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

ABSTRACT

Cancer-associated fibroblasts (CAFs), an activated subpopulation 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. Herein, we report that tumor-secreted exosomal long non-coding RNAs (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 that it mediated fibroblast activation. Activated fibroblasts further promoted proliferation and cisplatin resistance of ESCC cells through secreting interleukin 6 (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 that this effect is mediated through exosomal lncRNA POU3F3-induced transformation of NFs to CAFs.