Cisplatin is a widely used chemotherapeutic agent; however, its therapeutic efficacy is often limited by severe cytotoxic side effects, particularly gastrointestinal toxicity, which manifests as intestinal mucositis.MicroRNAs (miRNAs) are small non-coding RNAs that play critical roles in both normal physiological and pathological processes by regulating gene expression.However, their role in cisplatin-induced gastrointestinal toxicity remains unclear.In this study, we investigated the regulatory effects of miRNAs on cisplatin-induced inflammation in intestinal epithelial cells (IEC-6).Our results demonstrate that cisplatin significantly decreases cell viability while inducing interleukin-6 (IL-6) expression in a dose-dependent manner.Moreover, we observed that cisplatin activates the phosphorylation of p38 and ERK but does not activate JNK in IEC-6 cells.Using specific inhibitors of p38 and ERK, we confirmed their roles in regulating IL-6 expression.Through analysis of the miRNA database, we identified several miRNAs that potentially target IL-6.Notably, rno-let-7f-5p and rno-let-7g-5p showed significant downregulation following cisplatin treatment.Transfection mimics and inhibitors of rno-let-7f-5p and rno-let-7g-5p further confirmed their regulatory role in IL-6 expression.Importantly, inhibition of the p38 and ERK pathways attenuated the cisplatin-induced reduction of rno-let-7f-5p and rno-let-7g-5p levels, suggesting a potential regulatory link between MAPK signaling and miRNA expression.In conclusion, our findings support a model in which cisplatin promotes inflammation in intestinal epithelial cells by activating the p38 and ERK pathways and is associated with the suppression of rno-let-7f-5p and rno-let-7g-5p.These findings provide mechanistic rationale that may inform future efforts to mitigate cisplatin-associated gastrointestinal toxicity.
Chang et al. (Tue,) studied this question.