Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis
Organelle Specific O-Glycosylation Drives MMP14 Activation, Tumor Growth, and Metastasis
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DOI：
10.1016/j.ccell.2017.10.001
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发表时间：
2017-11-13
期刊：
影响因子：
50.3
通讯作者：
Bard, Frederic
中科院分区：
文献类型：
--
作者：
Anh Tuan Nguyen;Chia, Joanne;Bard, Frederic
癌症通过分子机制在组织内生长仍不清楚。侵袭性与受干扰的 O-糖基化（细胞表面蛋白的共价修饰）相关。在这里，我们发现，在人和小鼠肝癌中，GALNT 糖基转移酶引发的 O-糖基化增加，并从高尔基体转移到内质网 (ER)。在小鼠肝癌模型中，表达 ER 靶向 GALNT1 (ER-G1) 会大幅增加肿瘤扩张，中位生存期从 23 周缩短至 10 周。体外细胞生长不受影响，但 ER-G1 强烈促进基质降解和组织侵袭。与高尔基体定位的对应物不同，ER-G1 糖基化基质金属蛋白酶 MMP14，这是肿瘤扩张所需的过程。总之，我们的结果表明，GALNT 在转移到 ER 后强烈促进肝脏肿瘤的生长。
Cancers grow within tissues through molecular mechanisms still unclear. Invasiveness correlates with perturbed O-glycosylation, a covalent modification of cell-surface proteins. Here, we show that, in human and mouse liver cancers, initiation of O-glycosylation by the GALNT glycosyl-transferases increases and shifts from the Golgi to the endoplasmic reticulum (ER). In a mouse liver cancer model, expressing an ER-targeted GALNT1 (ER-G1) massively increased tumor expansion, with median survival reduced from 23 to 10 weeks. In vitro cell growth was unaffected, but ER-G1 strongly enabled matrix degradation and tissue invasion. Unlike its Golgi-localized counterpart, ER-G1 glycosylates the matrix metalloproteinase MMP14, a process required for tumor expansion. Together, our results indicate that GALNTs strongly promote liver tumor growth after relocating to the ER.