Deguelin inhibits perineural invasion in esophageal squamous cell carcinoma via targeting BDNF/TrkB axis

Background: Perineural invasion (PNI) represents a uniquely distinctive pathway for tumor metastasis, but its underlying molecular mechanisms and therapy remain unclear.

Methods: Bioinformatics analysis and transcriptomic Sequencing were first employed to investigate the involvement of the BDNF/TrkB axis in the ESCC PNI, which was validated with ESCC cells co-cultured with a dorsal root ganglia system (ESCC/DRG model), a mouse PNI model, and ESCC tissues, mainly using microscopic imaging, IVIS Spectrum in vivo imaging, Western blot (WB), and immunohistochemistry (IHC). Additionally, transcriptomic Sequencing and WB were conducted to analyze the downstream molecular mechanisms of the BDNF/TrkB axis. Similar experiments were applied to investigate the role of Deguelin in ESCC PNI. Deguelin's interaction with BDNF was assessed using computational docking, pull-down assays, cellular thermal shift assays, surface plasmon resonance (SPR) and WB. Its inhibitory effects on the ESCC PNI were further evaluated through rescue experiments, where BDNF overexpression was used to counteract Deguelin's activity.

Results: The BDNF/TrkB axis is closely associated with the PNI in ESCC. This pathway plays a pivotal role in driving PNI progression via Akt signaling. Deguelin was identified as an effective inhibitor of PNI in ESCC. Mechanistically, BDNF was revealed to be a key binding target of Deguelin, which disrupts PNI development by modulating the BDNF/TrkB/Akt axis. Notably, overexpression of BDNF can counteract Deguelin's inhibitory effects on ESCC growth and PNI progression.

Conclusion: The BDNF/TrkB axis promotes the progression of ESCC PNI, and Deguelin inhibits ESCC PNI by targeting this axis, enhancing the understanding of PNI's molecular mechanisms and offering new therapeutic options.

BDNF; Deguelin; PNI; TrkB; esophageal squamous cell carcinoma.