Extracellular AGR2 triggers lung tumour cell proliferation through repression of p21CIP1
Extracellular AGR2 triggers lung tumour cell proliferation through repression of p21CIP1
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DOI：
10.1016/j.bbamcr.2020.118920
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发表时间：
2021-03-01
影响因子：
5.1
通讯作者：
Delom, Frederic
中科院分区：
文献类型：
--
作者：
Fessart, Delphine;de Barbeyrac, Claire;Delom, Frederic
人类前梯度2 （AGR2）蛋白是一种内质网（ER）常驻蛋白，属于蛋白质二硫异构酶（PDI）超家族，参与内质网中蛋白质折叠的产生。因此，在腺癌中经常发现过表达的AGR2，通过增强内质网蛋白酶抑制作用来促进肿瘤的发展。我们之前证明了AGR2在肿瘤微环境中分泌（细胞外AGR2 (eAGR2)），并在细胞外发挥独立于其内质网功能的作用。在此，我们表明eger2触发细胞增殖并描述了潜在的分子机制。我们证明eger2通过抑制肿瘤抑制因子p21（CIP1）来促进肿瘤细胞的生长。我们的发现揭示了一种新的机制，通过这种机制，eger2作为肿瘤微环境中的生长因子，独立于其内质网功能，从而通过抑制p21（CIP1）来促进肿瘤细胞生长。我们的研究结果为靶向eAGR2/p21（CIP1）信号作为潜在的治疗靶点来阻止肿瘤生长提供了理论依据。
The human Anterior GRadient 2 (AGR2) protein is an Endoplasmic Reticulum (ER)-resident protein which belongs to the Protein-Disulfide Isomerase (PDI) superfamily and is involved to productive protein folding in the ER. As such AGR2, often found overexpressed in adenocarcinomas, contributes to tumour development by enhancing ER proteostasis. We previously demonstrated that AGR2 is secreted (extracellular AGR2 (eAGR2)) in the tumour microenvironment and plays extracellular roles independent of its ER functions. Herein, we show that eAGR2 triggers cell proliferation and characterize the underlying molecular mechanisms. We demonstrate that eAGR2 enhances tumour cell growth by repressing the tumour suppressor p21(CIP1). Our findings shed light on a novel mechanism through which eAGR2 behaves as a growth factor in the tumour microenvironment, independently of its ER function, thus promoting tumour cell growth through repression of p21(CIP1). Our results provide a rationale for targeting eAGR2/p21(CIP1)-based signalling as a potential therapeutic target to impede tumour growth.