Institute of Molecular and Cell Biology, Proteos, Singapore 138673.
Proc Natl Acad Sci U S A. 2013 Aug 20;110(34):E3152-61. doi: 10.1073/pnas.1305269110. Epub 2013 Aug 2.
Invasiveness underlies cancer aggressiveness and is a hallmark of malignancy. Most malignant tumors have elevated levels of Tn, an O-GalNAc glycan. Mechanisms underlying Tn up-regulation and its effects remain unclear. Here we show that Golgi-to-endoplasmic reticulum relocation of polypeptide N-acetylgalactosamine-transferases (GalNAc-Ts) drives high Tn levels in cancer cell lines and in 70% of malignant breast tumors. This process stimulates cell adhesion to the extracellular matrix, as well as migration and invasiveness. The GalNAc-Ts lectin domain, mediating high-density glycosylation, is critical for these effects. Interfering with the lectin domain function inhibited carcinoma cell migration in vitro and metastatic potential in mice. We also show that stimulation of cell migration is dependent on Tn-bearing proteins present in lamellipodia of migrating cells. Our findings suggest that relocation of GalNAc-Ts to the endoplasmic reticulum frequently occurs upon cancerous transformation to enhance tumor cell migration and invasiveness through modification of cell surface proteins.
侵袭性是癌症侵袭性的基础，也是恶性肿瘤的标志。大多数恶性肿瘤中 Tn 的水平升高，Tn 是一种 O-GalNAc 聚糖。Tn 上调的机制及其作用尚不清楚。在这里，我们表明，高尔基体内质网重定位的多肽 N-乙酰半乳糖胺转移酶（GalNAc-Ts）导致癌细胞系和 70%的恶性乳腺癌中 Tn 水平升高。这个过程刺激细胞与细胞外基质的黏附，以及迁移和侵袭。GalNAc-Ts 的凝集素结构域介导高密度糖基化，对这些效应至关重要。干扰凝集素结构域的功能会抑制体外癌细胞的迁移和在小鼠中的转移潜能。我们还表明，细胞迁移的刺激依赖于迁移细胞的片状伪足中存在的 Tn 结合蛋白。我们的研究结果表明，GalNAc-Ts 向内质网的重定位在癌变时经常发生，通过修饰细胞表面蛋白来增强肿瘤细胞的迁移和侵袭。
