Ferroptosis is a relatively new form of programmed cell death, which can enhance the efficacy of tumor immunotherapy by regulating the tumor microenvironment (TME). In the face of the dilemma of a great difference in the efficacy of immunotherapy for gastric cancer (GC) patients, the exploration of ferroptosis may assist us in predicting immunotherapy efficacy prior to treatment. The potential role of ferroptosis in TME still needs further elucidation. Based on ferroptosis-related genes (FRGs), we systematically evaluated ferroptosis molecular subtypes in gastric cancer. Additionally, the association between these molecular subtypes and the characteristics of TME was examined. A ferroptosis score was constructed to further explore the predictive efficacy of ferroptosis on the immunotherapy response in gastric cancer. There were also 32 other cancers that were evaluated. Three molecular subtypes of ferroptosis in gastric cancer were identified. The three immunophenotypes of tumor immune inflamed, immune excluded, as well as immune desert were mostly in agreement with the TME features of these three subtypes. The individual tumor genetic variation, TME characteristics, immunotherapy response, and prognosis could be assessed by a ferroptosis score. High ferroptosis scores in gastric cancer suggest stromal activation and immunosuppression. It is noted that tumors with a low ferroptosis score are characterized by extensive tumor mutations as well as an immune activation, which are associated with an enhanced immunotherapy response and an improved prognosis. This study reveals that ferroptosis plays an integral role in the regulation of the tumor immune microenvironment. The ferroptosis score may serve as an independent prognostic factor for GC and will deepen our understanding of the TME infiltration mechanisms as well as lead to more rational immunotherapy regimens.
Angiogenesis has been identified to assume a critical role in skin wound healing. Moreover, zinc finger E‐box binding homeobox 1 (ZEB1) was capable of promoting skin wound healing. Herein, cell and animal experiments were implemented in this study to figure out whether ZEB1 orchestrated angiogenesis during skin wound healing. Subsequent to gain‐ and loss‐of‐function approaches in human dermal microvascular endothelial cells (HDMECs), HDMEC proliferation, migration and angiogenesis were evaluated by CCK8, EdU, wound healing, Transwell and angiogenesis in vitro assays. The relationship among ZEB1, microRNA (miR)‐206 and vascular endothelial growth factor A (VEGFA) was assessed by microarray analysis, dual‐luciferase, ChIP and RIP assays. Finally, the mechanism of ZEB1 in skin wound healing was confirmed by in vivo experiments. Mechanically, ZEB1 upregulation resulted in miR‐206 downregulation by binding to miR‐206 promoter, and miR‐206 repressed VEGFA expression by directly targeting. ZEB1 overexpression enhanced HDMEC proliferation, migration and angiogenesis, which was neutralized by miR‐206 upregulation or VEGFA inhibition. Moreover, ZEB1 significantly promoted skin wound healing in mice, which was negated by overexpression of miR‐206. Conclusively, ZEB1 augmented angiogenesis to promote skin wound healing by elevating VEGFA expression via miR‐206 repression.
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