Gastric cancer cell-derived exosomal miR-541-5p induces M2 macrophage polarization through DUSP3/JAK2/STAT3 pathway.

PURPOSE: Exosomal microRNAs have been identified as important mediators of communication between tumor cells and macrophages in the microenvironment. miR-541-5p was reported to be involved in hepatocellular carcinoma progression, but its role in gastric cancer (GC) and in GC cell-macrophage crosstalk is unknown. METHODS: Cell proliferation, migration and invasion were respectively assessed by CCK-8 assay, scratch and Transwell assays. RT-qPCR was used to detect the level of miR-541-5p, macrophage markers and DUSP3. The percentage of CD11b+CD206+ cell population was analyzed by flow cytometry. Western blotting was employed to evaluate DUSP3-JAK2/STAT3 pathway proteins and exosome markers. The interaction between miR-541-5p and DUSP3 was verified by luciferase assay. RESULTS: The results showed that miR-541-5p was upregulated in GC tissues and cells, and stimulated GC cell growth, migration and invasion in vitro. GC cells induce M2 macrophage polarization by secreting the exosomal miR-541-5p. Exosomal miR-541-5p maintained JAK2/STAT3 pathway activation in macrophages by targeting negative regulation of DUSP3. Inhibiting miR-541-5p significantly limited tumor growth in vivo. CONCLUSION: In conclusion, miR-541-5p promotes GC cell progression. GC cells may induce macrophage M2 polarization through the exosomal miR-541-5p-mediated DUSP3/JAK2/STAT3 pathway. miR-541-5p may be a potential therapeutic target for GC.

Tumor-derived exosomal hyaluronidase 1 induced M2 macrophage polarization and promoted esophageal cancer progression.

The communication between tumor-derived exosomes and macrophages plays an important role in facilitating the progression of tumors. However, the regulatory mechanisms by which exosomes regulate tumor progression in esophageal squamous cell carcinoma (ESCC) have not been fully elucidated. We constructed a coculture system containing an ESCC cell line and macrophages using a Transwell chamber. We isolated exosomes from the conditioned medium of cancer cells, and characterized them with transmission electron microscopy and western blotting and used then to treat macrophages. We used co-immunoprecipitation to evaluate the interaction between hyaluronidase 1 (HYAL1) and Aurora B kinase (AURKB). We evaluated HYAL1 and AURKB expression in tissues and cells with quantitative reverse-transcription polymerase chain reaction (RT-qPCR) and western blotting. We used RT-qPCR, enzyme-linked immunosorbent assay (ELISA) and flow cytometry to detect macrophage polarization. We assessed cell viability, invasion and migration with the cell counting kit-8 (CCK-8), Transwell and wound healing assays. HYAL1 was highly expressed in ESCC tissues and cells and cancer cell-derived exosomes, and exosomes can be delivered to macrophages through the cancer cell-derived exosomes. The exosomes extracted from HYAL1-overexpressed ESCC cells suppressed M1 macrophage polarization and induced M2 macrophage polarization, thereby promoting ESCC cell viability, invasion and migration. HYAL1 silencing in ESCC cells produced the opposite effects on macrophage polarization and cancer cell functions. We found that HYAL1 interacted with AURKB and further activated the phosphoinositide 3-kinase (PI3K)/AKT signaling pathway in macrophages. In conclusion, ESCC-derived exosomes containing HYAL1 facilitate M2 macrophage polarization by targeting AURKB to active the PI3K/AKT signaling pathway, which in turn promotes ESCC progression.

Safety and efficacy of indocyanine green near-infrared fluorescent imaging-guided lymph nodes dissection during radical gastrectomy for gastric cancer: A systematic review and meta-analysis.

Background: Indocyanine green (ICG) fluorescence imaging has been a new surgical navigation technique for gastric cancer. However, its clinical value should still be evaluated further. In this meta-analysis, we investigated the safety and efficacy of ICG near-infrared fluorescent imaging-guided lymph nodes (LNs) dissection during radical gastrectomy. Methods: Studies comparing ICG fluorescence imaging with standard care in patients with gastric cancer were systematically searched from PubMed, Embase, Web of Science, and Cochrane Library through August 2021. The current meta-analysis was performed according to the preferred reporting items for systematic review and meta-analysis guidelines. A pooled analysis was performed for the available data regarding the number of LNs dissection, the number of metastatic LNs dissection, other operative outcomes, and postoperative complications. R software version 4.2.0 and Stata 16.0 software were used for the present meta-analysis. Results: This analysis included 12 studies with a total of 1365 gastric cancer patients (569 in the ICG group and 796 in the non-ICG group). The number of retrieved LNs in the ICG group was significantly higher (weighted mean difference [WMD]=7.67, 95% confidence intervals [CI]: 4.73 to 10.62, P<0.05) compared to the non-ICG group with moderate heterogeneity (P<0.001, I2 = 70%). The number of metastatic LNs, operative time, and postoperative complications were all comparable and without significant heterogeneity. Additionally, ICG near-infrared fluorescent imaging was associated with reduced intraoperative blood loss (WMD=-10.28, 95% CI: -15.22 to -5.35, P<0.05) with low heterogeneity (P=0.07, I2 = 43%). Conclusions: ICG near-infrared fluorescent imaging-guided lymphadenectomy was considered to be safe and effective in gastrectomy. ICG was used to increase the number of LNs harvested while reducing intraoperative blood loss without increasing operative time or postoperative complications. Systematic Review Registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42021291863.