ABSTRACT

Anterior gradient 2 (AGR2) is a protein disulfide isomerase over-expressed in numerous types of cancer. Although AGR2 plays a role in ER homeostasis, its function(s) in tumorigenesis is still elusive. Here we demonstrate that AGR2 is involved in the regulation of the β-subunit of dystroglycan (β-DG), a component of the multi-protein complex linking the extracellular matrix and cytoskeletal network. In breast cancer cells, AGR2 over-expression led to the up-regulation of β-DG but not that of α-DG, while the transcript levels of these subunits were unchanged. Conversely, the reduced expression of AGR2 caused the down-regulation of β-DG. Interestingly, induced expression of AGR2 increased the degree of co-localization of AGR2 and β-DG in the cytoplasm suggesting that AGR2 facilitates the trafficking of β-DG. In addition, AGR2 over-expression caused the re-arrangement of the actin cytoskeletal network. Presumably over-expressed AGR2 up-regulates β-DG post-transcriptionally and facilitates its trafficking, which then causes re-arrangement of the cytoskeletal network, which plays a role in the adhesion and invasion of cancer cells.

抽象的

前梯度2（AGR2）是在多种类型的癌症中过表达的蛋白质二硫键异构酶。尽管AGR2在ER稳态中起作用，但其在肿瘤发生中的功能仍然难以捉摸。在这里，我们证明AGR2参与了dystroglycan（β-DG）的β亚基的调节，β-DG是连接细胞外基质和细胞骨架网络的多蛋白复合物的组成部分。在乳腺癌细胞中，AGR2的过度表达导致β-DG的上调，但不导致α-DG的上调，而这些亚基的转录水平未发生变化。相反，AGR2的表达降低导致β-DG的下调。有趣的是，AGR2的诱导表达增加了AGR2和β-DG在细胞质中的共定位程度，表明AGR2促进了β-DG的运输。此外，AGR2的过表达引起肌动蛋白细胞骨架网络的重新排列。推测过表达的AGR2在转录后上调了β-DG并促进了其运输，然后引起细胞骨架网络的重新排列，这在癌细胞的黏附和侵袭中发挥了作用。