Abstract
BackgroundCancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). However, the underlying mechanism by which CAFs promote chemotherapy resistance remains unexplored. Here, we explored the role of circRNAs in CAF-induced GEM resistance in PDAC.MethodscircRNA sequencing and quantitative real-time PCR (qRT–PCR) were utilized to screen CAF-specific circRNAs. The effects of CAF circFARP1 expression on GEM resistance in tumor cells were assessed in vitro and in vivo. RNA-seq, RNA pulldown, RNA immunoprecipitation, and luciferase reporter assays were used to screen the downstream target and underlying mechanism of circFARP1.ResultscircFARP1 (hsa_circ_0002557), a CAF-specific circRNA, was positively correlated with GEM chemoresistance and poor survival in an advanced PDAC cohort. Silencing or overexpressing circFARP1 in CAFs altered the ability of CAFs to induce tumor cell stemness and GEM resistance via leukemia inhibitory factor (LIF). Mechanistically, we found that circFARP1 directly binds with caveolin 1 (CAV1) and blocks the interaction of CAV1 and the E3 ubiquitin-protein ligase zinc and ring finger 1 (ZNRF1) to inhibit CAV1 degradation, which enhances LIF secretion. In addition, circFARP1 upregulated LIF expression by sponging miR-660-3p. Moreover, high circFARP1 levels were positively correlated with elevated serum LIF levels in PDAC and poor patient survival. Decreasing circFARP1 levels and neutralizing LIF significantly suppressed PDAC growth and GEM resistance in patient-derived xenograft models.ConclusionsThe circFARP1/CAV1/miR-660-3p/LIF axis is critical for CAF-induced GEM resistance in PDAC. Hence, circFARP1 may be a potential therapeutic target for PDAC.
Highlights
Cancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC)
Identification of a CAF‐specific circRNA, circFARP1, that correlated with GEM resistance in PDAC To characterize upregulated circRNAs in CAFs that mediate GEM resistance in PDAC, we first analyzed RNA-seq in CAFs and paired normal fibroblasts (NFs) (GSE172096) and identified 50 upregulated circRNAs in CAFs (Fig. 1A)
Quantitative real-time PCR was performed to screen the expression of CAF-specific circRNAs, and the results showed that 3 circRNAs, circFARP1, circCUL2 and circARMC9, were significantly expressed in CAFs but not in cancer cells or other stromal cells (Fig. 1B and Fig. S1AB)
Summary
Cancer-associated fibroblasts (CAFs) are critically involved in gemcitabine (GEM) resistance in pancreatic ductal adenocarcinoma (PDAC). The underlying mechanism by which CAFs promote chemotherapy resistance remains unexplored. We explored the role of circRNAs in CAF-induced GEM resistance in PDAC. Despite constant progress in the application of multiple therapeutic strategies and expanded research efforts, pancreatic ductal adenocarcinoma (PDAC) remains one of the most aggressive and lethal malignancies [1]. In the course of chemotherapy or radiotherapy, tumor cells dynamically adapt to stress via self-mutation and phenotypic transformation [5, 6], but the key roles of various components of the TME in the response to chemo- and radiotherapy remain unclear. Cancer-associated fibroblasts (CAFs) are the predominant cell type within the tumor stroma; they exhibit heterogeneity and plasticity during cancer evolution and can have tumor-promoting, tumor-restraining or homeostatic functions in PDAC [7]. To precisely target heterogeneous CAFs that contribute to cancer progression, it is necessary to enhance our understanding of the modulation of CAFs in the TME
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