Acrolein Contributes to Human Colorectal Tumorigenesis Through Activation of RAS/MAPK Pathway

Abstract

Background. Colorectal cancer (CRC) is one of the most well-known malignancies with high prevalence and poor 5-year survival. Previous studies have demonstrated that intake of food rich in fat, and with low fiber content (as known as high-fat diet, HFD) is capable of increasing the odds of developing CRC. Acrolein, an IARC group 2A carcinogen, can be formed by thermal treatment of animal and vegetable fats, carbohydrates and amino acids through Maillard reaction. Also, acrolein has been shown to be produced from microbial glycerol metabolism in human gut. Consequently, humans are at risk of acrolein exposure through consumption of foods rich in fat. However, whether acrolein contributes to HFD-induced CRC tumorigenesis remains elusive.Methods. The effect of acrolein in oncogenic transformation was analyzed using NIH/3T3 cells with xenograft tumorigenesis mice models. Furthermore, cDNA microarray analysis with Ingenuity Pathway Analysis (IPA) was performed in acrolein-transformed NIH/3T3 cells. Finally, acrolein-induced DNA damages (Acr-dG) were analyzed in tumor tissues and normal epithelial of CRC patients using immunohistochemical analysis. The levels of Acr-dG adducts were associated with tumor characteristics and CRC patients’ survival using Chi-Square analysis and Kaplan Meier survival analysis, respectively.Results. In this present study, we found that acrolein induced oncogenic transformation including faster cell cycling, proliferation, soft agar formation, sphere formation, cell migration in NIH/3T3 cells. Using xenograft tumorigenicity assays, the acrolein-transformed NIH3T3 clone formed tumors whereas no tumors were observed in mice inoculated with NIH3T3 parental cells. In addition, RAS/MAPK pathway contributing to colon tumorigenesis was activated in NIH/3T3 Acr-clone using cDNA microarray analysis with IPA. Finally, Acr-dG adducts were higher in CRC tumor tissues compared to normal epithelial cells in CRC patients. Intriguingly, CRC patients with higher Acr-dG adducts have better prognosis. Conclusions. Taken together, this is the first study to demonstrate that acrolein is important in oncogenic transformation through activating RAS/MAPK signaling pathway contributing to colon tumorigenesis. Thus, acrolein might be a novel target for early detection, prevention and treatment of tumors in the future.