circFARP1 enables cancer-associated fibroblasts to promote gemcitabine resistance in pancreatic cancer via the LIF/STAT3 axis

Abstract

Background Cancer-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. Methods circRNA 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. Results circFARP1 (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. Conclusions The 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.

Cancer-Associated Fibroblasts Confer Gemcitabine Resistance to Pancreatic Cancer Cells through PTEN-Targeting miRNAs in Exosomes

“…In addition to RNA expression changes, it is also important to note that changes to the secreted exosome proteome also play a critical role in sensitizing cells to chemotherapy, as shown by recent studies which found that increasing the efficacy of gemcitabine was possible through a mechanism that disrupted glutamine metabolic pathways [ 53 , 54 ]. In addition to such cell-intrinsic mechanisms, other CAF-based alterations including changes in circular RNAs (circRNAs) have been shown to play a role in the chemoresistance in PDAC cells [ 55 ]. CircRNAs acting as sponges are also known to promote gastric cancer progression via the AKT pathway [ 56 ].…”

Non-coding RNA in cancer drug resistance: Underlying mechanisms and clinical applications

“…Hu et al showed that circFARP1 was involved in the regulation of stemness and gemcitabine resistance in pancreatic ductal adenocarcinoma by altering the ability of cancer-associated fibroblasts via leukemia inhibitory factor (LIF). Functional assays revealed that circFARP1 directly interacted with caveolin 1 to inhibit its degradation by blocking the binding of caveolin 1 to its ubiquitin E3 ligase zinc and ring finger 1 (ZNRF1), thereby enhancing LIF secretion (227). In addition, Chen et al demonstrated that the overexpression of circRNA cia-MAF drove LCSC propagation, self-renewal, and metastasis by facilitating MAFF expression via recruiting the TIP60 complex to its promoter, indicating that cia-MAF may contribute to the drug resistance of liver cancer by modulating CSCs (228).…”

“…showed that circFARP1 was involved in the regulation of stemness and gemcitabine resistance in pancreatic ductal adenocarcinoma by altering the ability of cancer-associated fibroblasts via leukemia inhibitory factor (LIF). Functional assays revealed that circFARP1 directly interacted with caveolin 1 to inhibit its degradation by blocking the binding of caveolin 1 to its ubiquitin E3 ligase zinc and ring finger 1 (ZNRF1), thereby enhancing LIF secretion ( 227 ). In addition, Chen et al.…”

The Molecular Basis and Therapeutic Potential of Leukemia Inhibitory Factor in Cancer Cachexia

“…It has been shown that numerous cancers, including pancreatic, colorectal, esophageal, ovarian, renal, gastric, uterine squamous, and testicular cancers, could aberrantly highly express LIF [ 44 ]. In addition, because cachexia is a systemic disease, elevated serum LIF is seen as an indicator of poor prognosis for cancer patients, further demonstrating its potential key role in this pathological process [ 45 , 46 , 47 ]. Studies have shown that some cancer deaths are attributed to cancer-associated cachexia (CAC), such as pancreatic, esophageal, stomach, lung, liver, and colon cancers [ 2 ].…”