Gremlin-1 Promotes Colorectal Cancer Cell Metastasis by Activating ATF6 and Inhibiting ATF4 Pathways

Ruohan Li; Huaixiang Zhou; Mingzhe Li; Qiuyan Mai; Zhang Fu; Youheng Jiang; Changxue Li; Yunfei Gao; Yunping Fan; Kaiming Wu; Clive Da Costa; Xia Sheng; Yulong He; Ningning Li

doi:10.3390/cells11142136

Gremlin-1 Promotes Colorectal Cancer Cell Metastasis by Activating ATF6 and Inhibiting ATF4 Pathways

Cells. 2022 Jul 7;11(14):2136. doi: 10.3390/cells11142136.

Authors

Ruohan Li¹, Huaixiang Zhou¹, Mingzhe Li², Qiuyan Mai¹, Zhang Fu¹, Youheng Jiang^{1

3}, Changxue Li^{1

3}, Yunfei Gao^{1

4}, Yunping Fan⁴, Kaiming Wu^{2

3}, Clive Da Costa⁵, Xia Sheng⁶, Yulong He^{2

3}, Ningning Li^{1

7}

Affiliations

¹ Tomas Lindahl Nobel Laureate Laboratory, The Seventh Affiliated Hospital of Sun Yat-sen University (SYSU), No. 628, Zhenyuan Road, Guangming Dist., Shenzhen 518107, China.
² Center for Digestive Disease, The Seventh Affiliated Hospital of Sun Yat-sen University (SYSU), No. 628, Zhenyuan Road, Guangming Dist., Shenzhen 518107, China.
³ Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628 Zhenyuan Road, Shenzhen 518107, China.
⁴ Department of Otolaryngology, The Seventh Affiliated Hospital of Sun Yat-sen University, No. 628, Zhenyuan Road, Guangming Dist., Shenzhen 518107, China.
⁵ The Francis Crick Institute, 1 Midland Road, London NW1 1AT, UK.
⁶ Ministry of Education Key Lab of Environment and Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430074, China.
⁷ China-UK Institute for Frontier Science, Shenzhen 518107, China.

Abstract

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.

Keywords: ATF4; ATF6; Gremlin-1; colorectal cancer; epithelial–mesenchymal transition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Activating Transcription Factor 4* / genetics
Activating Transcription Factor 4* / metabolism
Activating Transcription Factor 6* / genetics
Activating Transcription Factor 6* / metabolism
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / metabolism
Colorectal Neoplasms* / pathology
Epithelial-Mesenchymal Transition / genetics
Humans
Intercellular Signaling Peptides and Proteins* / genetics
Intercellular Signaling Peptides and Proteins* / metabolism
Phosphatidylinositol 3-Kinases / metabolism
Signal Transduction

Substances

ATF4 protein, human
ATF6 protein, human
Activating Transcription Factor 6
GREM1 protein, human
Intercellular Signaling Peptides and Proteins
Activating Transcription Factor 4

Grants and funding

This research was funded by the National Natural Science Foundation of China (81874176 and 82072766, N.L.); Technology Planning Project of Guangdong Province, China (No. 2019B030316031); Shenzhen Science, Technology and Innovation Commission (SZSTI) Basic Research Program (JCYJ20190809154411427, N.L.); Shenzhen Sanming Project of Medicine (SZSM201911003, N.L.; SZSM202111005, Y.F.); the Hundred Talents Program of Sun Yat-sen University (392007, N.L.); Preclinical Development Program of the Seventh Affiliated Hospital of Sun Yat-sen University.