Abstract
The relevance of microRNA-15a (miR-15a) to autoimmunity has been reported. Herein, we intended to probe the potential roles of miR-15a shuttled by adipose-derived mesenchymal stem cells (adMSCs)-derived extracellular vesicles (Evs) in colorectal cancer (CRC). Initially, CRC cells were treated with interferon gamma (IFN-γ) to screen out differentially expressed genes by transcriptome sequencing. Following a 24-h co-culture with 20 μM adMSCs-derived Evs, CRC cell viability, migration, invasion, and apoptosis were assessed. After the determination of histone lysine demethylase 4B (KDM4B) as our target, its regulatory miRNA was predicted by the bioinformatics websites and verified by dual-luciferase and RNA pull-down assays. Intriguingly, KDM4B downregulated homeobox C4 (HOXC4) expression, while HOXC4 bound to the promoter sequence of programmed death-ligand 1 (PD-L1). Thus, we conducted rescue experiments to study the role of KDM4B and HOXC4. Finally, we evaluated the effects of adMSCs on CRC cell growth and immune evasion through in vivo tumorigenesis experiments. AdMSCs-derived Evs overexpressing miR-15a repressed proliferation, migration, and invasion, while it promoted the apoptosis of CRC cells via downregulation of KDM4B. These in vivo findings were reproduced in vitro on CRC immune evasion. Collectively, adMSCs-derived Evs overexpressing miR-15a restricted the immune evasion of CRC via the KDM4B/HOXC4/PD-L1 axis.
Highlights
Colorectal cancer (CRC) ranks the fourth place regarding the new diagnosis in 2018, accounting for 6.1% of all new cancer cases (Bray et al, 2018)
We found that KDM4B expression increased with the promotion of IFN-γ treatment time and concentration (Figure 1F)
We analyzed the changes of cell migration or invasion ability by Transwell assay, and the results showed that IFN-γ treatment significantly promoted the migration and invasion of CRC cells
Summary
Colorectal cancer (CRC) ranks the fourth place regarding the new diagnosis in 2018, accounting for 6.1% of all new cancer cases (Bray et al, 2018). AdMSCs-Derived Evs in CRC importantly in cancer progression and treatment, and immune response induced by chronic infection and inflammation may enhance the risk for cancers (Ruan H. et al, 2020). It is of importance to examine the mechanisms of action underlying the immune evasion of CRC cells stimulated by IFN-γ. MiR-15a released by human liver stem-like cells-derived Evs was found to significantly suppressed the angiogenic properties of tumorderived endothelial cells in vitro (Lopatina et al, 2019). We aim to investigate the relevance and molecular mechanism of adMSCsderived Evs containing miR-15a on immune evasion in CRC cells. Our findings might promote our understanding of IFN-γ-induced immune evasion, and provide further information that will facilitate the development of effective strategies for CRC treatment
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