RRC ID 67070
著者 Torii C, Maishi N, Kawamoto T, Morimoto M, Akiyama K, Yoshioka Y, Minami T, Tsumita T, Alam MT, Ochiya T, Hida Y, Hida K.
タイトル miRNA-1246 in extracellular vesicles secreted from metastatic tumor induces drug resistance in tumor endothelial cells.
ジャーナル Sci Rep
Abstract Tumor endothelial cells (TECs) reportedly exhibit altered phenotypes. We have demonstrated that TECs acquire drug resistance with the upregulation of P-glycoprotein (P-gp, ABCB1), contrary to traditional assumptions. Furthermore, P-gp expression was higher in TECs of highly metastatic tumors than in those of low metastatic tumors. However, the detailed mechanism of differential P-gp expression in TECs remains unclear. miRNA was identified in highly metastatic tumor extracellular vesicles (EVs) and the roles of miRNA in endothelial cell resistance were analyzed in vitro and in vivo. In the present study, we found that treatment of highly metastatic tumor-conditioned medium induced resistance to 5-fluorouracil (5-FU) with interleukin-6 (IL-6) upregulation in endothelial cells (ECs). Among the soluble factors secreted from highly metastatic tumors, we focused on EVs and determined that miR-1246 was contained at a higher level in highly metastatic tumor EVs than in low metastatic tumor EVs. Furthermore, miR-1246 was transported via the EVs into ECs and induced IL-6 expression. Upregulated IL-6 induced resistance to 5-FU with STAT3 and Akt activation in ECs in an autocrine manner. These results suggested that highly metastatic tumors induce drug resistance in ECs by transporting miR-1246 through EVs.
巻・号 11(1)
ページ 13502
公開日 2021-7-5
DOI 10.1038/s41598-021-92879-5
PII 10.1038/s41598-021-92879-5
PMID 34226586
PMC PMC8257582
MeSH Animals Case-Control Studies Cell Line Drug Resistance, Neoplasm* Endothelial Cells / metabolism Extracellular Vesicles / metabolism* Female Interleukin-6 / metabolism Melanoma / metabolism* Mice, Nude MicroRNAs / physiology* Neoplasm Metastasis* Proto-Oncogene Proteins c-akt / metabolism Receptors, Androgen / metabolism STAT3 Transcription Factor / metabolism
IF 3.998
リソース情報
ヒト・動物細胞 HeLa(RCB0007) HSC-3(RCB1975) OS-RC-2(RCB0735)