Hedgehog-Gli1-derived exosomal circ-0011536 mediates peripheral neural remodeling in pancreatic cancer by modulating the miR-451a/VGF axis

Abstract

Background Hedgehog-Gli1 signaling induces development of two common neurological features seen in pancreatic ductal adenocarcinoma (PDAC): peripheral neural invasion (PNI) and peripheral neural remodeling (PNR). However, the underlying molecular mechanisms in cancer cells and nerves within Gli1-derived PNR have not previously been comprehensively analyzed. Methods In this study, RNA sequencing was used to screen meaningful circRNAs in PNR. An in vitro model of PNR was subsequently constructed through a co-culture system comprising PDAC cells and murine dorsal root ganglia (DRG) (as the neuronal element), and the relevant mechanisms were explored using a series of molecular biology experiments. A subcutaneous nude mouse tumorigenesis model was established to further verify the occurrence of PNR that was detected in human PDAC samples. Results We first confirmed the molecular mechanisms of PNR development through crosstalk between exosomal circ-0011536 and DRG. In Gli1-overpressed PDAC, circ-0011536 is mainly secreted by exosomes. After being ingested by DRG, it can promote the activity of DRG by degrading miR-451a and upregulating the expression of VGF. Overexpression of Gli1 can accelerate the proliferation of subcutaneous tumors in mice and is closely related to the density of nerve plexuses, while downregulating circ-RNA inhibits tumor proliferation and reduces the density of nerve plexuses. In addition, TMA results confirmed that Gli1 overexpression significantly increased the expression of VGF and was closely associated with increased nerve plexus density. Conclusion Hedgehog-Gli1-induced exosomal circ-0011536 promoted PNR via the miR-451a/VGF axis, thereby establishing that it may contribute to PDAC-associated nerve changes with activated Hedgehog signaling.