Purpose: Tumor growth induces the tumor margin to become a transition zone rich in immune cells.EVPL is a potential prognostic biomarker for melanoma.Melanoma is difficult to cure because of its high metastasis, so it is urgent to find effective genes to inhibit tumor progression and regulate tumor microenvironment.Methods: Firstly, differentially expressed genes (DEGs) among normal skin, nevus and melanoma samples in GSE3189 were screened.Bioinformatics was used to further explore the hub genes and enriched pathways closely related to the inflammatory response of DEGs in melanoma.We selected EVPL, which is associated with the Ras/Raf signaling pathway, for in vitro study.CCK-8, colony formation, wound healing, Transwell and flow cytometry assays were respectively used to evaluate the proliferation, migration, invasion, and apoptosis of cancer cells.Enzyme-linked immunosorbent assay was conducted for the monitoring of changes in the tumor microenvironment.To evaluate the effect of EVPL on macrophage recruitment, we established a co-culture system in a Transwell chamber.The polarization of macrophages was examined after treatment of cells with RAS/ERK signaling inhibitors SCH772984 and sh-EVPL.Additionally, changes in the expression of pathway proteins were measured by Western blot.Results: Among the screened hub genes, EVPL was associated with the Ras/Raf pathway, a key signaling pathway in melanoma, and may be involved in regulating the inflammatory microenvironment of melanoma.Oe-EVPL was proved to suppress melanoma cell malignant progression.By inhibiting EVPL expression, the inhibitory effects on melanoma progression induced by the addition of SCH772984 were reversed.Furthermore, EVPL was found to inhibit the expression of chemokines, the recruitment of macrophages, and the polarization of macrophages through the Ras/Raf/ERK signaling pathway.Conclusion: EVPL can inhibit the progression of melanoma through the RAS/ERK signaling pathway, change the inflammatory tumor microenvironment of melanoma, and inhibit the recruitment of macrophages.
Keratinocyte proliferation and migration are crucial steps during skin wound healing. The functional role of microRNAs (miRs) remains relatively unknown during this process. miR-93 levels have been reported to increase within 24 h of skin wound healing; however, whether miR-93-3p or miR-93-5p plays a specific role in wound healing is yet to be studied. In this study, with the use of an in vivo mouse skin wound-healing model, we demonstrate that miR-93-3p is significantly upregulated, whereas there is no change in the expression of miR-93-5p during skin wound healing. In HaCaT cells, miR-93-3p overexpression increased proliferation and migration of the cells, whereas miR-93-3p inhibition had the reverse effect. Additionally, it was evident that ZFP36L1 was a direct target of miR-93-3p in keratinocytes. Further, ZFP36L1 silencing mirrored the consequences observed during miR-93-3p overexpression on both proliferation and migration of keratinocytes. In addition, we demonstrate that zinc-finger X-linked (ZFX), as a target for ZFP36L1, is involved in the promotion of the miR-93-3p/ZFP36L1 axis in keratinocyte proliferation and migration. Ultimately, we found that mouse skin wound model treatment with anti-miR-93-3p delayed wound healing. Overall, our results show that miR-93-3p is a crucial regulator of skin wound healing that facilitates keratinocyte proliferation and migration through ZFP36L1/ZFX axis. Keratinocyte proliferation and migration are crucial steps during skin wound healing. The functional role of microRNAs (miRs) remains relatively unknown during this process. miR-93 levels have been reported to increase within 24 h of skin wound healing; however, whether miR-93-3p or miR-93-5p plays a specific role in wound healing is yet to be studied. In this study, with the use of an in vivo mouse skin wound-healing model, we demonstrate that miR-93-3p is significantly upregulated, whereas there is no change in the expression of miR-93-5p during skin wound healing. In HaCaT cells, miR-93-3p overexpression increased proliferation and migration of the cells, whereas miR-93-3p inhibition had the reverse effect. Additionally, it was evident that ZFP36L1 was a direct target of miR-93-3p in keratinocytes. Further, ZFP36L1 silencing mirrored the consequences observed during miR-93-3p overexpression on both proliferation and migration of keratinocytes. In addition, we demonstrate that zinc-finger X-linked (ZFX), as a target for ZFP36L1, is involved in the promotion of the miR-93-3p/ZFP36L1 axis in keratinocyte proliferation and migration. Ultimately, we found that mouse skin wound model treatment with anti-miR-93-3p delayed wound healing. Overall, our results show that miR-93-3p is a crucial regulator of skin wound healing that facilitates keratinocyte proliferation and migration through ZFP36L1/ZFX axis.
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