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 ESCCrelated 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.

Exosomal Long Non-coding RNAs: Emerging Players in the Tumor Microenvironment

“… 139 High levels of lncRNAs in serum exosomes are associated with a poor response to chemotherapy treatment, suggesting that targeting exosomal lncRNAs could be a potential therapy for drug-resistant tumors. 140 , 141 lncRNA-based anticancer therapies could involve the use of lncRNA antagonists against oncogenic lncRNAs or the introduction of tumor-suppressive lncRNA mimics. However, the strategy of delivering lncRNAs to their target cells and their safety profiles remain to be determined.…”

Remodeling of Stromal Cells and Immune Landscape in Microenvironment During Tumor Progression

“…POU3F3 regulates fibroblast differentiation to CAFs and causes cisplatin resistance in ESCC. Many lncRNAs with similar roles in different cancers are known: CASC9, PART1, CCAT1, TTN-AS1, DNM3OS, FMR1-AS1, LINC01419, NMR, PCAT1, ROR ( 40 ). Aberrant circRNA expression is co-related with myofibroblast differentiation and tumorigenesis.…”

Noncoding RNAs in the Interplay between Tumor Cells and Cancer-Associated Fibroblasts: Signals to Catch and Targets to Hit

“…Similarly, microvesicles from patients with hormone-treatment resistant metastatic breast cancer expressed high levels of miR-221 [ 88 ], thus making this miRNA a possible predictive or monitoring biomarker. High levels of plasma exosomal lncRNA POU3F3 correlated significantly with lack of complete response to cisplatin and poor survival in esophageal squamous cell carcinoma patients [ 94 ].…”