Extracellular Vesicles from Carcinoma-associated Fibroblasts Promote EMT of Salivary Adenoid Cystic Carcinoma Via IL-6
Hyat Ahmed Ibrahim Al-Raimi, Jing Kong, Ran Yan, Lei Zhu, Jiao Li, Xue Liu, Xuesong Yang, Dongyuan Qi, Tingjiao Liu
Abstract
BACKGROUND: Carcinoma-associated fibroblasts (CAFs) play a pivotal role in cancer progression. Salivary adenoid cystic carcinoma (SACC) has a high tendency to invade and metastasize. Understanding how CAFs interact with SACC cells is essential for developing new targeted therapies for SACC. Extracellular vesicles (EVs) play important roles in intercellular communication. However, the role of CAFs-derived EVs in SACC invasion remains poorly understood. AIM OF THE STUDY: To show that CAFs EVs are involved in the EMT of SACC and promote tumor invasion. METHODS: CAFs-derived EVs were characterized by western blot and transmission electron microscopy. Wound healing and transwell assay were performed for assessing biological foundation of CAFs-EVs for tumor cells. RNA interference transfection, western blot, wound healing and transwell assay were applied to study the effect of IL6 from CAFs-EVs on SACC cells and the mechanism. A subcutaneous xenograft model was used to evaluate the EMT of SACC induced by CAFs in vivo. RESULTS: In this study, we show that CAFs EVs promote the migration and invasion of SACC cells. The expression of biomarkers of epithelial-mesenchymal transition (EMT) was higher in SACC cells treated with CAFs EVs than in the negative controls, and high levels of IL6 were detected in CAFs and their EVs. Knockdown of IL6 in CAFs decreased tissue invasiveness and EMT biomarker expression in SACC cells induced by CAFs EVs. CAFs EV-associated IL6 promoted SACC EMT by activating the JAK2/STAT3 signaling pathway. CONCLUSION: CAFs-derived EVs carry IL6 to improve EMT of SACC by activating the JAK2/STAT3 signaling pathway.