NEU4 inhibits motility of HCC cells by cleaving sialic acids on CD44.
NEU4 inhibits motility of HCC cells by cleaving sialic acids on CD44.
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NEU4 通过裂解 CD44 上的唾液酸来抑制 HCC 细胞的运动。
作者：
Zhang Xiaoqing;Dou Peng;Akhtar Muhammad Luqman;Liu Fei;Hu Xibo;Yang Lijun;Yang Depeng;Zhang Xiaohan;Li Yiqun;Qiao Shupei;Li Kai;Tang Ran;Zhan Chao;Ma Yue;Cheng Qixiang;Bai Yan;Han Fang;Nie Huan;Li Yu
肝细胞癌是一种转移性极强的肿瘤。唾液酸(SA)与癌症的发展和转移有关。NEU4是一种唾液酸酶，可将SA从糖结合物中去除，而NEU4在肝细胞癌中的作用尚不清楚。在我们的研究中，我们发现NEU4在肝细胞癌组织中的表达显著下调，这与肝细胞癌的高级别和不良预后有关。NEU4的表达受组蛋白乙酰化的调控。在NEU4的功能分析中，当NEU4过表达时，细胞的运动受到抑制，当NEU4表达下调时，细胞的运动能力恢复。同样，NEU4过表达的肝癌细胞在裸鼠体内转移较少。进一步研究发现，NEU4可通过酶解SAS抑制细胞迁移。我们的结果证实了NEU4活性位点(NEU4E235)和过度表达使NEU4E235A失活，从而削弱了对细胞迁移的抑制能力。进一步通过质谱学鉴定了包括CD44在内的70种NEU4特异性相互作用蛋白。此外，当α过表达或激活时，CD442，3连接的SA减少，透明质酸(HA)结合能力增强。此外，与野生型CD44相比，具有6个N-糖基化位点的CD44突变对NEU4在细胞迁移方面的敏感性较低。综上所述，我们的研究结果揭示了NEU4在肝癌中低表达的机制及其通过去除CD44上的SAS抑制细胞迁移的作用，这可能为控制肝癌的运动和转移提供新的治疗策略。
Hepatocellular carcinoma (HCC) is an extremely metastatic tumor. Sialic acids (SAs) are associated with cancer development and metastasis. NEU4 is a sialidase that removes SAs from glycoconjugates, while the function of the NEU4 in HCC has not been clearly explored. In our research, we found the NEU4 expression was significantly down-regulated in HCC tissues, which was correlated with high grades and poor outcomes of HCC. The NEU4 expression could be regulated by histone acetylation. In the functional analysis of NEU4, the cell motility was inhibited when NEU4 was overexpressed, and restored when NEU4 expression was down-regulated. Similarly, NEU4 over-expressed HCC cells showed less metastasis in athymic nude mice. Further study revealed that NEU4 could inhibit cell migration by enzymatic decomposition of SAs. Our results verified a NEU4 active site (NEU4E235) and overexpressing inactivates NEU4E235Athat weakens the inhibition ability to cell migration. Further, 70 kinds of specific interacting proteins of NEU4 including CD44 were identified through mass spectrum. Moreover, the α2,3-linked SAs on CD44 were decreased and the hyaluronic acid (HA) binding ability was increased when NEU4 over-expressed or activated. Additionally, the mutation of CD44 with six N-glycosylation sites showed less sensibility to NEU4 on cell migration compared with wild-type CD44. In summary, our results revealed the mechanism of low expression of NEU4 in HCC and its inhibitory effect on cell migration by removal of SAs on CD44, which may provide new treatment strategies to control the motility and metastasis of HCC.