Ferroptosis heterogeneity within the tumor microenvironment revealed a genetic blueprint of breast cancer.

The tumor microenvironment (TME) significantly influences disease progression through immune infiltration, while ferroptosis, a recently discovered cell death mechanism, plays a crucial role in tumor suppression. However, its role in breast cancer is not clear. In this study, we analyzed bulk RNA and single-cell RNA sequencing data from 1217 samples, including 1104 breast cancer patients and 113 controls, to identify ferroptosis-related genes (FRGs) and construct a prognostic model. Using univariate cox regression, LASSO regression, and multivariate cox regression analysis, we discovered 21 FRGs and 3 TME-related immune cell types with prognostic value. Dimensionality reduction clustering and visualization were performed using the UMAP method, while the immune infiltration process was calculated with the TIP online tool. We employed GSEA enrichment analysis, WGCNA clustering analysis, and correlation analysis to examine functional differences, and the mutation analysis of the best and worst prognosis groups was conducted using the maftools package. Our findings revealed that knocking down the expression of the hub gene SLC39A7 significantly impacted cancer cell apoptosis and combining ferroptosis and TME scores yielded high prognostic power. Epithelial cells and B cells exhibited higher ferroptosis scores, which were independently associated with immune checkpoint blockade (ICB) response and ICB gene expression. This study provides a foundation for further exploration of the relationship between ferroptosis and ICB response in breast cancer. In conclusion, we developed a prognostic model based on ferroptosis and infiltrated immune cells that effectively stratified breast cancer patients and demonstrated the role of SLC39A7 in breast cancer pathogenesis through the regulation of apoptosis.

KMT2A maintains stemness of gastric cancer cells through regulating Wnt/ß-catenin signaling-activated transcriptional factor KLF11.

The molecular mechanisms of epigenetic regulation in gastric cancer development are not yet well established. In this study, we demonstrated that KMT2A was highly expressed in gastric cancer and associated with poor outcomes of patients and revealed that KMT2A was significantly associated with stemness and increased nuclear ß-catenin in gastric cancer. Mechanistically, KMT2A activated the translocation of ß-catenin into the nucleus of gastric cancer cells, and then, ß-catenin served as a coactivator of KLF11, which promoted the expression of specific gastric cancer stemness-related molecules, including SOX2 and FOXM1. Together, KMT2A is an important epigenetic regulator of gastric cancer stemness, which provides a novel insight to the potential application of targeting against KMT2A in treating gastric cancer.

Integrated analysis of RNA-seq in hepatocellular carcinoma reveals competing endogenous RNA network composed of circRNA, lncRNA, and mRNA.

BACKGROUND: Circular RNAs (circRNAs) and long non-coding RNAs (lncRNAs) have been hypothesized to have important roles in the etiology of hepatocellular carcinoma (HCC). However, the synergistic effect of circRNA and lncRNA in the pathogenesis of HCC has rarely been studied. METHODS: In this study, the Gene Expression Omnibus database was used to get the expression profiles of circRNAs, micro RNAs (miRNAs), lncRNAs, and messenger RNAs (mRNAs) in HCC tissues and normal tissues. The accession numbers for this database are GSE101728, GSE155949, and GSE108724. We found 291 differentially overexpressed lncRNAs and 541 differentially overexpressed mRNA in GSE101728, 30 differentially overexpressed circRNA in GSE155949, and 48 significantly downregulated miRNA in GSE198724. Meanwhile, based on Pearson correlation test, we established lncRNA-mRNA networks. We constructed lncRNA/circRNA-miRNA pairs through Starbase database prediction and identified the common miRNAs. The intersection of co-predicted miRNAs and the 48 significantly low expression miRNAs in GSE198724 were included in the following study. miRDB, Targetscan, miRwalk, and lncRNA-related mRNA jointly determined the miRNA-mRNA portion of the circRNA/lncRNA-miRNA-mRNA co-expression network. And, among 55 differentially expressed mRNA in circRNA/lncRNA-miRNA-mRNA network, CPEB3, EFNB3, FATA4, growth hormone receptor, GSTZ1, KLF8, MFAP4, PAIP2B, PHACTR3, PITPNM3, RPS6KA6, RSPO3, SLITRK6, SMOC1, STEAP4, SYT1, TMEM132E, TSPAN11, and ZFPM2 were intimately related to the prognosis of HCC patients in Kaplan-Meier plotter analysis (P < .05). CONCLUSION: We have discovered that the prognosis-related lncRNAs/circRNAs-miRNA-mRNA network plays a significant role in the pathogenesis of HCC. These findings may offer fresh perspectives for further research into the pathogenesis of HCC and the search for novel treatments for HCC.