The accumulation of adenosine in the tumor microenvironment is associated with tumor progression in many cancers. However, whether adenosine is involved in gastric cancer (GC) metastasis and progression, and the underlying molecular mechanism, is largely unclear. In this study, we find that GC tissues and cell lines had higher A2aR levels than nontumor gastric tissues and cell lines. A2aR expression correlated positively with TNMstage, and associated with poor outcomes. Adenosine enhanced the expression of the stemness and epithelial–mesenchymal transition-associated genes by binding to A2aR. A2aR expression on GC cells promoted metastasis in vivo. The PI3K-AKT-mTOR signaling pathway was involved in adenosine-stimulated GC cell migration and invasion. Our results indicate that adenosine promotes GC cell invasion and metastasis by interacting with A2aR to enhance PI3K–AKT–mTOR pathway signaling.
Background. Programmed cell death ligand 1 (PD-L1) is a key inhibitor to the immune response by binding to the specific receptor PD-1. Adenosine receptor 2 (A2aR) can play an immunosuppressive role in tumor microenvironment by binding to its ligand adenosine (ADO). However, the expression of these two markers has been rarely studied in colorectal cancer simultaneously. Materials and Methods. We, respectively, collected tumor and adjacent nontumor tissue specimens of 204 patients with colorectal cancer. The expressions of PD-L1 and A2aR were detected by immunohistochemistry. The association among their expressions with clinicopathological characteristics and prognostic parameters were analyzed as well. Results. The expressions of PD-L1 and A2aR in tumor tissues were both higher than those in matched adjacent nontumor tissues. PD-L1 expression was significantly correlated with lymph node metastasis and tumor TNM stage. A2aR expression was significantly correlated with tumor size, depth of tumor invasion, and TNM stage. Univariate analysis showed that the high expressions of PD-L1 and A2aR were inversely correlated with the overall survival, respectively. Multivariate analysis further confirmed that both of them were independent prognostic markers for patients. Conclusion. The results of this study suggested that the high expressions of PD-L1 and A2aR were associated with a poor prognosis of colorectal cancer. Coinhibition of these two proteins may be a new breakthrough in the treatment of this disease.
Colon cancer is a common malignant tumor in the digestive tract, with relatively high rates of morbidity and mortality. It is the third most common type of tumor in the world. The effective treatment of advanced colon cancer is limited, so it is particularly important to study the new pathogenesis of colon cancer. Ferroptosis is a nonapoptotic regulated cell death mode driven by iron-dependent lipid peroxidation, a process which has been discovered in recent years. Autophagy involves lysosomal degradation pathways that promote or prevent cell death. High levels of autophagy are associated with ferroptosis, but a clear association has not yet been made between ferroptosis and autophagy in colon cancer. Through the analysis of transcriptome expression profiling data in colon cancer, we obtained the common upregulated genes and downregulated genes by recording the intersection of the differentially expressed genes in each dataset. Solute Carrier Family 2 Member 1 (SLC2A1) was identified by combining autophagy genes obtained from GeneCards and ferroptosis genes obtained from FerrDb. In order to explore the clinical significance and prognostic value of SLC2A1, we utilized massive databases to conduct an in-depth exploration of the methylation of SLC2A1, and we also investigated the differences in immune infiltration between tumor and normal tissues. We found that there are abundant methylation sites in SLC2A1 and that the methylation of SLC2A1 is correlated with the immunosuppression of tumor tissue. We discovered that during the induction of environmental factors, the transcription and methylation levels of SLC2A1 were greatly increased, autophagy and ferroptosis were inhibited, and the immune system was defective, resulting in a poor prognosis for patients. These results suggest that the autophagy and ferroptosis-related gene SLC2A1 is involved in the tumor immune regulation of colon cancer, and SLC2A1 may become a new therapeutic target for colon cancer.
Background: ZEB2 is a protein-coding gene that is differentially expressed in tumors and can regulate the growth of tumor cells. This study investigated the specific regulatory mechanism of ZEB2 in COAD, a common cancer with high rates of morbidity and mortality.Methods: Multi-omics panoramic display of expression and function of ZEB2 in colon cancer. R software was used to study the expression of ZEB2 in 33 types of cancer. Furthermore, RT-PCR was used to detect the expression of ZEB2 in colon cancers and para-cancer tissues, as well as in colon cancer cells and normal cells. The ssGSEA was then used to explore the relationship between ZEB2 and immune cells, with UALCAN, EWAS and MEXPRESS applied to explore the methylation of ZEB2. The relationship between immunomodulators and chemokines (or receptors) based on expression data, copy number data, methylation data, and mutation data of ZEB2 was investigated using TISIDB. Finally, a protein interaction network of ZEB2 was constructed, and GO and KEGG analyses were performed on the differentially expressed genes.Results: ZEB2 is downregulated in most cancers, including COAD. The infiltration of the immune cells NK CD56 and Th17 cells was negatively correlated with ZEB2 expression, while the other 22 cells were positively correlated with ZEB2 expression. The DNA methylation of ZEB2 and the methylation of the ZEB2 protein on the EWAS website increased significantly. Analysis of the methylation levels and ZEB2 expression revealed that only the DNA methylation level and the expression of ZEB2 were significantly negatively correlated. The tumor-infiltrating lymphocytes positively correlated with the expression of ZEB2 but negatively correlated with the methylation of ZEB2. The same trend was observed for immunomodulators, chemokines, and receptors. The network showed that the protein performed certain biological functions, thereby affecting disease symptoms.Conclusion: These findings provide evidence that ZEB2-based therapy may represent a powerful treatment strategy for COAD.
Colorectal cancer (CRC) ranks as the most common gastrointestinal solid carcinoma globally. Substantial evidence has established a pivotal role for circular RNAs (circRNAs) in CRC progression. In this study, differentially expressed cir-cRNAs were analyzed based on a public dataset (GSE126094) and elevated expression of circCASK (hsa_circ_0001917) was validated in CRC. Moreover, increased circCASK was also confirmed in CRC patients. Functionally, circCASK knockdown led to a significant decrease in CRC cell growth and attenuated cell migration and invasion. Similarly, circCASK knockdown markedly attenuated tumor growth in vivo. Mechanistically, circCASK sponged miR-1271-5p and enhanced sine oculis homeobox homolog 1 (SIX1) expression. More importantly, both SIX1 overexpression and miR-1271-5p knockdown could reverse the cellular behavior inhibition induced by circCASK knockdown. Furthermore, SIX1 was most strongly and positively linked with Wnt/β-catenin signaling pathways, cir-cCASK triggered Wnt/β-catenin signaling through the miR-1271-5p/SIX1 axis, and FOXC2 transcriptionally induced circCASK expression. In conclusion, cir-cCASK induced by FOXC2 accelerated CRC progression through the miR-1271-5p/SIX1 axis, thus providing an interesting insight into CRC tumorigenesis.
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