Abstract
Small extracellular vesicles (sEVs) play a pivotal role in tumor progression by mediating intercellular communication in the tumor microenvironment (TME). Syntenin-1 induces malignant tumor progression in various types of human cancers, including human lung cancer and regulates biogenesis of sEVs. However, the function of syntenin-1-regulated sEVs and miRNAs in sEVs remains to be elucidated. In the present study, we aimed to demonstrate the role of oncogenic Ras/syntenin-1 axis in the release of sEVs and elucidate the function of syntenin-1-mediated miRNAs in sEVs in lung cancer progression. The results revealed that oncogenic Ras promoted the release of sEVs by inducing syntenin-1 expression; disruption of syntenin-1 expression impaired the release of sEVs as well as sEV-mediated cancer cell migration and angiogenesis. Moreover, we identified three miRNAs, namely miR-181a, miR-425-5p, and miR-494-3p, as onco-miRNAs loaded into syntenin-1-dependent sEVs. Remarkably, miR-494-3p was highly abundant in sEVs and its release was triggered by syntenin-1 expression and oncogenic Ras. Ectopic expression of the miR-494-3p mimic enhanced the migration and proliferation of lung cancer cells as well as tube formation in endothelial cells; however, the miR-494-3p inhibitor blocked sEV-mediated effects by targeting tyrosine-protein phosphatase nonreceptor type 12 (PTPN12), a tumor suppressor. sEVs promoted tumor growth and angiogenesis by downregulating PTPN12 expression; however, the miR-494-3p inhibitor significantly suppressed these effects in vivo, confirming that miR-494-3p acts as a major onco-miRNA loaded into lung cancer cell-derived sEVs. Eventually, the oncogenic Ras/syntenin-1 axis may induce cancer progression by increasing miR-494-3p loading into sEVs in lung cancer cells in the TME.
Highlights
Extracellular vesicles (EVs) are nanosized membrane-bound vesicles that are released in a majority of cell types; these include (1) small extracellular vesicles, known as exosomes, with a size range of ~40–160 nm, which are released upon fusion of multivesicular bodies (MVBs) with the plasma membrane, and (2) microvesicles (MVs), known as ectosomes with a size range of 100–1000 nm, which are generated by the direct outward budding of the plasma membrane [1, 2]. sEVs are generated during invagination of the endosomal limiting membrane and formation of intraluminal vesicles (ILVs), thereby resulting in specialized endosomal compartments, known as MVBs
We demonstrated that oncogenic Ras/syntenin-1 axis stimulates the release of sEVs and loading of onco-miRNAs, including miR-494-3p, into sEVs to promote the growth, migration, and metastasis of human lung cancer cells as well as tumor angiogenesis by targeting protein phosphatase nonreceptor type 12 (PTPN12); the suppression of oncogenic Ras or syntenin-1 inhibited
Syntenin-1 is overexpressed in various types of human cancers, and its expression level is correlated with poor prognosis in patients with cancer, including human lung and breast cancer [6, 7, 35, 36]
Summary
Extracellular vesicles (EVs) are nanosized membrane-bound vesicles that are released in a majority of cell types; these include (1) small extracellular vesicles (sEVs), known as exosomes, with a size range of ~40–160 nm, which are released upon fusion of multivesicular bodies (MVBs) with the plasma membrane, and (2) microvesicles (MVs), known as ectosomes with a size range of 100–1000 nm, which are generated by the direct outward budding of the plasma membrane [1, 2]. sEVs are generated during invagination of the endosomal limiting membrane and formation of intraluminal vesicles (ILVs), thereby resulting in specialized endosomal compartments, known as MVBs. Syntenin-1-syndecanALIX (ALG-2-Interacting Protein X) is required for the biogenesis of sEVs [9]. Syntenin-1 directly interacts with ALIX through LYPX(n)L motif, and ALIX further connects the syntenin-1-syndecan complexes to ESCRT components that are crucial in ILV formation [9, 10]. This process is regulated by the small GTPase ADP ribosylation factor 6 (ARF6) and phospholipase D2 [10]. Syntenin mediates tyrosine kinase Src function in sEV-mediated cell-to-cell communication by controlling exosome activity and biogenesis [11]. Src stimulates the secretion of sEVs by phosphorylating syntenin Y46 and the DEGSY motif of the syndecan cytosolic domain [11]; tyrosine phosphatase Shp decreases the secretion of sEVs by dephosphorylating syntenin Y46 [12]
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