Cory Ziegler

Colorectal cancer (CRC) is the third most common cause of cancer and the fourth most common cancer-related death worldwide. Risk factors for developing CRC include age, chronic disease history, physical activity, and diet. As mutations accumulate, normal colon and rectal mucosa can develop into adenomatous polyps and further develop into carcinoma, resulting in uncontrolled cell growth and clonal tumor development. Sporadic CRC accounts for approximately 70% of cases. Methods to reduce the occurrence of sporadic CRC are currently under investigation.¹ One such method is to decrease the risk of developing CRC by changing dietary habits. Multiple epidemiological studies have shown that individuals who adhere to a Mediterranean diet have a decreased risk for developing CRC.^2,3 Emerging evidence indicates that polyunsaturated fatty acids (PUFAs) may have a role in epigenetically modifying the regulation of the genes involved in cancer development.⁴ Specifically, the Mediterranean diet has a higher ratio of ω-3: ω-6 PUFAs compared to the standard Western diet. The benefit of this dietary change has been demonstrated using mice susceptible to adenomatous polyps, APC (min/+). Feeding these mice a diet with a higher ω-3: ω-6 PUFA ratio resulted in a decreased number and volume of adenomatous polyps.⁵ It is believed that this result is correlated with decreased expression of IL-6 and subsequent downregulation of the STAT3 pathway. The STAT3 pathway is a JAK/STAT pathway leading to the expression of multiple anti-apoptotic proteins.^6,7 APC (min/+) mice fed a high ω-3: ω-6 PUFA diet had decreased expression of activated p-STAT3, resulting in less expression of the STAT3 pathway. As expected, these mice with reduced expression of the STAT3 pathway have decreased concentrations of anti-apoptotic proteins, especially BCL-2.⁵ The STAT3 pathway can be activated by various growth factors and cytokines, such as IL-6. An analytical study combined population and in vitro studies to investigate the relationship between ω-3 PUFA and IL-6 expression. They found that higher concentrations of circulating ω-3 PUFA led to decreased methylation of the IL6 promoter cg01770232 and consequently decreased concentrations of circulating IL-6.⁴ At the moment it is still unclear how ω-3 PUFAs directly affect these epigenetic changes.⁸ These studies indicate that a possible anti-tumorigenic mechanism of the Mediterranean diet in the colon and rectum correlates with its high ω-3 PUFA: ω-6 PUFA ratio, leading to decreased IL-6 concentrations via epigenetic changes, and subsequent decreased expression of anti-apoptotic proteins through the STAT3 pathway.

1. Mármol al. Colorectal carcinoma: A general overview and future perspectives in colorectal cancer. Int J Mol Sci (2017) 18, 197.
2. Farinetti al. Mediterranean diet and colorectal cancer: A systematic review. Nutrition (2017) 43-44:83-88.
3. Donovan al. Mediterranean diet: Prevention of colorectal cancer. Front Nutr (2017) 4:59.
4. Ma al. The effects of omega-3 polyunsaturated fatty acids and genetic variants on methylation levels of the interleukin-6 gene promoter. Mol Nutr Food Res (2016) 60:410–419.
5. Barone al. Olive oil and omega-3 polyunsaturated fatty acids suppress intestinal polyp growth by modulating the apoptotic process in APC(Min/+) mice. Carcinogenesis (2014) 35, 7:1613–1619.
6. Huang al. Regulation of Metastases by Signal Transducer and Activator of Transcription 3 Signaling Pathway: Clinical Implications. Clin Cancer Res(2007) 13, 5:1362-6.
7. Corvinus al. Persistent STAT3 Activation in Colon Cancer Is Associated with Enhanced Cell Proliferation and Tumor Growth. Neoplasia (2005) 7, 6:545 – 555.
8. Burdge GC. Polyunsaturated Fatty Acid Metabolism. Elsevier (2018) 225-238.