Hypoxic Tumor-Derived Exosomal miR-199a-3p Promote Gastric Cancer Metastasis via MAP3K4

Background: Accumulating evidence has suggested the significant role of hypoxic tumor-derived exosomal miRNA in regulating gastric cancer metastasis, while its regulatory mechanism in gastric cancer remains unelucidated. Methods: AGS and HGC-27 cell were cultured in hypoxia, and the expression of exosome miR-199a-3p was extracted and detected. Label free proteomic analysis, bioinformatics analysis, biluciferase assay and Westblot were used to verify the signaling pathway and target genes regulated by miR-199a-3p. Invasion and migration experiments were conducted to verify whether exosome miR-199a-3p can promote tumor growth and metastasis under hypoxia. Immunohistochemistry was used to detect the expression of MAP3K4 in gastric cancer. Results: We first demonstrated that expression of tumor-derived exosomal miR-199a-3p is upregulated in AGS and HGC-27 cells in hypoxic conditions and tumor-derived exosomal miR-199a-3p promoted invasion and metastasis, which was evidenced by invasion and migration assays. Mechanistically, we validated that miR-199a-3p may act as a oncogene by modulating the expression of its downstream molecule MAP3K4. Conclusion: Our results demonstrate that tumor-derived exosomal miR-199a-3p promotes invasion and metastasis in hypoxic conditions and the MAP3K4 signal axis may serve as a therapeutic target for gastric cancer.