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.
Highlights
Breast cancer, one of the most frequent cancers in women worldwide, is known to have a high chance of cure if it is detected early
These results show that Docosahexaenoic acid (DHA) has an inhibitory effect on Epithelial-to-mesenchymal transition (EMT) in human breast cancer cells
Our results showed that GREM1 is a new inducer of EMT in human breast cancer cells
Summary
One of the most frequent cancers in women worldwide, is known to have a high chance of cure if it is detected early. Many patients experience chemotherapy resistance, tumor recurrence, and metastasis [1,2,3]. Chemotherapy and/or hormonal suppression for breast cancer patients can cause serious side effects [4]. HER2 protein is one of the most overexpressed receptors in breast cancer and is considered a biomarker involved in the treatment of HER2-positive breast cancer [7,8]. There is still a need for research and development of targeted therapies for triple negative cancers (lack of estrogen/ progesterone receptors and HER2) and other types of breast cancer patients [9,10]. The identification of molecular markers involved in the metastasis of breast cancer can be developed as an effective therapeutic target in breast cancer
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