Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University (SYSU), No. 628, Zhenyuan Road, Guangming Dist., Shenzhen 518107, China.
Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University (SYSU), No. 628, Zhenyuan Road, Guangming Dist., Shenzhen 518107, China.
Cells. 2022 Jul 7;11(14):2136. doi: 10.3390/cells11142136.
Cancer cell survival, function and fate strongly depend on endoplasmic reticulum (ER) proteostasis. Although previous studies have implicated the ER stress signaling network in all stages of cancer development, its role in cancer metastasis remains to be elucidated. In this study, we investigated the role of Gremlin-1 (GREM1), a secreted protein, in the invasion and metastasis of colorectal cancer (CRC) cells in vitro and in vivo. Firstly, public datasets showed a positive correlation between high expression of GREM1 and a poor prognosis for CRC. Secondly, GREM1 enhanced motility and invasion of CRC cells by epithelial-mesenchymal transition (EMT). Thirdly, GREM1 upregulated expression of activating transcription factor 6 (ATF6) and downregulated that of ATF4, and modulation of the two key players of the unfolded protein response (UPR) was possibly through activation of PI3K/AKT/mTOR and antagonization of BMP2 signaling pathways, respectively. Taken together, our results demonstrate that GREM1 is an invasion-promoting factor via regulation of ATF6 and ATF4 expression in CRC cells, suggesting GREM1 may be a potential pharmacological target for colorectal cancer treatment.
癌细胞的存活、功能和命运在很大程度上取决于内质网（ER）的蛋白质稳态。尽管先前的研究已经表明 ER 应激信号网络存在于癌症发展的所有阶段，但它在癌症转移中的作用仍有待阐明。在这项研究中，我们研究了分泌蛋白 Gremlin-1（GREM1）在体外和体内结直肠癌（CRC）细胞侵袭和转移中的作用。首先，公共数据集显示 GREM1 高表达与 CRC 预后不良呈正相关。其次，GREM1 通过上皮-间充质转化（EMT）增强 CRC 细胞的迁移和侵袭能力。第三，GREM1 上调激活转录因子 6（ATF6）的表达并下调 ATF4 的表达，并且 UPR 的两个关键参与者的调节可能分别通过激活 PI3K/AKT/mTOR 和拮抗 BMP2 信号通路。综上所述，我们的研究结果表明，GREM1 通过调节 CRC 细胞中 ATF6 和 ATF4 的表达是一种促进侵袭的因子，提示 GREM1 可能是治疗结直肠癌的潜在药物靶点。
