Tumor-derived exosomal BCYRN1 activates WNT5A/VEGF-C/VEGFR3 feedforward loop to drive lymphatic metastasis of bladder cancer

Background: Patients with lymph node (LN) metastatic bladder cancer (BCa) usual to very poor prognosis. BCa-derived exosomes work as crucial bioactive cargo carriers to mediate the signal transduction in tumor microenvironment triggering tumor metastasis. However, the mechanisms underlying exosome-mediated LN metastasis in BCa are unclear.

Methods: We conducted our prime-throughput sequencing look around the expression profile of lengthy noncoding RNA (lncRNA) in urinary exosomes (urinary-EXO) from patients with BCa and additional evaluated the clinical relevance of exosomal lncRNA BCYRN1 inside a bigger 210-situation cohort. The running role of exosomal BCYRN1 was evaluated with the migration and tube formation assays in vitro and also the footpad-popliteal LN metastasis model in vivo. RNA pull-lower assays, luciferase assays, and actinomycin assays were conducted to identify the regulatory mechanism of exosomal BCYRN1.

Results: LncRNA BCYRN1 was substantially upregulated in urinary-EXO from patients with BCa, and connected using the LN metastasis of BCa. We shown that exosomal BCYRN1 markedly promoted tube formation and migration of human lymphatic endothelial cells (HLECs) in vitro and lymphangiogenesis and LN metastasis of BCa in vivo. Mechanistically, BCYRN1 epigenetically upregulated WNT5A expression by inducing hnRNPA1-connected H3K4 trimethylation in WNT5A promoter, which activated Wnt/ß-catenin signaling to facilitate the secretion of VEGF-C in BCa. Furthermore, exosomal BCYRN1 was transmitted to HLECs to stabilize the VEGFR3 mRNA and therefore created an hnRNPA1/WNT5A/VEGFR3 feedforward regulatory loop, ultimately promoting the lymphatic metastasis of BCa. Importantly, blocking VEGFR3 with specific inhibitor, SAR131675 considerably impaired exosomal BCYRN1-caused the LN metastasis in vivo. Clinically, exosomal BCYRN1 was positively connected using the shorter survival of BCa patients and recognized as an SAR131675 undesirable prognostic factor of patients.

Conclusion: Our results uncover a singular mechanism through which exosomal BCYRN1 synergistically enhances VEGF-C/VEGFR3 signaling-caused lymphatic metastasis of BCa, indicating that BCYRN1 is a good therapeutic target for patients with BCa.