Abstract
The oncogene c-Jun is activated by Jun N-terminal kinase (JNK). Exosomes are nanometer-sized membrane vesicles released from a variety of cell types, and are essential for cell-to-cell communication. By using specific JNK inhibitor SP600125 or CRISPR/Cas9 to delete c-Jun, we found that exosomes from SP600125-treated A549 cancer cells (Exo-SP) or from c-Jun-KO-A549 cells (Exo-c-Jun-KO) dramatically inhibited tube formation of HUVECs. And the miR-494 levels in SP600125 treated or c-Jun-KO A549 cells, Exo-SP or Exo-c-Jun-KO, and HUVECs treated with Exo-SP or Exo-c-Jun-KO were significantly decreased. Meanwhile, Exo-SP and Exo-c-Jun-KO enhanced expression of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Addition of miR-494 agomir in Exo-c-Jun-KO treated HUVECs inhibited PTEN expression and promoted tube formation, suggesting the target of miR-494 might be PTEN in HUVECs. Moreover, A549 tumor xenograft model and Matrigel plug assay demonstrated that Exo-c-Jun-KO attenuated tumor growth and angiogenesis through reducing miR-494. Taken together, inhibition of c-Jun in A549 cancer cells exhibited antiangiogenic activity in vitro and in vivo through exosome/miRNA-494-3p/PTEN signal pathway.
Highlights
C-Jun, encoded by the c-jun proto-oncogene, appears to play a central role in cellular signal transduction and positively regulate cell proliferation through inhibiting tumor suppressor gene expression and function [1, 2]
We investigated the detailed mechanism of c-Jun in cancer cells to regulate angiogenesis through mediating exosome/Micro RNAs (miRNAs)/tensin homolog deleted on chromosome ten (PTEN) signal pathway
Since the c-Jun activation domain is phosphorylated only by the Jun N-terminal kinase (JNK), and the c-Jun promoter activity is autoregulated by c-Jun/AP-1, we treated the above 7 kinds of cancer cell lines with specific JNK inhibitor SP600125 to find out the most sensitive cancer cells to c-Jun
Summary
C-Jun, encoded by the c-jun proto-oncogene, appears to play a central role in cellular signal transduction and positively regulate cell proliferation through inhibiting tumor suppressor gene expression and function [1, 2]. Suppression of tumor angiogenesis has become an essential strategy for cancer therapy. Different cell types such as hematopoietic cells, primary and normal cells, and tumor cells release exosomes to epigenetically reprogram their neighboring cells [6]. Numerous miRNAs are enriched in tumor-derived exosomes, and are transferred to endothelial cells to regulate angiogenesis [12]. We investigated the detailed mechanism of c-Jun in cancer cells to regulate angiogenesis through mediating exosome/miRNA/tensin homolog deleted on chromosome ten (PTEN) signal pathway
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