DHA inhibits Gremlin-1-induced epithelial-to-mesenchymal transition via ERK suppression in human breast cancer cells

Abstract

Docosahexaenoic acid (DHA) is an omega-3 fatty acid abundant in fish oils. It is known to have an inhibitory effect on various diseases such as inflammation, diabetes, and cancer. Epithelial-to-mesenchymal transition (EMT) is a process that epithelial cells gain migratory property to become mesenchymal cells involved in wound healing, organ fibrosis, and cancer progression. Gremlin-1 (GREM1) is a bone morphogenetic protein antagonist known to play a role in EMT. However, the role of GREM1 in the induction of EMT in human breast cancer cells and the effect of DHA on GREM1-induced EMT remain unclear. Establishment of GREM1 knockdown cell lines was performed using lentiviral shRNAs. Expression of EMT markers was determined by qRT-PCR and Western blotting. Effect of GREM1 and/or DHA on cell migration was investigated using wound healing assay. The level of GREM1 expression in human breast cancer tissues was determined by Oncomine database mining. GREM1 induced the expression of genes including N-cadherin, vimentin, and Slug. GREM1 promoted the migration of human breast cancer cells. GREM1 enhanced the expression of phosphorylated extracellular signal-regulated kinase (p-ERK) and the ERK activation was involved in EMT. Interestingly, DHA reduced the expression of GREM1. DHA also inhibited the expression of mesenchymal cell-associated genes and cell migration induced by GREM1. Furthermore, DHA suppressed the expression of p-ERK induced by GREM1. These results indicate that GREM1-ERK axis plays a role in EMT in human breast cancer cells and DHA is a putative compound that can inhibit EMT by inhibiting GREM1 signal transduction.

Analysis of genomics and immune infiltration patterns of epithelial-mesenchymal transition related to metastatic breast cancer to bone

“…In this study, we used bioinformatics analysis methods to construct a full-genome expression profile of BC metastasis samples combined with an EMT-related gene weighted co-expression network and BC prognosis evaluation model to provide the basis and reference for calculating prognostic risk values for BC patients. Several studies have confirmed that genes, such as BMP-2, BMPR2, GREM1, CEMIP, HGF, ITGA5, ITGB1, MCAM , and TGFBR1 , are closely related to the EMT process in BC cells, which is also consistent with our research results [6 , 7 , [10] , [11] , [12] , [13] , [14] , [15] , [16] , [17] ].…”

“…With in-depth studies of BC, people gradually realized the importance of EMT in the occurrence and metastasis [6 , 7 , [10] , [11] , [12] ]. Tumor cells often need to lose their epithelial-like phenotypic characteristics, such as polarity and intercellular contact via EMT to invade normal tissues and metastasize [6 , 7 , [10] , [11] , [12] , [13] , [14] ]. The metastasis of BC epithelial cells, the development of breast ductal carcinomas in situ into invasive BC, the poor efficacy of BC treatment, and the resistance of patients to chemotherapy drugs are all closely related to the EMT process [6 , 7 , [10] , [11] , [12] , [13] , [14] ].…”

“…Tumor cells often need to lose their epithelial-like phenotypic characteristics, such as polarity and intercellular contact via EMT to invade normal tissues and metastasize [6 , 7 , [10] , [11] , [12] , [13] , [14] ]. The metastasis of BC epithelial cells, the development of breast ductal carcinomas in situ into invasive BC, the poor efficacy of BC treatment, and the resistance of patients to chemotherapy drugs are all closely related to the EMT process [6 , 7 , [10] , [11] , [12] , [13] , [14] ]. In this study, we used bioinformatics analysis methods to construct a full-genome expression profile of BC metastasis samples combined with an EMT-related gene weighted co-expression network and BC prognosis evaluation model to provide the basis and reference for calculating prognostic risk values for BC patients.…”

Do Olive and Fish Oils of the Mediterranean Diet Have a Role in Triple Negative Breast Cancer Prevention and Therapy? An Exploration of Evidence in Cells and Animal Models

“…Activating the EMT and progressing through the metastatic process is a key determinant of BC prognosis as the median survival rate for metastatic TNBC is ~10–13 mo ( 5 ). In addition to proliferation, DHA was shown to inhibit migration ( 44 , 49 , 51 , 52 ) and invasion ( 41 , 44 , 50 ) of TNBC in culture. Mouse experiments using the tail vein injection model in Fat-1 mice, which produce higher amounts of endogenous ω-3 essential fatty acids, also suggested a potential anti-metastatic effect ( 41 ).…”

“…Transforming growth factor (TGF)β is a cytokine that promotes EMT of epithelial cells ( 82 ). In two different TNBC cell lines, MDA-MB-435 and Hs578T, DHA (25 μM) suppressed transforming growth factor (TGF)β-mediated increases in the expression of the EMT mediators gremlin (GREM)1, N-cadherin, vimentin, and Slug ( 49 ). Stimulation of MDA-MB-435 cells with TGFβ had a pro-migratory effect in wound healing assays that was attenuated by either GREM1 silencing or treatment with DHA.…”