2. Academic Validation
  3. Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non-canonical Wnt signaling

Secreted AGR2 promotes invasion of colorectal cancer cells via Wnt11-mediated non-canonical Wnt signaling

  • Exp Cell Res. 2018 Mar 15;364(2):198-207. doi: 10.1016/j.yexcr.2018.02.004.
Shaobo Tian 1,  Jia Hu 2,  Kaixiong Tao 3,  Jian Wang 2,  Yanan Chu 2,  Jing Li 3,  Zhibo Liu 3,  Xueliang Ding 2,  Luming Xu 2,  Qilin Li 2,  Ming Cai 3,  Jinbo Gao 3,  Xiaoming Shuai 3,  Guobin Wang 4,  Lin Wang 5,  Zheng Wang 6
Affiliations

Affiliations

  • 1 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.
  • 2 Research Centre for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 3 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
  • 4 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: wgb@hust.edu.cn.
  • 5 Research Centre for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China; Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China. Electronic address: lin_wang@hust.edu.cn.
  • 6 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. Electronic address: zhengwang@hust.edu.cn.
PMID: 29427622 DOI: 10.1016/j.yexcr.2018.02.004
Abstract

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 CA2+/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.

Keywords

Anterior gradient 2; CaMKII; Cell migration; Colorectal cancer; JNK.

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