Tumor-Secreted Exosomal lncRNA POU3F3 Promotes Cisplatin Resistance in ESCC by Inducing Fibroblast Differentiation into CAFs

Abstract Cancer-associated fibroblasts (CAFs), an activated sub-population of fibroblasts, occupy a central position in the tumor microenvironment and have been shown to promote chemoresistance in multiple cancer types by secreting inflammatory cytokines. Here we report that tumor-secreted exosomal lncRNAs can regulate cisplatin resistance in esophageal squamous cell carcinoma (ESCC) through transformation of normal fibroblasts (NFs) to CAFs. Primary CAFs and matched NFs were isolated from tumor tissues and matched normal esophageal epithelial tissues of ESCC patients. Fluorescence microscopy and qRT-PCR were used to investigate the transportation of exosomal lncRNAs from ESCC cells to NFs. To identify the specific lncRNAs involved, 14 ESCC-related lncRNAs were measured in NFs after incubation with exosomes from ESCC cells. We demonstrated that lncRNA POU3F3 can be transferred from ESCC cells to NFs via exosomes, and mediated fibroblasts activation. Activated fibroblast further promoted proliferation and cisplatin resistance of ESCC cells through secreting IL-6. Moreover, our clinical data showed that high levels of plasma exosomal lncRNA POU3F3 correlated significantly with lack of complete response and poor survival in ESCC patients. Therefore, these data demonstrate that lncRNA POU3F3 is involved in cisplatin resistance in ESCC and this effect is mediated through exosomal lncRNA POU3F3-induced transformation of NFs to CAFs.