Plasma membrane-associated sialidase (NEU3) promotes formation of colonic aberrant crypt foci in azoxymethane-treated transgenic mice
Plasma membrane-associated sialidase (NEU3) promotes formation of colonic aberrant crypt foci in azoxymethane-treated transgenic mice
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DOI：
10.1111/j.1349-7006.2008.01080.x
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发表时间：
2009-04-01
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：
Shiozaki, Kazuhiro;Yamaguchi, Kazunori;Miyagi, Taeko
人质膜相关唾液酸酶（NEU 3）特异性水解神经节苷脂，在结肠癌中上调，并在恶性表型的表达中起重要作用。为了阐明NEU 3在体内肿瘤发生中的作用，我们研究了NEU 3转基因小鼠对氧化偶氮甲烷诱导结肠异常隐窝灶（ACF）的敏感性。小鼠注射氧化偶氮甲烷（i. p.，15 mg/kg/周）持续6周，4周后，在NEU 3转基因小鼠中形成的ACF显著多于对照野生型小鼠。在转基因结肠粘膜中观察到表皮生长因子（EGF）受体、Akt和ERK的磷酸化增强以及Bcl-xL蛋白的上调，但未发现细胞增殖的变化，这表明ACF形成的增加是由于细胞凋亡的抑制。免疫组织化学分析与抗切割半胱天冬酶3抗体显示，在第一次注射氧化偶氮甲烷后6小时，在结肠隐窝发生凋亡时，在转基因粘膜中的凋亡细胞的实际减少。与我们先前对人结肠癌的观察一致，来自转基因结肠粘膜的神经节苷脂的薄层色谱显示与来自对照粘膜的那些相比GM 3减少和乳糖神经酰胺增加，这可能是由于NEU 3对神经节苷脂的催化。这项研究的结果提供了第一个证据，即NEU 3基本上增加氧化偶氮甲烷诱导的ACF形成的结肠粘膜细胞凋亡的抑制，可能通过激活的EGF信号通路，从而表明，上调NEU 3是重要的促进阶段的结直肠癌在体内发生。（Cancer Sci 2009; 100：588-594）
Human plasma membrane-associated sialidase (NEU3) specifically hydrolyzes gangliosides, and it is up-regulated in colon cancer and plays an essential role in the expression of malignant phenotypes. To clarify the role of NEU3 in tumorigenesis in vivo, we examined the susceptibility of NEU3 transgenic mice to induction of colonic aberrant crypt foci (ACF) by azoxymethane. Mice were injected with azoxymethane (i.p., 15 mg/kg/week) for 6 weeks, and 4 weeks later ACF had formed in the NEU3 transgenic mice significantly more than in the control wild-type mice. Enhanced phosphorylation of epidermal growth factor (EGF) receptor, Akt and ERK and up-regulation of Bcl-xL protein were observed in the transgenic colon mucosa, but no changes were found in cell proliferation, suggesting that the increased ACF formation is due to suppression of apoptosis. Immunohistological analysis with anti-cleaved caspase 3 antibody showed an actual reduction in apoptotic cells in the transgenic mucosa at 6 h after the first azoxymethane injection, when apoptosis in the colonic crypt occurs. Consistent with our previous observations of human colon cancer, thin-layer chromatography of the gangliosides from the transgenic colon mucosa revealed decreased GM3 and increased lactosylceramide as compared to those from the control mucosa, probably because of catalysis of gangliosides by NEU3. The results of this study provide the first evidence that NEU3 essentially increases azoxymethane-induced ACF formation in colon mucosa by suppression of apoptosis, possibly via activation of the EGF signaling pathway, and thus indicate that up-regulation of NEU3 is important to the promotion stage of colorectal carcinogenesis in vivo. (Cancer Sci 2009; 100: 588-594)