MIAT shuttled by tumor-secreted exosomes promotes paclitaxel resistance in esophageal cancer cells by activating the TAF1/SREBF1 axis

Chemoresistance remains a major obstacle to the treatment of esophageal Cancer (EC). Exosome-mediated transfer of long noncoding RNAs (lncRNAs) has recently been unveiled to correlate with the regulation of drug resistance in EC. This study aimed to investigate the physiological mechanisms by which exosome-encapsulated lncRNA myocardial infarction-associated transcript (MIAT) derived from tumor cells might mediate the paclitaxel (PTX) resistance of EC cells. First, MIAT was experimentally determined to be upregulated in PTX nonresponders and PTX-resistant EC cells. Silencing of MIAT in PTX-resistant EC cells decreased cell viability and enhanced Apoptosis, corresponding to a reduced half-maximal inhibitory concentration (IC₅₀ ) value. Next, exosomes were isolated from EC109 and EC109/T cells, and EC109 cells were cocultured with EC109/T-cell-derived exosomes. Accordingly, MIAT was revealed to be transmitted through exosomes from EC109/T cells to EC109 cells. Tumor-derived exosomes carrying MIAT increased the IC₅₀ value of PTX and suppressed Apoptosis in EC109 cells to promote PTX resistance. Furthermore, MIAT promoted the enrichment of TATA-box binding protein-associated Factor 1 (TAF1) in the promoter region of sterol regulatory element binding transcription factor 1 (SREBF1), as shown by a chromatin immunoprecipitation assay. This might be the mechanism by which MIAT could promote PTX resistance. Finally, in vivo experiments further confirmed that the knockdown of MIAT attenuated the resistance of EC cells to PTX. Collectively, these results indicate that tumor-derived exosome-loaded MIAT activates the TAF1/SREBF1 axis to induce PTX resistance in EC cells, providing a potential therapeutic target for overcoming PTX resistance in EC.

SREBF1; TAF1; esophageal cancer cells; exosomes; long noncoding RNA MIAT; paclitaxel resistance.