Extracellular shuttling miR‐21 contributes to esophageal cancers and human umbilical vein endothelial cell communication in the tumor microenvironment and promotes tumor angiogenesis by targeting phosphatase and tensinhomolog

Abstract

Abstract Background Cell‐cell communication by carcinoma‐derived exosomes can influence the tumor microenvironment (TME) and regulate cancer progression. Based on the overexpression of microRNA‐21‐5p (miR‐21) in plasma from patients diagnosed with esophageal squamous cell carcinoma (ESCC) and exosomes from ESCC cell lines identified earlier, this study aimed to explore the influence of exosomal miR‐21 within the TME. Method ScRNA‐Seq and Bulk RNA‐Seq were integrated to elucidate the communication between cancer and endothelial cells. The functionality and mechanisms by which exo‐miR‐21 derived from carcinoma regulate endothelial cell‐mediated angiogenesis were assessed using a cocultivation model of EC9706 cells and recipient human umbilical vein endothelial cells (HUVECs), through blood vessel formation experiments, luciferase reporter assays, RT‐qPCR, and western blot analysis. Result A total of 3842 endothelial cells were extracted from the scRNA‐seq data of ESCC samples and reclustered into five cell subtype. Cell‐cell communication analysis revealed cancer cells presented a strong interaction with angiogenesis‐like endothelial cells in secreted signaling. MiR‐21 was unregulated in ESCC and the carcinoma‐derived exo‐miR‐21 was significantly raised in HUVECs. The exo‐miR‐21 promoted the proliferation and migration of HUVECs while also enhancing, closed mesh count, and junction number in HUVECs. Mechanistically, dual‐luciferase reporter assay revealed that PTEN was the target of miR‐21. Meanwhile, p‐Akt was significantly increased and suppressed by inhibition of miR‐21 and PI3K inhibitor LY294002. Conclusion Exo‐miR‐21‐mediated communication between endothelial and cancer cells plays a pivotal role in promoting the angiogenesis of ESCC. Therefore, controlling exo‐miR‐21 could serve as a novel therapeutic strategy for ESCC by targeting angiogenesis.

Keywords

• angiogenesis
• ESCC
• exo‐miR‐21
• PTEN/Akt
• scRNA‐seq