Myc manipulates the miRNA content and biologic functions of small cell lung cancer cell-derived small extracellular vesicles.

Abstract

MYC genes are amplified/overexpressed in 20% of SCLCs, showing that Myc and Myc-dependent cellular mechanisms are strong candidates as therapeutic targets in SCLC. Small extracellular vesicles support the carcinogenesis process by acting as messengers delivering nucleic acids and proteins-moreover, no reports associate Myc and the functional effect of small extracellular vesicles in small cell lung cancer. After the effects of small extracellular vesicles (sEVs) obtained from H82 and H209 cells on HUVEC and MRC-5 cells were observed, the Myc-dependent effect of the sEVs on oncogenic potentials was further evaluated by manipulating Myc expression via lentiviral vectors in H82 and H209 cells. Then, small extracellular vesicles of Myc-manipulated SCLC cells were isolated using sEVs isolation reagents. Finally, HUVEC and MRC5 cells were treated with SCLC-derived small extracellular vesicles. Cellular activity of recipient normal lung cells was investigated by cell growth assay, wound healing assay, and transwell assay. miRNA composition changes in small extracellular vesicles and SCLC cells were investigated using miRNA microarray and QRT-PCR assay. Our results indicated that normal lung cells treated with SCLC-derived small extracellular vesicles had higher proliferation, migration capability than non-treated counterparts. Additionally, after investigating the potential effects of small extracellular vesicles derived from Myc-dysregulated SCLC cell lines, we further evaluated the Myc-dependent miRNA composition in the small extracellular vesicles. The present study revealed that Myc regulates hsa-miR-7, hsa-miR-9, hsa-miR-125b, hsa-miR-181a_2, hsa-miR-455, hsa-miR-642, and hsa-miR-4417 expressions in SCLC cell lines, not only in cellular but also in exosomal content. Small extracellular vesicles and MYC are essential targets for therapeutic strategy in SCLC. Our study revealed that the expression level of MYC can affect the function of sEVs and encapsulate the miRNA composition in SCLC. Besides, small extracellular vesicles derived from SCLC cells can modulate normal lung cells.