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Background: The prevalence of breast cancer (BRCA), which is common among women, is on the rise. This study applied network pharmacology to explore the potential mechanism of action of herba sarcandrae in BRCA and construct a prognostic signature composed of inflammation-related genes. Methods: The active ingredients of herba sarcandrae were screened using the SymMap, TCMID, and TCMSP platforms, and the molecular targets were determined in the UniProt database. The "drug-active compound-potential target" network was established with Cytoscape 3.7.2. The molecular targets were subjected to disease ontology, gene ontology (GO), and Kyoto Encyclopedia of Genes (KEGG) analyses. AutoDock software was used for molecular docking. Differentially expressed genes (DEGs) related to inflammation were obtained from the BRCA Cancer Genome Atlas (TCGA) database. In the training cohort, the univariate Cox regression model was applied to preliminarily screen prognostic genes. A multigene signature was built by the least absolute shrinkage and selection operator (LASSO) regression model, followed by validation through KaplanâMeier, Cox, and receiver operating characteristic (ROC) analyses. Results: Forty-one active compounds were identified, and 265 therapeutic targets for herba sarcandrae were predicted. GO enrichment results revealed significant enrichment of biological processes, such as response to xenobiotic stimuli, response to nutrient levels, and response to lipopolysaccharide. KEGG analysis revealed significant enrichment of pathways such as AGE-RAGE and chemical carcinogenesis receptor activation signaling pathways. In addition, the herbs Marc-Andre and rutin were shown to mediate BRCA cell proliferation and apoptosis via the interferon regulatory factor 1 (IRF1)/signal transducer and activator of transcription 3 (STAT3)/programmed death-ligand 1 (PD-L1) pathway. Sixteen inflammatory signatures, including BST2, GPR132, IL12B, IL18, IL1R1, IL2RB, IRF1, and others, were constructed, and the risk score was found to be a strong independent prognostic factor for overall survival in BRCA patients. The 16-inflammation signature was associated with several clinical features (age, clinical stage, T, and N classifications) and could reflect immune cell infiltration in tumor microenvironments with different immune cells. Conclusions: Herba sarcandrae and rutin were shown to mediate BRCA cell proliferation and apoptosis via the IRF1/STAT3/PD-L1 pathway, and the 16-member inflammatory signature might be a novel biomarker for predicting BRCA patient prognosis, providing more accurate guidance for clinical treatment prognosis evaluation and having important reference value for individualized treatment selection.
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BACKGROUND: Colorectal cancer (CRC) is one of the most usual malignant tumors, and its incidence continues to rise. Our purpose was to explore the function and potential regulatory mechanisms of SALL1, a differentially methylated gene in CRC, in vivo and in vitro. METHODS: Firstly, methylation differential gene SALL1 in CRC was screened and validated. SALL1 overexpression plasmids or SALL1 siRNAs were transfected in HT-29 and SW480 cells. Moreover, 10 µM T-5224 was added in SALL1-overexpressed CRC cells. CCK-8, flow cytometry and transwell assays were utilized to assess cell proliferation, cycle, migration, and invasion, respectively. Then CRC organoids were cultured. Next, HT-29 and SW480 cells transfected with SALL1 overexpression lentivirus were analyzed by transcriptome sequencing. Finally, in vivo tumorigenesis was used to analyze the effect of SALL1 overexpression on subcutaneous tumorigenesis in nude mice. RESULTS: The methylation level of CpG island in SALL1 promoter was increased in CRC tissues and could distinguish tumor tissues. Overexpression of SALL1 accelerated proliferation, migration and invasion of HT-29 and SW480 cells, and silencing of SALL1 attenuated proliferation, migration and invasion of HT-29 and SW480 cells. Through analysis and validation, we found that overexpression of SALL1 also could upregulate p-p65 and p-JUN expressions. Besides, c-Fos/activator protein (AP)- 1 inhibitor (T-5224) could reverse the induction of CRC progression by SALL1 overexpression. In vivo, we also proved that overexpression of SALL1 significantly increased tumor volume, tumor weight, and p-JUN expression. CONCLUSIONS: SALL1 could promote the proliferation, migration, and invasion of CRC cells and activate phosphorylation of p65 and JUN.
