circCUL2 induces an inflammatory CAF phenotype in pancreatic ductal adenocarcinoma via the activation of the MyD88-dependent NF-κB signaling pathway

Abstract

Background Pancreatic ductal adenocarcinoma (PDAC) is characterized by clusters of cancer cells surrounded by a dense desmoplastic stroma. However, little is known about stromal cell heterogeneity in the pancreatic tumor microenvironment. Methods We conducted circRNA profiling in primary fibroblasts by high-throughput sequencing and detected circCUL2 levels in PDAC tissues by qRT–PCR. We subsequently investigated the effect of circCUL2 on inflammatory cancer-associated fibroblast (iCAF) activation, heterogeneity and protumor activity by ELISA, flow cytometry, colony formation and transwell assays in vitro and by xenograft models in vivo. The regulatory effect of circCUL2 on miR-203a-3p/MyD88/IL6 was examined by RNA pulldown, FISH, and luciferase reporter assays. Results We identified that circCUL2 was specifically expressed in cancer-associated fibroblasts (CAFs) but not in cancer cells. Moreover, the enrichment of circCUL2 in tumor tissues was significantly correlated with the poor prognosis of PDAC patients. Upregulation of circCUL2 expression in normal fibroblasts (NFs) induced the iCAF phenotype, and then iCAFs promoted PDAC progression through IL6 secretion in vitro. Furthermore, circCUL2-transduced NFs promoted tumorigenesis and metastasis of PDAC cells in vivo, which was blocked by an anti-IL6 antibody. Mechanistically, circCUL2 functioned as a ceRNA and modulated the miR-203a-3p/MyD88/NF-κB/IL6 axis, thereby further activating the STAT3 signaling pathway in pancreatic cancer cells to induce PDAC progression. Conclusions We showed that the circCUL2/miR-203a-5p/MyD88/NF-κB/IL6 axis contributes to the induction of iCAFs and established a distinct fibroblast niche for PDAC progression, which could help the development of strategies that selectively target tumor-promoting CAFs in PDAC.

Prognostic, Diagnostic, and Clinicopathological Significance of Circular RNAs in Pancreatic Cancer: A Systematic Review and Meta-Analysis

“…Another 149 studies were removed for not being related to PC or circRNAs, or not providing sufficient data. Ultimately, a total of 48 papers were included in our meta-analysis, including 34 on prognosis [ 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 , 58 , 59 ], 11 on diagnosis [ 29 , 30 , 31 , 48 , 55 , 56 , 60 , 61 , 62 , 63 , 64 ], and 30 on relationship with clinicopathological features [ 28 , 29 , 30 , 31 , 32 , 33 , 34 ,…”

Effects of TP53 Mutations and miRs on Immune Responses in the Tumor Microenvironment Important in Pancreatic Cancer Progression

“…ceRNAs function by binding miRs and inhibiting their function. CircCUL2 inhibited miR-203a-3a and suppressed its ability to inhibit MyD88 and downstream NF-κB and IL-6 and subsequent signal transducer and activator of transcription 3 (STAT3) signaling [ 36 ].…”

“…In this figure, we have indicated where the miRs, LncRNAs and CircRNAs (ncRNAs) affect either the PDAC tumor cells or the CAFs. The effects of the circCUL2 RNA were examined in cells with an inflammatory CAF phenotype in the PDAC microenvironment [36]. This occurred by a myeloid differentiation primary response protein MyD88 (MyD88)-dependent nuclear factor-κB cell (NF-κB) signaling pathway activation.…”

Roles of circular RNAs in the pathogenesis and treatment of pancreatic cancer

“…Some circRNAs interact directly with proteins and stabilize them by inhibiting ubiquitin-proteasomal degradation. For example, circFARP1, which is upregulated in CAFs, interacts with CAV1 and blocks the interaction between CAV1 and the E3 ubiquitin ligase ZNRF1 to inhibit CAV1 degradation (Hu et al, 2022). As CAV1 mediates caveola-mediated exocytosis, CAV1 stabilization enhances LIF exocytosis from CAFs and activates the JAK-STAT signaling pathway in pancreatic cancer cells.…”