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

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.

A proteogenomic analysis of the adiposity colorectal cancer relationship identifies GREM1 as a probable mediator

“…GREM1, a bone morphogenic protein (BMP) antagonist 33 , has previously been linked with CRC 16,17,34,35 , and is expressed in many tissues, including adipose and colon tissue. BMPs play an important role in embryonic development and morphogenesis and may be considered tumour repressors as inhibition of BMP signalling has been associated with a number of cancers 36,37 .…”

“…BMPs play an important role in embryonic development and morphogenesis and may be considered tumour repressors as inhibition of BMP signalling has been associated with a number of cancers 36,37 . GREM1 is associated with proliferation, angiogenesis, and epithelial-to-mesenchymal transition of cancer cells 36 and may be involved in colon cancer tumour progression 38 , with a number of studies linking GREM1 to CRC development 34,35,39 . In addition, a recent gene-environment interaction analysis identified a locus in the FMN1 / GREM1 gene region that interacted with BMI on the positive association with CRC risk 40 .…”

Inferring spatial transcriptomics markers from whole slide images to characterize metastasis-related spatial heterogeneity of colorectal tumors: A pilot study

“…For the Inception model, differentially spatially autocorrelated genes included: CALD1, 59 CCN2, 60 COL6A2, DPYSL3, FSTL1, 61 PCOLCE, 62 SERPINE1, 63 THBS1, 64 and WIPF1. 65 For the GAT model, these genes included: ACTA2, CDH11, 66 COL12A1, COL3A1, COL5A1, COL5A2, CTHRC1, 67 DCN, 68 FBLN1, GREM1, 69 ITGA5, 70 NNMT, 71 PCOLCE, POSTN, THBS1, THY1, TPM2, 72 and VCAN. 73 It is interesting to note that while the identified genes are tied to an E2M phenotype, only 2 of these genes ( PCOLCE and THBS1 ) were found in common between both methods.…”

PI3K/AKT signaling pathway as a critical regulator of epithelial-mesenchymal transition in colorectal tumor cells

“…There was GREM1 up regulation in advanced stage CRC patients that was correlated with an unfavorable prognosis. Additionally, GREM1 stimulated the PI3K/AKT/mTOR pathway as a target of the VEGF-VEGFR2 axis, which up regulated the ATF6 [ 41 ].…”