1. General Surgery, Cancer Center, Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital (Affiliated People's Hospital, Hangzhou Medical College), Hangzhou, Zhejiang 310014, China.
2. Key Laboratory of Gastroenterology of Zhejiang Province, Zhejiang Provincial People's Hospital, Affiliated People's Hospital, Hangzhou Medical College, Hangzhou, Zhejiang, China.
3. Department of Gastrointestinal Surgery, Central Hospital Affiliated to Shandong First Medical University, Jinan 250013, China.
4. Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310053, China.
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.
Keywords: Hypoxic, Tumor-Derived Exosomal, miR-199a-3p, Gastric Cancer, Metastasis, MAP3K4