Down-regulation of sialidase NEU4 may contribute to invasive properties of human colon cancers
Down-regulation of sialidase NEU4 may contribute to invasive properties of human colon cancers
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DOI：
10.1111/j.1349-7006.2007.00403.x
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发表时间：
2007-03-01
期刊：
影响因子：
5.7
通讯作者：
Miyagi, Taeko
中科院分区：
文献类型：
--
作者：
Yamanami, Hideaki;Shiozaki, Kazuhiro;Miyagi, Taeko
在哺乳动物细胞中，已经描述了四种类型的唾液酸酶，并发现它们在癌症发生过程中以不同的方式发挥作用。我们先前证明了一种与质膜相关的人唾液酸酶(NEU3)在人类结肠癌中上调，并参与抑制细胞凋亡。在这里，我们记录了另一种人类唾液酸酶，最近发现的NEU4的表达变化，以及它对结肠癌恶性表型的影响的证据。人结肠粘膜中NEU4的含量相对较高，有短的和长的两种亚型，但几乎不含后者。与NEU3病例形成鲜明对比的是，定量RT-PCR发现该唾液酸酶在结肠癌组织中的表达水平显著降低。在培养的人结肠癌细胞中，在死亡配体TRAIL或血清耗竭诱导的早期，该酶表达上调，而NEU4的转染会加速细胞的凋亡，降低侵袭力和运动能力。另一方面，siRNA介导的NEU4靶向显著抑制了细胞的凋亡，促进了细胞的侵袭和运动。凝集素印迹分析表明，在NEU4转基因细胞中，随着PNA的增加，近100 kDa糖蛋白的期望形式显著增加，而薄层层析仅检测到糖脂的轻微变化。这些结果表明，NEU4在维持正常粘膜方面起着重要作用，主要是通过抑制糖蛋白，下调可能与结肠癌的侵袭特性有关。
In mammalian cells, four types of sialidase have been described and found to behave in different ways during carcinogenesis. We previously demonstrated that a human sialidase associated with plasma membranes (NEU3) is up-regulated in human colon cancer and is involved in suppression of apoptosis. Here we document altered expression of another human sialidase, the recently identified NEU4, and evidence of its influence on the malignant phenotype in colon cancers. Human colon mucosa was relatively rich in NEU4, which has been observed to possess short and long isoforms, but hardly contained the latter form. In clear contrast to the NEU3 case, the levels of mRNA for this sialidase were found by quantitative RT-PCR to be markedly decreased in colon cancers. In cultured human colon cancer cells, the enzyme was up-regulated in the early stage of apoptosis induced by either the death ligand TRAIL or serum-depletion, and transfection of NEU4 resulted in acceleration of apoptosis and in decreased invasion and motility. The siRNA-mediated NEU4 targeting, on the other hand, caused a significant inhibition of apoptosis and promotion of invasion and motility. Lectin blot analyses revealed that desialylated forms of nearly 100 kDa glycoproteins were prominently increased with PNA in NEU4 transfectants, whereas only slight changes in glycolipids were detected as assessed by thin layer chromatography. These results suggest that NEU4 plays important roles for maintenance of normal mucosa mostly through desialylation of glycoproteins and that down-regulation may contribute to invasive properties of colon cancers.