Abstract

Thymic carcinoma (THYM) is a mediastinal malignant tumor that seriously endangers human health. Cancer-associated fibroblasts (CAFs) are implicated in many cancers, but their role in THYM remains unclear. Western blot and reverse transcription-quantitative polymerase chain reaction were used to analyze expression levels. Exosomes were isolated and characterized by transmission electron microscopy and nanoparticle tracking analysis, and their uptake was assessed using PKH26 labeling. Cell functions were evaluated with cell counting kit-8, colony formation, and Transwell assays, while M2 macrophages were identified by flow cytometry for CD206. Bioinformatics databases analyzed gene correlations. The interaction between signal transducer and activator of transcription 3 (STAT3) and the kelch-like family member 5 (KLHL5) promoter was confirmed by chromatin immunoprecipitation and dual-luciferase reporter assay. Xenograft models were established to verify the effects of STAT3 in tumor growth, and protein expression in tissues was assessed by immunohistochemistry. Exosomes were successfully isolated from CAFs. STAT3 was up-regulated in CAF-derived exosomes compared to those from normal fibroblasts (NFs). Knockdown of STAT3 in CAF-derived exosomes repressed THYM cell viability, colony formation, migration, and invasion, as well as M2 macrophage polarization. STAT3 expression was positively correlated with KLHL5 and bound to the KLHL5 promoter. Furthermore, KLHL5 silence inhibited THYM cell malignant behaviors and M2 macrophage polarization, whereas KLHL5 overexpression attenuated the inhibitory effects of STAT3 knockdown. Similarly, silencing STAT3 in CAF-derived exosomes blocked tumor growth in vivo. CAF-derived exosomes transfer STAT3 to THYM cells, promoting THYM malignant progression and M2 macrophage polarization by transcriptionally activating KLHL5.