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.
Background Gastric cancer has a high incidence and mortality rate. Angiogenesis is necessary for tumor infiltration and metastasis and affects patient prognosis. YKL-39 has monocyte chemotactic activity and pro-angiogenic activity in some tumors. In this study, we investigated the relationship between YKL-39 and tumor-associated macrophages and microangiogenesis in gastric cancer to determine its potential as a prognostic biomarker. Materials and methods A total of 119 patients with gastric cancer who had undergone gastrectomy at the 940th Hospital of the Joint Security Force between 2014 and 2018 were included in this study. We assayed the protein expression of YKL-39, CD68, and CD34 by immunohistochemistry in tissues of 119 patients with gastric cancer, as well as the intracellular expression of YKL-39 and CD68 by immunofluorescence. Data were analyzed with SPSS Statistics 25.0 to explore the impact of expression of YKL-39, CD68, and CD34 in gastric cancer patients and the relationship among them. Results Our results show that YKL-39 was expressed in both the nucleus and cytoplasm of gastric cancer cells and tumor mesenchyme. YKL-39 protein expression was associated with the depth of tumor infiltration, lymph node metastasis, and TNM stage; CD68 protein expression was associated with lymph node metastasis and TNM stage; CD34 protein expression was not associated with clinicopathological characteristics. Expression of YKL-39 was positively correlated with CD68 and CD34 (p < 0.001), and high expression of YKL-39 was associated with poor prognosis (p < 0.05). Conclusion In gastric cancer, YKL-39 expression is positively correlated with the degree of tumor-associated macrophage infiltration and angiogenesis, and is a potential prognostic marker for gastric cancer.
Background. Gastric adenocarcinoma (GAD) is one of the most common tumors in the world and the prognosis is still very poor. Objective. We sought to identify reliable prognostic biomarkers for the progression of GAD and the sensitivity to drug therapy. Method. The RNA sequencing data of GAD was downloaded from the Cancer Genome Atlas (TCGA) database and used for analysis. Differentially expressed, immune-related lncRNA (DEIRlncRNA) was characterized by differential analysis and correlation analysis. Univariate Cox regression analysis was used to identify DEIRlncRNA associated with prognosis. Least absolute shrinkage and selection operator (LASSO) regression analysis allowed us to determine a signature composed of eight IRlncRNAs. Based on this signature, we further performed gene set enrichment analysis (GSEA) and somatic mutation analysis to evaluate the ability of this signature to predict prognosis. Results. In total, 72 immune-related lncRNAs (DEIRlncRNAs) with prognostic value were identified. These lncRNAs were used to construct a model containing eight immune-related lncRNAs (8-IRlncRNAs). Based on this risk model, we divided GAD patients into high-risk and low-risk groups. The analysis showed that the prognosis of the two groups was different and that the high-risk group had worse overall survival (OS). Immune cell infiltration analysis showed that the proportion of memory B cells increased in the high-risk group while the proportion of macrophages M1, T cells, CD4 memory-activated cells, and T cell follicular helpers decreased. GSEA results showed that 8-IRlncRNA was significantly enriched in tumorigenesis pathways such as myc. The results of somatic mutation analysis showed that the CDH1 gene was significantly mutated in the high-risk group. Conclusion. A prognostic signature of 8-IRlncRNAs in GAD was established and this signature was able to predict the prognosis of GAD patients.
Background. Gastric cancer (GC) is the fifth most common malignant tumor and the third leading cause of cancer-related deaths. Because GC has the characteristics of high heterogeneity, unclear mechanism, limited treatment methods, and low five-year survival rate, it is necessary to find the prognostic biomarkers of GC and explore the mechanism of GC. Methods. We first identified differentially expressed genes (DEGs) between gastric cancer and normal gastric cells through expression analysis. A protein-protein interaction (PPI) network was constructed to find tightly connected modules. We performed survival analysis on the DEGs in the modules to identify genes with prognostic significance. Gene set enrichment analysis (GSEA) was used to identify gene enrichment pathways. Finally, we used our own collected clinical samples of 119 gastric adenocarcinoma (STAD) tissues and 40 normal gastric tissues to perform immunohistochemical (IHC) staining to verify the differential expression of COL8A1 in STAD tissues and normal gastric tissues and its correlation with epithelial-mesenchymal transition- (EMT-) related factors. Results. We identified 356 DEGs through differential expression analysis. Through PPI analysis and survival analysis, we determined that the collagen type VII alpha-1 chain (COL8A1) gene has prognostic significance. GSEA analysis showed that COL8A1 was significantly enriched in the EMT. IHC results showed that COL8A1 was upregulated in STAD tissues and could be used as an independent prognostic factor and was related to EMT. Conclusion. This study shows that COL8A1 is related to the prognosis of GC patients and might affect the progress of GC through the EMT pathway. Therefore, COL8A1 may be a biomarker for predicting the prognosis of GC.
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