repair pathway and Brca2, Rad51, and Xrcc2 of the homologous recombination pathway were all up-regulated in both 75 and 125 mM FA. However, the same genes were down-regulated with 175 mM FA. The expressions of Chek1 and Hus1, which are involved in cell cycle regulation, were altered in the same manner with 75, 125, and 175 mM FA. These results indicated that Xpa, Xpc, Brca2, Rad51, Xrcc2, Chek1, and Hus1 were essential for the BM-MSCs to counteract the effects of FA.
Introduction Host immunity plays a vital role in tumorigenesis, including in tumor invasion and metastasis. However, the precise underlying mechanism remains to be explored. The enzyme 15-PGDH, which plays a key role in prostaglandin degradation, is a critical inflammatory mediator in gastric cancer (GC) tumorigenesis. Materials and Methods Immunohistochemistry was performed to determine 15-PGDH expression in GC and the corresponding adjacent non-neoplastic tissues (n=92). Results The expression of 15-PGDH in GC tissues was significantly lower than that in paracancerous tissues ( P <0.001) and found to correspond inversely with GC differentiation ( P= 0.043) and lymph node metastasis ( P= 0.046). In contrast, FOXP3 expression was increased in poorly differentiated GC tissues ( P= 0.001). Kaplan–Meier analysis revealed that GC patients with low expression of 15-PGDH (Log rank test, P= 0.007) and high expression of FOXP3 (Log rank test, P= 0.009) had shorter overall survival (OS) than those with high 15-PGDH and low FOXP3 expression. OS was also correlated with pathological tumor-node-metastasis stage (Log rank test, P= 0.014). Furthermore, using Cox proportional hazard regression, 15-PGDH expression [hazard ratio (HR): 0.605 (0.440–0.833); P= 0.002] was identified as an independent factor for OS. Conclusion Our data suggest that 15-PGDH may contribute to anti-tumor immunity by regulating FOXP3 + Treg cells. The findings are useful for the identification of therapeutic targets for the management of GC.
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