Journal
EXPERIMENTAL CELL RESEARCH
Volume 364, Issue 2, Pages 198-207Publisher
ELSEVIER INC
DOI: 10.1016/j.yexcr.2018.02.004
Keywords
Anterior gradient 2; Colorectal cancer; Cell migration; JNK; CaMKII
Categories
Funding
- National Natural Science Foundation of China [81402875, 81441077, 81572866, 81576822, 81773104]
- Frontier Exploration Program of Huazhong University of Science and Technology [2015TS153]
- Natural Science Foundation Program of Hubei Province [2015CFA049]
- Research Fund of Public Welfare in Health Industry of the Health Ministry of China [201402015]
- Integrated Innovative Team for Major Human Diseases Program of Tongji Medical College, RUST
- Hubei Hundreds of Talents Program
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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/beta-Acatenin 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.
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