Notch1+ cervical cancer cells may promote perineural invasion by secreting neurotrophin-4

This study aimed to evaluate the prognostic value of PNI and investigate a possible role of Notch1 in the progression of PNI in cervical cancer. This retrospective cohort study evaluated the prognostic implications of PNI in cervical cancer patients. Survival outcomes were assessed using Kaplan–Meier analysis, while prognostic factors were identified through univariate and multivariate cox regression analyses. Clinical characteristics and the prognostic impact of PNI were analyzed using Chi-square and Log-rank tests. ROC curves were established to calculate the prediction performance of clinicopathological features for cervical cancer PNI. Additionally, the spatial distribution of Notch1 in cervical cancer tissues was visualized through immunofluorescence staining. The role of Notch1 in PNI was assessed by examining sciatic nerve invasion in cervical cancer tumor-bearing mice. Bioinformatics analysis of publicly available transcriptomic data combined with experimental validation were used to identify possible correlations between neurotrophin-4 (NT-4) and Notch1 signaling. A retrospective analysis of 755 cervical cancer patients revealed a PNI incidence of 9.4% (71/755). After propensity score matching (PSM), patients with PNI exhibited significantly reduced overall survival (OS) (p < 0.001***) and disease-free survival (DFS) (p = 0.003**) intervals compared to PNI-negative patients. Moreover, multivariate analysis identified PNI as an independent risk factor for both OS (HR = 3.062, 95% CI = 1.185–7.912, p = 0.021*) and DFS (HR = 3.761, 95% CI = 1.958–7.224, p < 0.001***). Lymph node metastasis (AUC = 0.596, p = 0.013*), tumor type (AUC = 0.858, p = 0.000***), vascular invasion (AUC = 0.633, p = 0.001***), and depth of cervical invasion (AUC = 0.898, p = 0.000***) have significant value in PNI prediction. Immunofluorescence staining assays demonstrated Notch1+ cervical cancer cells are preferentially distributed along nerve fibers. Mechanistically, we observed colocalization and strong positive correlation between Notch1 and NT-4 expression. NT4 administration rescued the impaired proliferation of neural stem cells (NSCs) resulting from Notch1 knockdown. PNI is significantly associated with poor clinical outcomes and can guide adjuvant treatment in cervical cancer patients. Additionally, Notch1+ cervical cancer cells might serve as targets for interventions aimed at suppressing PNI development.