唾液酸酶NEU1调节纤连蛋白和整合素α5β1的相互作用抑制膀胱癌发展的机制研究

Abnormal high expression of sialic acid (Sia) on cancer cell surface is a distinctive feature associated with malignant properties including invasiveness and metastatic potential. However, the biological function of sialidase (also termed as Neuraminidase, NEU), but not sialyltransferases, were less documented in cancer research. In preliminary study, higher expression of Sias, but lower expression of neuraminidase 1 (NEU1) in bladder cancer cells than in normal epithelial bladder cells were observed. In NEU1 expressed bladder cancer cells, expression of fibronectin (FN) and integrinα5β1 were down-regulated, cell proliferation was inhibited and cell apoptosis was enhanced. Furthermore, overexpression of NEU1 in bladder cancer cells suppressed tumor growth in vivo. However, the mechanism of NEU1 on the suppression of bladder cancer remains unclear. Based on above observations, we proposed that NEU1 could enhance cell apoptosis and decrease cell proliferation by disrupting the interaction of FN and integrinα5β1 and attenuating downstream signaling pathway. This proposal will explore the correlation of NEU1 expression and the progression of bladder cancer, explain the mechanism how NEU1 modulates the interaction of FN and integrinα5β1 and its signaling pathway, evaluate the efficiency and safety of NEU1 in vivo, and make a contribution to the clinical therapy of bladder cancer.

唾液酸的高表达显著影响肿瘤细胞的侵袭及迁移，但肿瘤中唾液酸酶的生物学功能很少受到关注。申请人在预实验中发现膀胱癌细胞中唾液酸酶NEU1的低表达是唾液酸升高的主要因素；在膀胱癌细胞过表达NEU1，纤连蛋白（FN）和整合素α5β1表达显著下降；细胞增殖受到抑制，凋亡升高；过表达NEU1的膀胱癌细胞在小鼠体内成瘤能力显著下降。但是NEU1抑制膀胱癌的分子机制尚不清楚。基于预实验结果，本项目推测：NEU1通过调节FN和整合素α5β1的相互作用及其下游的信号通路，影响膀胱癌细胞的增殖与凋亡。本项目将评估NEU1表达与膀胱癌病情发展的相关性，阐明NEU1如何调节FN和整合素α5β1互相作用及相关的信号通路，并通过小鼠模型对NEU1抑制膀胱癌的有效性及安全性进行论证，以期为膀胱癌的临床诊疗开拓新思路并提供理论依据。