Reduced Susceptibility to Colitis-Associated Colon Carcinogenesis in Mice Lacking Plasma Membrane-Associated Sialidase

Sialic acids are acidic monosaccharides that bind to the sugar chains of glycoconjugates and change their conformation, intermolecular interactions, and/or half-life. Thus, sialidases are believed to modulate the function of sialoglycoconjugates by desialylation. We previously reported that the membrane-associated mammalian sialidase NEU3, which preferentially acts on gangliosides, is involved in cell differentiation, motility, and tumorigenesis. The NEU3 gene expression is aberrantly elevated in several human cancers, including colon, renal, prostate, and ovarian cancers. The small interfering RNA-mediated knock-down of NEU3 in cancer cell lines, but not in normal cell-derived primary cultures, downregulates EGFR signaling and induces apoptosis. Here, to investigate the physiological role of NEU3 in tumorigenesis, we established Neu3-deficient mice and then subjected them to carcinogen-induced tumorigenesis, using a sporadic and a colitis-associated colon cancer models. The Neu3-deficient mice showed no conspicuous accumulation of gangliosides in the brain or colon mucosa, or overt abnormalities in their growth, development, behavior, or fertility. In dimethylhydrazine-induced colon carcinogenesis, there were no differences in the incidence or growth of tumors between the Neu3-deficient and wild-type mice. On the other hand, the Neu3-deficient mice were less susceptible than wild-type mice to the colitis-associated colon carcinogenesis induced by azoxymethane and dextran sodium sulfate. These results suggest that NEU3 plays an important role in inflammation-dependent tumor development.唾液酸（sialic acids）是一类酸性单糖，可结合于糖缀合物的糖链，改变其构象、分子间相互作用及/或半衰期。因此，唾液酸酶（sialidases）被认为可通过去唾液酸化（desialylation）作用调控唾液酸糖缀合物（sialoglycoconjugates）的功能。我们此前的研究表明，优先作用于神经节苷脂（gangliosides）的膜结合型哺乳动物唾液酸酶NEU3，参与细胞分化、运动及肿瘤发生过程。NEU3基因的表达在结直肠癌、肾癌、前列腺癌及卵巢癌等多种人类癌症中异常升高。通过小干扰RNA（small interfering RNA）介导的NEU3敲低（knock-down），可在癌细胞系中下调表皮生长因子受体（EGFR）信号通路并诱导细胞凋亡，但该效果并未在正常细胞来源的原代培养物中观察到。本研究中，为探究NEU3在肿瘤发生中的生理功能，我们构建了Neu3基因敲除小鼠，并分别采用散发性结肠癌模型与结肠炎相关性结肠癌模型，对其开展致癌物诱导的肿瘤造模实验。结果显示，Neu3基因敲除小鼠的大脑及结肠黏膜中未出现明显的神经节苷脂蓄积，且其生长、发育、行为及生育能力均无显著异常。在二甲基肼（dimethylhydrazine）诱导的结肠癌发生模型中，Neu3基因敲除小鼠与野生型小鼠的肿瘤发生率及肿瘤生长速度均无明显差异。与之相反，在偶氮甲烷（azoxymethane）与葡聚糖硫酸钠（dextran sodium sulfate）诱导的结肠炎相关性结肠癌模型中，Neu3基因敲除小鼠的肿瘤易感性显著低于野生型小鼠。上述结果表明，NEU3在炎症依赖性肿瘤发生发展过程中发挥重要作用。