Effect of the inflammatory mediator TNF-alpha on colorectal cancer epithelial cells development and metastasis, role of ietary carcinogens and miRNA

Abstract

Colorectal cancer (CRC) is the third most common cancer world-wide and second leading cause of mortality. The majority of CRC cancer cases result from epigenetic and genetic alterations that promote development and metastasis of the disease. Exposure to environmental and dietary carcinogens are strongly associated with CRC. Also, inflammatory mediators are known as a major risk factor for CRC, however the underlying mechanisms are still understudied. Upregulation of pro-inflammatory mediators and dysregulation of miRNAs in the tumour microenvironment (TME) have been observed in CRC. Tumour necrosis factor alpha (TNF-α) is a pleiotropic cytokine thought to play numerous roles in tumour progression including epigenetic gene regulation, activation of tumour promoting signalling pathways, thus presence of TNF- in CRC tumour microenvironment may be key to promoting CRC progression. I hypothesise that the presence of TNF- α in the TME could regulate miRNAs and enzyme expression to induce DNA damage caused by dietary carcinogens, thereby stimulating changes that promote CRC development and metastasis. The present study investigated this hypothesis through a mechanistic approach with in vitro cell line culture. Effects of TNF-α on phenotypic changes were observed and the potential involvement of miRNAs were determined. The results showed that TNF-α enhances dietary carcinogen-induced DNA damage through activation of JNK signalling pathway. Also, TNF-α induced metastatic phenotype cell proliferation and migration through miRNA regulation. Moreover TNF-α regulated expression of CYP450 enzymes through miRNA regulation, which can promote chemical carcinogen genotoxicity. Taken together, the data indicated that CRC progression and metastasis may be related to epigenetic and inflammatory mediators active at the tumour site. Understanding these molecular mechanisms could provide better prevention and therapeutic strategies.