## 3 Molecular Mechanisms of Omega-3 Fatty Acids in Cancer
### Regulation of Cancer Metastasis through n-3 PUFA  
The spread and proliferation of cancer cells in distant organs from the site of the primary tumor, known as metastasis, represents the most lethal aspect of cancer, accounting for a majority of cancer-related deaths and complications. Metastasis poses a significant threat to organ function and disrupts metabolic processes [77]. Despite its profound impact, the intricate and multi-step nature of metastasis presents a formidable challenge, with no existing drugs or treatments demonstrating efficient curative potential [77; 78]. Consequently, there is an imperative need for the development of novel drugs and therapies targeting metastasis. Considering their inhibitor growth, anti-inflammatory and anti-angiogenic effects, n-3 PUFAs may have potential anti-metastatic effects as well. [PERSON] et al. exhibited anti-metastatic effects in a dose-dependent manner of DHA in association with engaged autophagy in a human esophageal cancer cell line. This was measured by the ability of the cells to migrate in order to heal a wound, finding that DHA-treated cells had a significantly larger wound width [79]. Similar findings were observed by [PERSON] et al., where DHA induced cell cycle arrest at the G1 phase and decreased motility and migration in human gastric cancer cell lines. These effects were assessed also using a scratch wound healing assay [55]. [PERSON] et al. conducted a comparative analysis of cancer progression in mice inoculated with a murine mammary adenocarcinoma cell line, distinguishing between groups fed n-3 PUFA and n-6 PUFA diets. Their findings revealed that the n-3 PUFA group exhibiteddecreased tumor volume and weight, improved survival rates and reduced metastasis in various organs including the lung, liver, spleen, heart, kidney, ovary and bone. Additionally, enhanced apoptosis and decreased angiogenesis were observed in this group [80]. Another important signaling pathway which is described to trigger metastasis and is involved in different types of cancer, including conjunctival malignant melanoma, is the epidermal growth factor and epidermal growth factor receptor (EGFR) pathway [81]. Some studies on other cancer types [82; 83] have found that DHA treatment might alter the EGFR localization in the lipid rafts, thus inhibiting its activation and having an anti-metastasis effect. Recent investigations have revealed that metastasis and tumor growth is often associated with the upregulation of microRNA (miRNA), small noncoding RNAs pivotal in regulating gene expression post-transcriptionally. Among the pioneering oncogenic miRNAs identified, microRNA-21 (miR-21) has garnered attention for its significant involvement in various cancers [84] such as breast cancer and melanoma metastasis [25; 85; 86]. Interestingly, n-3 PUFAs have shown to downregulate miR-21 expression in breast and colon cell cancer lines [87; 88]. Several mechanisms have been elucidated through which miR-21 can facilitate metastasis in cancer, including its promotion of mesothelial-to-mesenchymal transition [89; 90] and upregulation of pro-inflammatory mediators such as TNF-\(\alpha\)[88]. The mechanisms underlying how n-3 PUFAs downregulate the expression of miR-21 remain somewhat elusive. Nevertheless, [PERSON] et al. demonstrated that DHA induced nuclear accumulation of Forkhead box O3 (FOXO3) in a colon cancer cell line. FOXOO3 was found to bind to the promoter region of miR-21, resulting in its suppression [88]. Regulation of Melanoma Metastasis through n-3 PUFA  
The role of n-3 PUFA and melanoma metastasis has been studied. [PERSON] et al. showed significantly fewer lung colonizations of a highly metastatic murine melanoma cell line in association with enhanced apoptosis and reduced angiogenesis in an n-3 PUFA diet group when compared to the control group [91]. [PERSON] et al. demonstrated the anti-metastatic effects of DHA in a murine melanoma cell line.