2. Academic Validation
  3. Intracellular AGR2 transduces PGE2 stimuli to promote epithelial-mesenchymal transition and metastasis of colorectal cancer

Intracellular AGR2 transduces PGE2 stimuli to promote epithelial-mesenchymal transition and metastasis of colorectal cancer

  • Cancer Lett. 2021 Oct 10:518:180-195. doi: 10.1016/j.canlet.2021.06.025.
Hongyan Zhang 1,  Jiangyang Chi 1,  Jia Hu 1,  Tiantian Ji 1,  Zhen Luo 1,  Caihong Zhou 1,  Lifeng Huang 1,  Zheng Dai 2,  Jing Li 1,  Guobin Wang 3,  Lin Wang 4,  Zheng Wang 5
Affiliations

Affiliations

  • 1 Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
  • 2 Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China.
  • 3 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China. Electronic address: [email protected].
  • 4 Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China; Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China. Electronic address: [email protected].
  • 5 Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China. Electronic address: [email protected].
PMID: 34216690 DOI: 10.1016/j.canlet.2021.06.025
Abstract

Human anterior gradient homolog 2 (AGR2) reportedly acts as an oncogene in multiple types of cancers. As a secreted protein, the oncogenic roles of extracellular AGR2 have been the focus of the increasing number of studies. In contrast, the oncological functions of intracellular AGR2 (iAGR2) remain elusive. Here, we report that intracellular AGR2 (iAGR2) is sufficient to promote CRC metastasis. iAGR2 binds to KDEL receptors (KDELRs) via its KTEL motif to activate downstream Gs-PKA signaling. Activated PKA upregulates the expression of NF-κB subunit c-Rel (REL) and acetylates histone H3 at lysine 9 (H3K9ac) to promote the transcription of SNAIL and SLUG. AGR2 can be upregulated by prostaglandin E2 (PGE2) via EP4-PI3K-AKT pathway and is indispensable for PGE2-induced CRC metastasis. AGR2 knockdown enhances therapeutic effects of a COX-2 Inhibitor, celecoxib, in CRC metastasis. Collectively, our study reveals a promoting role and molecular mechanisms of iAGR2 in CRC metastasis and uncovers a new tumor microenvironment signal regulating AGR2 expression, which may provide new targets for treating metastatic CRC.

Keywords

AGR2; Colorectal cancer; EMT; KDELR; Metastasis; PGE2.

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