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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. [ABSTRACT FROM AUTHOR]

Background: Perturbation of tryptophan (TRP) metabolism contributes to the immune escape of cancer; however, the explored TRP metabolites are limited, and their efficacy in clarifying the susceptibility and progression of esophageal cancer (EC) remains ambiguous. Our study sought to evaluate the effects of the TRP metabolic profile on the clinical outcomes of EC using a Chinese population cohort; and to develop a risk prediction model targeting TRP metabolism. Method: A total of 456 healthy individuals as control subjects and 393 patients with EC who were followed up for one year as case subjects were enrolled. Quantification of the plasma concentrations of TRP and its metabolites was performed using HPLC-MS/MS. The logistic regression model was applied to evaluate the effects of the clinical characteristics and plasma metabolites of the subjects on susceptibility and tumor metastasis events, whereas Cox regression analysis was performed to assess the overall survival (OS) of the patients. Results: Levels of creatinine and liver enzymes were substantially correlated with multiple metabolites/metabolite ratios in TRP metabolism, suggesting that hepatic and renal function would exert effects on TRP metabolism. Age- and sex-matched case–control subjects were selected using propensity score matching. Plasma exposure to 5-HT was found to be elevated 3.94-fold in case subjects (N = 166) compared to control subjects (N = 203), achieving an AUC of 0.811 for predicting susceptibility event. Subsequent correlation analysis indicated that a higher plasma exposure to 5-HIAA significantly increased the risk of lymph node metastasis (OR: 2.16, p = 0.0114). Furthermore, it was figured out that OS was significantly shorter for patients with elevated XA/KYN ratio (HR: 1.99, p = 0.0016), in which medium and high levels of XA/KYN versus low level had a significantly lower OS (HR: 0.48, p = 0.0080 and HR: 0.42, p = 0.0031, respectively). Conclusion: This study provides a pivotal basis for targeting endogenous TRP metabolism as a potential therapeutic intervention. [ABSTRACT FROM AUTHOR]