Abstract
Simple SummaryMacrophage polarization-associated extracellular vesicles (EVs) play crucial roles in tumor progression. The role of miR-21-5p in EVs during esophageal squamous cell carcinoma (ESCC) development must be clarified. This study aimed to identify the relationship between ESCC cells and macrophages in different polarization states during the delivery of EVs-miR-21-5p. We found that M0 macrophages took up overexpressed EVs-miR-21-5p secreted by EC109 or EC9706 cells, which transformed them into M2 macrophages through the PTEN/AKT/STAT6 pathway. This, in turn, contributed to secretion of high levels of TGF-β1 by M2 macrophages and promoted esophageal cancer cell epithelial-mesenchymal transition via the TGF-β/Smad2 axis. These findings indicate that EVs-miR-21-5p may be a critical molecule for ESCC.The disorganized polarization of tumor-associated macrophages (TAMs) exerts a critical effect on tumor progression. MicroRNAs (miRNAs) in extracellular vesicles (EVs) secreted from cancer cells may contribute to this process. However, the relationship between TAMs and EVs-miRNAs-mediated regulation in esophageal squamous cell carcinoma (ESCC) remains unclear. In the present study, immunoaffinity magnetic beads combined with antiepithelial cell adhesion molecules (EpCAM) were used to isolate and identify EVs-miR-21-5p from the plasma of ESCC patients. An in vitro coculture system was designed to evaluate the effect of esophageal cancer cells with miR-21-5p overexpression on macrophage polarization. We found that phorbol myristate acetate-induced THP-1 macrophages took up EVs-miR-21-5p from EC109 or EC9706 cells and were transformed into M2 macrophages. This, in turn, contributed to the excessive migration and invasion of esophageal cancer cells. The mechanism underlying these changes may involve activation of M2 macrophages by upregulated ESCC-derived EVs-miR-21-5p through the PTEN/AKT/STAT6 pathway. This may result in esophageal cancer cell epithelial-mesenchymal transition (EMT) via TGF-β/Smad2 signaling. Our results indicate positive feedback between M2 macrophage polarization and EMT of esophageal cancer cells in the tumor microenvironment via shuttling of miR-21-5p in tumor-derived EVs.
Highlights
IntroductionEsophageal cancer, a malignancy with high incidence and mortality, is a serious threat to human life and health
We found that EVsmiR-21-5p secreted by EC109 was ingested by M0 macrophages, which contributed to the polarization of M2 macrophages
To evaluate the level of miR-21-5p in plasma extracellular vesicles (EVs), EpCAM, a multifunctional transmembrane protein involved in the regulation of tumor cell adhesion, proliferation, mitional logistic regression demonstrated that elevated EVs-miR-21-5p in esophageal squamous cell carcinoma (ESCC) patients wa positively correlated with esophageal cancer risk
Summary
Esophageal cancer, a malignancy with high incidence and mortality, is a serious threat to human life and health. According to 2020 global cancer statistics, esophageal creativecommons.org/licenses/by/ 4.0/). Cancer ranks seventh in global cancer incidence (604,000 new cases) and sixth in total mortality (544,000 deaths). In China, esophageal squamous cell carcinoma (ESCC) accounts for approximately 90% of the overall incidence of esophageal cancer and nearly half of all esophageal cases worldwide [2]. The early symptoms of esophageal cancer are atypical and difficult to identify, which leads to late diagnoses and partly explains the high mortality and poor prognosis [3]. Identifying targets that would permit early diagnosis of esophageal squamous cell carcinoma (ESCC) is crucial [4]
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