Knockdown GREM1 suppresses cell growth, angiogenesis, and epithelial-mesenchymal transition in colon cancer.

Gremlin 1 (GREM1), as a bone morphogenetic protein (BMP) antagonist and vascular endothelial growth factor receptor-2 (VEGFR2) novel agonist, has been confirmed as overexpressed in colorectal cancer (CRC) tissues but its role in carcinogenesis remains unclear. Here we reported that the GREM1 expression in mesenchymal-like colon cancer cells (SW620 and SW480) was significantly higher than that of epithelial-like colon cancer cells (Caco-2, HTC116, and HT29) and normal colon cell. Simultaneously, we analyzed two series of CRC transcriptomes from Gene Expression Omnibus (GEO) databases and found the great majority of primary CRC tissues expressed high level of GREM1 messenger RNA (mRNA) compared with adjacent normal tissues, and that the GREM1 mRNA expression is correlated with low histological grade development and stage 2 to 3 metastatic recurrence in CRC based on a data analysis of 104 different stage CRC tissue from the GEO databases. Functional studies showed that GREM1 silencing by short hairpin RNA (shRNA) significantly inhibited CRC cells proliferation, migration, the formation of vascular endothelial growth factor (VEGF)-induced capillary structure of human umbilical vein endothelial cells (HUVECs), and epithelial-mesenchymal transition in colon cancer cells by repressing phosphorylation levels of BMP downstream signal Smad1, vascular endothelial growth factor (VEGF) downstream signal matrix metallopeptidase 2 (MMP2), and metastasis-related factor C-X-C motif chemokine ligand 12 (CXCL12) expression. In addition, shGREM1 combined with VEGF inhibitor BAW2881 displayed more effective antiangiogenesis to inhibit the tube formation of HUVEC. Hence, these experiments demonstrated that GREM1 is involved in CRC development and procession and provide a new idea for CRC diagnosis, resistance therapy, and prognosis.