Identification of a novel cancer-associated fibroblasts gene signature based on bioinformatics analysis to predict prognosis and therapeutic responses in breast cancer.

Cancer-associated fibroblasts (CAFs) provide suitable conditions for growth of tumor cell and facilitate tumor progression. Hence, we aimed to identify a CAFs-related gene signature associated with the prognosis of patients with breast cancer (BRCA). We downloaded datasets from Gene Expression Omnibus (GEO) and confirmed the correlation between CAFs infiltration scores and prognosis. By performing weighted gene co-expression network analysis (WGCNA) and Lasso Cox regression analysis, we constructed a four-gene (COL5A3, FN1, POSTN, and RARRES2) prognostic CAFs signature model. Based on the median risk score of CAFs, patients with BRCA were divided into high- and low-risk groups. Compared with low-risk group, patients in high-risk group exhibited a poor prognosis and limited response to immunotherapy. Furthermore, patients with high CAFs risk scores were found to have a detrimental prognosis due to the induction of immunosuppressive cell infiltration, resulting in an immunosuppressive tumor microenvironment. Importantly, we found that CAFs overexpressing FN1 and POSTN significantly promoted the wound healing and invasion ability of tumor cells in vitro validation. Taking together, we identified a four-gene prognostic CAFs signature, which was proven to be a reliable indicator for prognosis and therapeutic efficacy in patients with BRCA. This study provided evidence for novel CAFs-based stromal therapy.

Melatonin blunts the tumor-promoting effect of cancer-associated fibroblasts by reducing IL-8 expression and reversing epithelial-mesenchymal transition.

BACKGROUND: Most studies on melatonin have focused on tumor cells but have ignored the tumor microenvironment (TME), especially one of its important components, the cancer-associated fibroblasts (CAFs). Therefore, we attempted to explore the role of melatonin in TME. METHODS: We investigated the regulatory role of melatonin in the tumor-promoting effect of CAFs and its underlying mechanism by using cell and animal models. RESULTS: CAFs promoted tumor progression, but melatonin weakened the tumor-promoting effect of CAFs. Compared with tumor cells, IL-8 was mainly expressed in CAFs. CAFs-overexpressing IL-8 induced the epithelial-mesenchymal transition (EMT) of tumor cells, and a positive crosstalk was observed between CAFs and tumor cells undergoing EMT, thereby further promoting the IL-8 expression. Melatonin suppressed this crosstalk by inhibiting the NF-κB pathway, thereby impeding the IL-8 expression from CAFs. Importantly, melatonin reversed CAFs-derived IL-8-mediated EMT by inhibiting the AKT pathway. Melatonin was found to directly and indirectly inhibit tumor progression. CONCLUSION: Our research reveals the potential action mechanism of melatonin in regulating the CAF-tumor cell interaction and suggests the potential of melatonin as an adjuvant of tumor therapy.

Expression of the prognostic marker IL-8 correlates with the immune signature and epithelial-mesenchymal transition in breast cancer.

BACKGROUND: IL-8 has been implicated in the malignant progression of various types of cancers; however, the precise molecular mechanisms associated with IL-8 in breast cancer (BRCA) are unclear. METHODS: We analyzed the clinical signature and immune characteristics of BRCA patients and its correlation with IL-8 expression using The Cancer Genome Atlas (TCGA) datasets. The role of IL-8 in epithelial-mesenchymal transition (EMT) was verified through Western blotting, Cell Counting Kit-8 assay, and wound healing assays, as well as cell invasion experiments. RESULTS: Through a comprehensive bioinformatics study, we determined that high IL-8 expression was associated with poor prognosis. Enrichment analysis revealed that high IL-8 expression was enriched in immune-related processes and cancer-related signaling pathways. In addition, IL-8 was associated with most of the immune-infiltrating cells, and high IL-8 expression indicated poor response to immunotherapy. Importantly, we found that IL-8 induced EMT in vitro. CONCLUSIONS: Taken together, our data indicate that IL-8 may be a potential and valuable prognostic marker in BRCA, which may induce adverse outcomes by modulating the immune response and promoting EMT in BRCA patients.

Integrated analysis of intestinal microbiota and host gene expression in colorectal cancer patients.

Introduction. Colorectal cancer (CRC) is one of the most common cancers and poses heavy burden on global health. The relationship between mucosal microbiome composition and colorectal gene expression are rarely studied. In this study, we integrated transcriptome data with microbiome data to investigate the relationship between them in colorectal cancer patients.Gap statement. Previous studies have identified the contribution of gut microbiota and DEGs to the pathogenesis of CRC, but the relationship between mucosal microbiome composition and colorectal gene expression are rarely studied.Aim. In this study, we integrated transcriptome data with microbiome data to investigate the relationship between mucosal microbiome composition and colorectal gene expression.Methodology. First, three independent CRC gene expression profiles (GSE184093, GSE156355 and GSE146587) from Gene Expression Omnibus (GEO) were used to identify differentially expressed genes (DEGs). Second, another dataset (GSE163366) was used to analyse gut mucosal microbiome differential abundance. GO (Gene Ontology) function and KEGG (Kyoto Encyclopaedia of Genes and Genomes) pathway enrichment analyses of the DEGs were performed. Protein-protein interactions (PPIs) of the DEGs were constructed. The Spearman correlation analysis was computed between host DEGs and gut microbiome abundance data.Results. A total of 1036 upregulated DEGs and 1194 downregulated DEGs between noncancerous tissues and cancerous tissues were identified based on the analysis. One significant module with a score 37.65 was selected out via MCODE including 41 upregulated DEGs, which are were mostly enriched in two pathways, including microtubule binding and tubulin binding. In particular, significant negative correlations are prevalent between Fusobacterium and the 41 DEGs with the correlation ranging between -0.54 and -0.35, and there commonly exist significant positive correlations between Blautia and the 41 DEGs with the correlation ranging between 0.42 and 0.54, indicating that Fusobacterium and Blautia are two of the most important microbes interacting with the gene regulation.Conclusion. Our results demonstrate significant correlation between some gut microbes and DEGs, providing a comprehensive bioinformatics analysis of them for future investigation into the molecular mechanisms and biomarkers.