Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Research Centre for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Research Centre for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
Exp Cell Res. 2018 Mar 15;364(2):198-207. doi: 10.1016/j.yexcr.2018.02.004. Epub 2018 Feb 7.
Human anterior gradient-2 (AGR2), a member of protein disulfide isomerase (PDI) family, is present in both intracellular and extracellular compartments. Although AGR2 is overexpressed in various human cancers and reported to promote aggressive tumor features, little is known regarding AGR2's extracellular functions during tumorigenesis. Here, we demonstrate that secreted AGR2 promotes cell migration and metastasis of colorectal cancer (CRC) in vitro and in vivo. Mechanistically, secreted AGR2 elevated Wnt11 expression, triggering non-canonical Wnt signaling: the Ca/Calmodulin-dependent protein kinase II (CaMKII) and c-jun amino-terminal kinase (JNK) pathways. Knockdown of Wnt11 or pretreatment with CaMKII and JNK inhibitors reversed the secreted AGR2's migration-promoting effect. Further studies revealed that AGR2 antagonized canonical Wnt/β-catenin signaling via activating CaMKII. Collectively, our study uncovers a critical role of Wnt11-mediated non-canonical Wnt signaling (CaMKII and JNK pathways) in secreted AGR2's promoted migration of CRC cells. These results raise the possibility that secreted AGR2 may be a potential therapeutic target towards inhibiting CRC metastasis.
人类前梯度-2（AGR2）是蛋白质二硫键异构酶（PDI）家族的成员，存在于细胞内和细胞外区室中。尽管 AGR2 在各种人类癌症中过表达，并被报道促进侵袭性肿瘤特征，但对于 AGR2 在肿瘤发生过程中的细胞外功能知之甚少。在这里，我们证明分泌的 AGR2 在体外和体内促进结直肠癌（CRC）的细胞迁移和转移。在机制上，分泌的 AGR2 上调了 Wnt11 的表达，触发非经典 Wnt 信号：钙/钙调蛋白依赖性蛋白激酶 II（CaMKII）和 c-jun 氨基末端激酶（JNK）途径。敲低 Wnt11 或用 CaMKII 和 JNK 抑制剂预处理可逆转分泌的 AGR2 的促迁移作用。进一步的研究表明，AGR2 通过激活 CaMKII 拮抗经典的 Wnt/β-catenin 信号。总之，我们的研究揭示了 Wnt11 介导的非经典 Wnt 信号（CaMKII 和 JNK 途径）在分泌的 AGR2 促进 CRC 细胞迁移中的关键作用。这些结果提出了这样一种可能性，即分泌的 AGR2 可能是抑制 CRC 转移的潜在治疗靶点。
