HIF-1A upregulates IL-6 to promote Schwann cell migration and invasion: a potential mechanism for perineural invasion in pancreatic ductal adenocarcinoma

Perineural invasion (PNI) is a key prognostic factor in pancreatic ductal adenocarcinoma (PDAC), but the microenvironmental drivers remain unknown. This study sought to determine whether hypoxia-induced hypoxia-inducible factor 1-alpha (HIF-1A) initiates malignant crosstalk between cancer cells and Schwann cells that promotes PNI. PDAC and Schwann cell cocultures were established under hypoxia. Cell proliferation, migration, and viability were assessed by qRT-PCR, Western blot, CCK-8, wound healing, and Transwell assays. Chromatin immunoprecipitation and dual-luciferase reporter assays, along with rescue experiments, confirmed transcriptional regulation. HIF-1A was upregulated in PDAC and correlated with PNI severity. Mechanistically, hypoxia-induced HIF-1A bound to the IL-6 promoter and promoted its transcription in PDAC cells. Tumor-derived IL-6 induced proliferation, migration, and survival in Schwann cells, accompanied by increased nerve growth factor (NGF) secretion. Schwann cell-derived NGF in turn promoted epithelial-mesenchymal transition and invasiveness in PDAC cells. IL-6 suppression abolished HIF-1A-driven invasion and disrupted this pathological feedback loop. The IL-6/NGF axis, driven by hypoxia-activated HIF-1A, acts as an important contributor to the vicious bidirectional cycle connecting Schwann cells with pancreatic cancer cells. Consequently, targeting this signaling cascade may offer a potential therapeutic strategy to attenuate perineural invasion and warrants further exploration to improve prognostic outcomes in PDAC.