Hypersialylation of β1 integrins, observed in colon adenocarcinoma, may contribute to cancer progression by up-regulating cell motility
Hypersialylation of β1 integrins, observed in colon adenocarcinoma, may contribute to cancer progression by up-regulating cell motility
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DOI：
10.1158/0008-5472.can-04-3117
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发表时间：
2005-06-01
期刊：
影响因子：
11.2
通讯作者：
Beilis, SL
中科院分区：
文献类型：
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作者：
Seales, EC;Jurado, GA;Beilis, SL
已知结肠腺癌表达α 2-6唾液化水平升高和ST6Gal-I活性增加，ST6Gal-I是产生α 2-6键的高尔基糖基转移酶。升高的ST6Gal-I与转移和生存不良呈正相关，因此ST6Gal-I介导的高唾液化可能在结直肠肿瘤侵袭中起作用。先前我们发现致癌ras（存在于大约50%的结肠腺癌中）上调ST6Gal-I，进而增加结肠上皮细胞中β(1)整合素粘附受体的唾液化。然而，我们想知道这种模式在体内是否成立，如果是这样，β(1)高唾液化如何促进结肠肿瘤的进展。在本研究中，我们发现来自结肠腺癌的0]整合素始终携带较高水平的α 2-6唾液酸。为了探索α 2-6唾液化增加对β(1)-整合素功能的影响，我们在缺乏内源性ST6Gal-I的结肠上皮细胞系中稳定表达了ST6Gal-I。st6gai表达者（具有α 2-6唾液化的β(1)整合素）对I型胶原和层粘连蛋白的粘附上调，相对于亲本细胞（具有完全未唾液化的β(1)整合素），向I型胶原的触致迁移增加。用短干扰RNA阻断ST6Gal-I表达可逆转胶原结合回到ST6Gal-I非表达蛋白水平，证实α 2-6唾液化调节β(1)整合素功能。最后，我们发现来自ST6Gal-I表达体的β(1)整合素与talin的关联增加，talin是整合素激活的标记。总的来说，这些发现表明β(1)高唾液化可能通过改变细胞对某些细胞外基质环境的偏好以及刺激细胞迁移来促进结肠肿瘤的进展。
Colon adenocareinomas are known to express elevated levels of alpha 2-6 sialylation and increased activity of ST6Gal-I, the Golgi glycosyltransferase that creates alpha 2-6 linkages. Elevated ST6Gal-I positively correlates with metastasis and poor survival, and therefore ST6Gal-I-mediated hypersialylation likely plays a role in colorectal tumor invasion. Previously we found that oncogenic ras (present in roughly 50% of colon adenocarcinomas) up-regulates ST6Gal-I and, in turn, increases sialylation of beta(1) integrin adhesion receptors in colon epithelial cells. However, we wanted to know if this pattern held true in vivo and, if so, how beta(1) hypersialylation might contribute to colon tumor progression. In the present study, we find that 0] integrins from colon adenocarcinomas consistently carry higher levels of alpha 2-6 sialic acid. To explore the effects of increased alpha 2-6 sialylation on beta(1)-integrin function, we stably expressed ST6Gal-I in a colon epithelial cell line lacking endogenous ST6Gal-I. ST6GaI-I expressors (with alpha 2-6 sialylated beta(1) integrins) exhibited up-regulated attachment to collagen I and laminin and increased haptotactic migration toward collagen I relative to parental cells (with completely unsialylated beta(1) integrins). Blockade of ST6Gal-I expression with short interfering RNA reversed collagen binding back to the level of ST6Gal-I nonexpressors, confirming that alpha 2-6 sialylation regulates beta(1) integrin function. Finally, we show that beta(1) integrins from ST6Gal-I expressors have increased association with talin, a marker for integrin activation. Collectively, these findings suggest that beta(1) hypersialylation may augment colon tumor progression by altering cell preference for certain extracellular matrix milieus, as well as by stimulating cell migration.