Chitinase 3-like 1 expression associated with lymphatic metastasis and prognosis in urothelial carcinoma of the bladder.

OBJECTIVES: Lymphatic metastasis, an early stage of the metastasis process, is associated with adverse clinical outcomes in urothelial carcinoma of the bladder (UCB). However, the role of inflammation in triggering lymphatic metastasis remains unclear.

METHODS: We employed an RNA-sequencing cohort ( n  = 50) from Sun Yat-Sen Memorial Hospital (SYMH) to identify the most highly upregulated inflammatory gene associated with lymphatic metastasis. Using immunohistochemistry and immunofluorescence analyses, we validated the association of the identified molecule with clinical features and prognosis in an independent UCB cohort ( n  = 244) from SYMH. We also analysed TCGA-BLCA cohort ( n  = 408) to identify its potential biological pathways and immune landscape.

RESULTS: In our study, chitinase 3-like 1 (CHI3L1) emerged as a significantly overexpressed proinflammatory mediator in UCB tissues with lymphatic metastasis compared to those without lymphatic metastasis (81.1% vs. 47.8%, P  < 0.001). Within UCB tissues, CHI3L1 was expressed in both stromal cells (52.8%) and tumor cells (7.3%). Moreover, CHI3L1+ stromal cells, but not tumor cells, exhibited independent prognostic significance for both overall survival ( P  < 0.001) and recurrence-free survival ( P  = 0.006). CHI3L1+ stromal cells were positively associated with D2-40+ lymphatic vessel density ( P  < 0.001) and the immunosuppressive PD-L1/PD-1/CD8 axis in UCB tissues (all P  < 0.05). A bioinformatics analysis also identified a positive association between CHI3L1 expression and lymphangiogenesis or immunosuppression pathways.

CONCLUSION: Our study established a clear association between stromal CHI3L1 expression and lymphatic metastasis, suggesting that stromal CHI3L1 expression is a potential prognostic marker for bladder cancer patients.