Sialylation of vesicular integrin β1 of bladder cancer cells promotes its binding to fibronectin, and endocytic entry of small extracellular vesicles into recipient epithelial cells

Small extracellular vesicles (sEV) are closely associated with the development and metastasis of many types of mammalian cancer. Glycoconjugates are highly expressed on sEV and play important roles. However, functions in sEV of sialic acids, the terminal component of glycoconjugates, are poorly understood. We observed greatly increased sialic acid levels in sEV from bladder cancer cells. These sEV promoted the oncogenic transformation of recipient normal bladder epithelial cells. When sialic acids on sEV were eliminated, sEV uptake by recipient cells was significantly reduced. Sialylation of vesicular integrin β1 was found to play a key role in sEV uptake. Desialylation downstream of the hybrid domain of vesicular integrin β1 inhibited its binding to matrix fibronectin, reduced sEV entry into recipient cells, and suppressed metastasis of those cells. Our findings indicate important functional roles of sialic acids in sEV uptake and reprogramming plasticity of surrounding normal epithelial cells.

小细胞外囊泡（small extracellular vesicles, sEV）与多种哺乳动物癌症的发生、发展及转移密切相关。糖缀合物（glycoconjugates）在sEV表面高表达并发挥重要作用。然而，作为糖缀合物末端组分的唾液酸（sialic acids）在sEV中的功能却鲜有深入研究。我们观察到，膀胱癌细胞分泌的sEV中唾液酸水平显著升高。这类sEV可促进受体正常膀胱上皮细胞发生致癌转化。当sEV表面的唾液酸被清除后，受体细胞对sEV的摄取能力显著降低。研究发现，囊泡整合素β1（vesicular integrin β1）的唾液酸化修饰在sEV摄取过程中发挥关键作用。对囊泡整合素β1杂交域下游位点进行去唾液酸化修饰，可抑制其与基质纤连蛋白的结合，减少sEV进入受体细胞，并抑制这些细胞的转移能力。本研究结果表明，唾液酸在sEV摄取及周围正常上皮细胞的重编程可塑性中发挥重要的功能性作用。